There is a sentence I have heard too many times in medicine:

“The numbers look fine.”

It is usually said with kindness. A clinician looks at the chart, sees a BMI in the low 20s, a fasting glucose that is only slightly high, an LDL that is not dramatic, a ten-year risk score that prints out as low, and gives the patient what sounds like good news.

For a lot of South Asian patients, that sentence is where prevention goes to die.

Not because the doctor is careless. Not because the patient is unhealthy. Not because anyone is ignoring obvious disease.

Because the measuring system is miscalibrated.

A BMI of 23 does not mean the same thing in a South Asian body that it means in the European reference body most medical tools were built around. A “borderline” glucose in a young South Asian patient with family history may not be a mild footnote. A normal-looking LDL does not erase Lp(a), ApoB, visceral adiposity, or the fact that South Asians often develop cardiovascular disease earlier, leaner, and with fewer traditional warning signs.

This is the central problem Zinda was built around:

Normal by generic guidelines is often not normal for South Asians.

And now the question is becoming more urgent.

Because the next clinician to say “the numbers look fine” may not be a human at all.

It may be an AI.

The AI problem

Medical AI is arriving fast.

Doctors are already using tools that summarize evidence, generate differentials, interpret labs, and help with clinical decisions. Patients are using ChatGPT, Claude, Gemini, Perplexity, Open Evidence, and every other model they can get their hands on before clinic. This is not coming. It is here.

I am not a medical AI skeptic. I am probably more optimistic than most physicians I know. AI can read more papers than any human, notice patterns, and translate medical language into something patients understand.

But I do not think the final form of AI medicine is just a faster horse: quicker chart review, quicker note writing, quicker second opinions. I think it is more likely to be a car, a new modality that changes what it means to observe a patient, model risk, detect disease early, personalize therapy, and learn from every encounter.

But there is a quieter risk:

If the medical literature is calibrated around the wrong reference body, AI will scale that miscalibration with terrifying confidence.

This is what I have called the algorithmic black hole. A human doctor can miss a South Asian pattern one patient at a time. A clinical AI can miss it a million times per day, while sounding precise, neutral, and evidence-based.

So we decided to test it.

What we built

Over the last year, Zinda has quietly become a research engine: more than 1,500 South Asian case reports, case series, and landmark studies indexed from the medical literature, a growing South Asian Gene Atlas, verification passes where we tried to break our own claims, clinical pathways, and an internal benchmark for testing whether medical AI actually understands South Asian clinical risk.

The benchmark is called SA-CDS: South Asian Clinical Decision Support.

The first version contains 60 clinical vignettes built from published South Asian cases and studies. The cases span six broad patterns: thresholds, phenotype, pharmacogenomics, diagnostic misses, synthesis, and deeper South Asian clinical reasoning.

We then ran 15 AI platforms through the benchmark.

This included general-purpose LLMs, medical-specific tools, and a few models given access to a Zinda context layer. That context layer did not contain the test cases verbatim, but it did contain the South Asian thresholds, mechanisms, and evidence patterns a population-aware clinician should bring to the encounter.

I am intentionally not publishing the full internal layer here. That is part of what we are building.

But the results are worth sharing.

The complete internal pilot run table. Scores are directionally useful, but this is not yet publication-grade clinical validation.

The first finding. most models knew some medicine, but missed the calibration

The general-purpose AI models were not useless. They could identify obvious disease. They could name diabetes, heart disease, statin toxicity, autoimmune disease, kidney disease. They could write something that looked clinically reasonable.

But the benchmark was not asking, “Can this model pass a medical exam?”

It was asking:

Can this model tell when a South Asian patient is being falsely reassured by generic thresholds?

That is where the gap appeared.

The models often knew that “South Asians have higher risk.” But knowing a phrase is different from operationalizing it.

A model can say:

“South Asian ethnicity is a risk enhancer.”

and still fail to change the plan.

It can mention higher diabetes risk and still treat BMI 23.4 as basically normal. It can mention premature cardiovascular disease and still fail to ask for Lp(a) or ApoB.

This is the danger zone: the model sounds culturally aware, but the clinical decision has not changed.

The second finding. citations were the cliff

The most consistent failure was not diagnosis.

It was evidence.

And I want to spend some time here on why this matters.

Many models could produce a plausible answer about South Asian risk, but when asked to anchor that answer in literature, they fell apart. They cited generic guidelines. They gestured toward “studies.” They gave Western threshold logic in South Asian clothing.

This matters because citations are not decoration. They are the foundation everything else gets built on.

Clinical AI will not stop at answering questions. We are going to build care pathways, simulations, risk engines, population-health tools, and eventually some version of digital twins on top of these systems. If the evidence layer is weak, every layer above it compounds the weakness.

You cannot build a reliable simulation of South Asian cardiometabolic risk if the model cannot retrieve the right South Asian evidence. You cannot build a useful digital twin if the baseline map treats BMI, glucose, ApoB, Lp(a), liver fat, and family history as if they mean the same thing in every population. You cannot personalize care on top of a foundation that was never calibrated for the person in front of you.

The more ambitious the AI system becomes, the more the evidence layer matters.

The near-term harms still matter: a patient-facing app that reviews “borderline” labs and says no further testing is needed, a clinician copilot that quietly omits ApoB or Lp(a), a population-health tool that leaves lean, high-risk South Asians in the low-priority group.

This is why retrieval-based tools like OpenEvidence did better in some places. A system with access to better medical literature could find South Asian-specific references more reliably. But even then, the question becomes: what is in the library, what does it retrieve first, and what does it treat as authoritative?

If the corpus is Western-first, the answer will be Western-first.

Even when the patient is not.

The third finding: a knowledge layer changed the result

Here is the part that surprised me. When we gave the same base model a South Asian clinical context layer, performance improved.

That context layer was not a trick prompt or a list of answers. It was built from the same translational work underneath Zinda: published case reports and case series, cohort evidence, genetics and pharmacogenomics signals, South Asian threshold differences, repeated clinical phenotypes, and the failure modes we kept seeing across the case repository.

The goal was not to tell the model what to say. It was to give the model the kind of clinical map a population-aware physician should bring into the encounter.

The same model family performed differently when the clinical context became population-aware.

Paired runs make the core signal visible: the same model family can behave very differently once the clinical map becomes population-aware.

I would not overread the exact numbers yet. This is an early benchmark. But the direction is hard to ignore.

The same model, when given the right South Asian clinical context, stopped behaving like a generic medical assistant and started behaving more like a population-aware clinical reasoning tool.

The most interesting part was not simply that knowledge helped. It was that models absorbed the same knowledge differently.

Claude improved dramatically. Gemini improved meaningfully. GPT improved.

That matters.

In the next era of medicine, everyone will talk about “the model.” But the model, as we are seeing with harness and tooling, is only one layer. The context you give it, the evidence it can retrieve, the way it weighs population-specific information, and the clinical architecture around it may matter just as much.

One uncomfortable signal (and outside the scope of piece today): a purpose-built medical AI tool did not automatically outperform general-purpose models on South Asian-specific cases. That does not mean medical AI tools are bad. It means “medical” is not a magic word.

Medical-grade is not the same as population-grade.

All I will say is a tool can be clinically fluent and still not be calibrated for us. That is the difference between knowing medicine and knowing how medicine behaves in a specific body.

Why this gets more important as AI improves

The easy version of this argument is: the models are imperfect now, so we should test them. That is true, but it is not the whole point.

The deeper issue is that the models are going to get better. And more efficient. They will have longer context windows. They will read entire charts instead of snippets. They will connect to lab systems, wearables, genetic reports, imaging, medications, and prior notes. They will use retrieval pipelines, clinical tool calls, structured guidelines, and agentic workflows.

That sounds powerful. It is powerful.

And it is exactly why I am excited about medical AI.

The right system could notice South Asian risk earlier than the current system does. It could connect post-meal symptoms, family history, body composition, ApoB, Lp(a), liver fat, sleep, stress, migration, diet, and medication response in a way no rushed clinic visit can reliably do. It could help us move from episodic medicine to continuous pattern recognition.

But power amplifies calibration.

A short-context chatbot might miss a South Asian risk pattern in one answer. A long-context clinical agent could miss it after reading ten years of labs, family history, medications, diet notes, sleep data, and prior consults. A tool-connected system could then turn that miss into a normalized care pathway: no ApoB, no Lp(a), no earlier intervention, no change in follow-up interval.

This is why benchmark work matters now, before these systems become invisible infrastructure. The future will not just be “which model is smartest?”

It will be:

• what evidence does the model retrieve?

• what context does it carry into the case?

• what thresholds does it treat as meaningful?

• what clinical tools is it allowed to call?

• what pathway does it trigger after the answer?

• and who gets counted as the reference patient?

That is where the real safety question lives.

And underneath all of those:

Who gets counted as the reference patient?

That is where the real safety question lives.

What this does not prove yet

This is by no means a publication-grade study. Yes, it is a serious internal benchmark, but it is still a pilot.

Sensationalism has no place here.

The current version tells us that South Asian-specific context improved performance on South Asian-aligned cases. It does not yet prove, in the strict academic sense, that AI performs worse on South Asian cases than on matched non-South-Asian cases.

That is the next version: matched cases, blinded clinician scoring, multi-turn conversations, external cases, ablations, and HealthBench-style weighted criteria.

That is the difference between a signal and a paper. Right now, we have a signal. It is strong enough to share. It is not strong enough to declare victory.

The last-mile map

South Asian health does not suffer from zero research. It suffers from a last-mile translation failure.

The biology is universal. The integration is South Asian. And the integration is what medicine keeps missing.

The data exists across MASALA, INTERHEART, CARRS, UK Biobank, ICMR-INDIAB, genetics papers, case reports, and clinical anecdotes. It is just scattered, under-integrated, and rarely converted into physician-facing decisions.

As I wrote in my previous post on the evolution of cartography.

For centuries, maps contained errors because everyone copied the previous map. The Island of California. The Mountains of Kong. Medicine has maps like this too: BMI 25, LDL “near optimal,” HbA1c below the line, fasting glucose not high enough, ten-year risk score low.

These maps are useful. They are just not drawn at the resolution South Asian patients need.

AI trained on those maps will reproduce them. AI connected to better maps might finally help redraw them.

The clinical error is not that the evidence does not exist. It is that it fails to arrive in time, in the right form, inside the actual decision. A cardiometabolic insight lives in one cohort, a pharmacogenomic signal in a genetics paper, a diet pattern in a case report, and a repeated phenotype in a clinician’s memory. But the patient still arrives at the last mile and hears:

“The numbers look fine.”

This is also why LLMs are unusually well-suited to the problem.

For the first time, we have tools that can read across messy case reports, cohort studies, genetics papers, guidelines, and clinical anecdotes at scale. They can extract patterns, connect mechanisms, compare thresholds, and turn scattered evidence into physician-facing logic.

Finding and organizing more than 1,500 South Asian cases used to look like institution-scale labor: a team, a budget, and months to a year of work. With cheaper compute and modern LLMs, one person can now do much of that first-pass discovery in days.

That does not replace expert review, but it does change where and when that review happens. It changes the economics of translation. It compresses the distance between buried evidence and clinical decision support, and eventually automating, automated with intelligence, parts of it.

Zinda exists to turn fragmented South Asian health evidence into a clinical operating layer: something that can help physicians, patients, and eventually AI systems reason with the right map at the moment it matters.

We are building matched cases, designing physician review, and turning the benchmark from an internal signal into something that can survive peer review. The point is not to publish every mechanism.

This is why we are building Zinda Research, bringing togeterh both population level and individual level research to complete the last mile of the South asian framework.

The point is to prove the outcome:

South Asian patients should not be falsely reassured by tools calibrated to someone else.

Because one in four human beings should not be an edge case.

If you are a clinician, researcher, or AI evaluation person interested in helping validate this benchmark, reach out.

Email me at omar@zinda.health, or reply to this post.

The future of medical AI will become population-aware only if someone builds the missing ground truth.

-Omar

Dr. Omar Saleem is a double board-certified physician dedicated to health optimization, especially within the South Asian community. He runs Zinda, A South Asian Health Initiative, building the framework for South Asian precision medicine.

Disclaimer: This post is for informational purposes only and does not constitute medical advice. Always consult your physician before making changes to medications or supplements.

It also led me to build a deeper research layer for Zinda which we have been busy with for the past month. More on this later this week!

The Thrifty Engine left us with an unanswered question. If South Asian mitochondria are tightly coupled and our brown fat is sparse, surplus calories have no thermogenic exit. They can’t be burned off as heat, and at our typical activity levels they often can’t be burned off as ATP either. So where do they go?

The answer is the next layer of the framework: the Overflow Tank.

It’s where the surplus lands when the body’s safe storage shed, subcutaneous fat, has hit its ceiling and the dispersal routes are partly closed. The calories end up in the liver, the pancreas, the muscle, the heart, the kidneys, and the walls of the blood vessels. None of those organs are designed for that job.

This piece is the depot tour. It’s also, in my view, the framework’s most clinically important under-discussed concept; partly because the depots that matter most have the least research behind them. As full-body MRI, opportunistic CT, DEXA-derived body composition, and AI-assisted imaging become more common, medicine is going to start seeing what BMI has been hiding. South Asians may be the first population where that imaging shift rewrites the clinical story.

It’s a long piece so TL;DR

• South Asians don’t necessarily carry more fat than Europeans. We carry it in the wrong places, inside the liver, the pancreas, threaded through the muscle, wrapped around the heart, pressed into the kidneys

• Visceral fat and ectopic fat are not the same thing. Visceral fat is belly-cavity fat around organs. Ectopic fat is fat inside or directly on organs that are not supposed to store it; liver, pancreas, muscle, heart, kidney, blood vessels. Visceral fat is the warning light; ectopic fat is often where the organ damage happens

• The mechanism is “forced spillover”: our mitochondria are tightly tuned for efficiency and our brown fat is reduced, so we have no thermogenic route to dump surplus calories. At the same time, our subcutaneous fat hits its storage ceiling at lower BMI than Europeans. Surplus has nowhere to go but somewhere it doesn’t belong

• The medical literature obsesses over hepatic fat (NAFLD), 26 of 31 ethnic-comparison studies focus on liver fat, and largely ignores pancreatic, epicardial, intramuscular, renal sinus, and perivascular fat. The under-studied depots may matter most

• The pancreatic fat story is the one I’d most want patients and physicians paying attention to. Fat infiltrating the pancreas directly poisons beta cells. This is plausibly why so many lean South Asians develop diabetes at young ages despite “normal” weight

• The intervention story is not “lose weight.” It is expand safe storage capacity, shrink the surplus at source, and reopen the dispersal route. That changes how we think about exercise, food timing, and which medications are right for which patients

Picturing the Spillover

Imagine your body as a household with one shed in the backyard for storing surplus supplies. The shed is your subcutaneous fat, the soft fat under your skin. It is, when working properly, the safest place to keep extra calories. It’s quiet. It doesn’t bother anyone, it has valuable function in storing heat and energy. It releases supplies slowly when needed.

For most Europeans, the shed is large. It expands when more supplies arrive. New shelves get built. New rooms get added. The household stores its surplus calmly, even at higher caloric loads.

For most South Asians, the shed is smaller. And, this is the key, when the shed gets full, we don’t easily build new rooms. Our adipocytes (fat cells) tend to enlarge rather than multiply as we previously discussed. That works for a while. But there’s a ceiling.

When the shed fills up and can’t expand, the surplus has to go somewhere. So we start storing supplies in the kitchen. Then In the laundry room. Then the bedroom. Inside the engine (or frunk) of the car. Eventually, even the safe where the family heirlooms are kept.

That’s the Overflow Tank.

as you read through this, keep coming back to this.

In medical terms, the shed is your subcutaneous fat. The kitchen is your liver. The laundry room is your skeletal muscle. The bedroom is your pancreas. The car engine is your heart. The safe is your kidneys.

Each of these places can hold a little fat. None of them are designed to hold significant amounts. When they do, they break.

Why does this happen?

South Asian fat doesn’t end up in the wrong places by accident. It ends up there because the body has nowhere else to put it.

The Thrifty Engine substrate is real and quantified: about 34% less brown adipose tissue than Europeans, resting metabolic rate lower at the same body composition, and VO2max running about 22% lower than matched Europeans. Survival advantage in a world of food scarcity and physical movement. A trap in a world of caloric surplus and sedentary work.

Caloric surplus has three potential exits from the body. Burn it as ATP during exercise. Burn it as heat through brown fat or skin radiation. Store it safely in expandable subcutaneous fat.

For South Asians, all three doors are partly shut at once. Burning calories as ATP requires oxidative capacity we largely don’t have, compounded by sedentary diaspora work. Burning calories as heat requires brown fat we mostly don’t carry. Storing them safely requires subcutaneous capacity that hits its ceiling at lower BMI than Europeans.

So the surplus has to go somewhere. It goes everywhere it shouldn’t.

This is why “just eat less and move more” isn’t a complete answer for most South Asians. The mismatch is upstream of behavior. The biology is set up to push surplus into ectopic depots faster than other populations. Behavior matters, but so does understanding what we’re up against.

A Tour of the Wrong Places

Some of these you’ve heard of. Most you probably haven’t.

The Liver

Where Most of the Research Lives

Hepatic fat, what doctors call non-alcoholic fatty liver disease (NAFLD), now renamed MASLD, is the depot the field has studied the most, gaining further awareness post-GLP-1. About 30–40% of South Asians have fatty liver, and many at completely normal BMI. The definitive meta-analysis (Iliodromiti 2022) of over 7,000 patients found South Asian men have substantially more liver fat than matched White Europeans, the effect size is large and consistent.

Hepatic fat is bad in two ways.

It directly causes liver disease: fibrosis, cirrhosis, eventually liver cancer.

And it makes your liver insulin-resistant, which is what causes your fasting glucose to rise and your triglycerides to spike. The liver becomes a glucose factory that never closes.

The mechanism is more than “fat sitting in the liver.” When fatty-acid delivery and de novo lipogenesis exceed the liver’s ability to oxidize or export fat as VLDL, lipid intermediates build up inside hepatocytes. The best-studied culprit is diacylglycerol, which activates PKCε and blunts insulin signaling at the insulin receptor (Perry/Shulman 2014, PMID 24899308).

That’s why liver fat shows up clinically as the South Asian pattern we know too well: normal-ish BMI, high triglycerides, high ApoB, fasting glucose creeping upward, and ALT that may still sit inside the “normal” range.

A meaningful chunk of the SA hepatic-fat story is genetic. The PNPLA3 gene variant (rs738409-G) is present in about 30% of South Asians and dramatically amplifies hepatic fat at any insult. Fructose and refined carbs hit especially hard here because they feed hepatic de novo lipogenesis; ultra-processed oils may matter too, but the strongest evidence is still around substrate overload, insulin resistance, and genetic susceptibility.

The good news: hepatic fat is reversible. Even modest weight loss (5–10% of body weight) clears a substantial fraction. SGLT2 inhibitors, GLP-1 agonists, and the new MASH drug resmetirom all reduce hepatic fat. This is the depot we’re best at treating.

Visceral Fat

The Belly That Wasn’t There

Visceral fat is the commonly recognized, deep fat around your organs. It’s the fat your waist measurement is trying to estimate. South Asians accumulate it earlier, at lower BMI than Europeans, which is why our waist cutoffs are lower (≥90 cm men, ≥80 cm women instead of the 102/88 used for Europeans).

This is the fat that produces inflammatory cytokines (IL-6, TNF-α, MCP-1) that drive systemic inflammation and insulin resistance. But the key anatomical point is drainage.

Visceral fat is more than deeper subcutaneous fat. Much of it drains toward the portal circulation, meaning free fatty acids and inflammatory signals get delivered straight to the liver before the rest of the body ever sees them. That’s the classic “portal theory” of visceral adiposity: the belly depot talks directly to the organ that regulates fasting glucose, triglyceride production, and ApoB particle export.

So visceral fat is dangerous partly because of what it secretes, and partly because of where its plumbing goes. It is the fat that explains why a South Asian with a 35-inch waist can have the metabolic profile of a European with a 42-inch waist.

One honest perspective we have to keep in the framework: at the same BMI, South Asian visceral fat may not be dramatically higher than European visceral fat. Filipino women actually may even exceed us. Rather, the South Asian story is about threshold, we cross harmful waist cutoffs at lower BMI, more than absolute amount. Either way, the clinical message is the same: measure waist, not BMI. Waist-to-height ratio above 0.5 means trouble regardless of what the scale says.

Intramuscular Fat

The Quiet Killer

Now we move into the territory most people haven’t heard of.

Imagine cutting open a healthy steak. The lean part is muscle fiber. The white streaks running through it are intramuscular fat. In meat, marbling is desirable. In your body, it’s a metabolic disaster.

A 2025 UK Biobank MRI study (Tejani et al., PMID 41473010) compared 397 South Asians to matched White Europeans. At the same body weight, South Asians had higher intramuscular fat infiltration and lower muscle volume. About 20% of South Asians had what the study called “adverse muscle composition”, versus just 8% of Europeans.

This is critical because skeletal muscle is the body’s largest glucose sink. When you eat a meal, the bulk of that glucose is supposed to go into muscle. But fat-infiltrated muscle is insulin resistant. Glucose can’t get in. So glucose stays in the blood, insulin spikes, the pancreas works overtime, and the cycle keeps reinforcing itself.

The mitochondrial piece makes this even more interesting. South Asian muscle isn’t simply “weak” or low-energy. In the Nair study of Asian Indians, skeletal muscle showed higher mitochondrial DNA copy number, higher oxidative phosphorylation gene expression, higher citrate synthase activity, and higher ATP production capacity than matched Northern European Americans, despite worse insulin resistance (PMID 18285554).

At the whole-body level, though, South Asians have lower VO2max and lower fat oxidation during exercise (PMID 21152018). That is the flooded-engine problem: the oxidative machinery is not simply absent. In that study, South Asian muscle did not show lower expression of oxidative or lipid-metabolism genes. The problem appears to be flux (echoing our previous mentions of bioenergetics). The system has less capacity to move fatty acids cleanly through oxidation during real-world exercise, and that impaired fat utilization tracks with worse insulin signaling. So fuel begins to accumulate around the machinery that should be clearing it. The muscle becomes metabolically “lipidized,” not because the engine is missing, but because the fuel traffic is jammed.

Combine this with the South Asian “blunted hypertrophy response” to resistance training, South Asian men gain less muscle and improve metabolic markers less after the same workout (Iyengar 2022), and you have a thin-but-fatty-muscle phenotype that is invisible on BMI and devastating to glucose control.

The clinical translation: when a thin South Asian patient says “I work out and I still have high blood sugar,” the muscle is the place to look. DEXA scans give you appendicular lean mass. MRI is better. Grip strength is the cheap proxy that’s genuinely useful.

For those interested in learning more about intramuscular fat, Sean O’Mara, who has been speaking about this for a few years, provides excellent insights.

Pancreatic Fat

The Most Important Depot You’ve Never Heard Of

Your pancreas has two jobs. The exocrine part makes digestive enzymes. The endocrine part, about 1 - 2% of pancreatic tissue, makes insulin. Those endocrine cells, the beta cells, are what fail in Type 2 diabetes.

Now imagine fat infiltrating the pancreas. Not just sitting nearby, threading into the pancreatic parenchyma, around the islets of Langerhans, in the neighborhood where beta cells are trying to sense glucose and release insulin.

That local neighborhood matters. Pancreatic fat releases free fatty acids and inflammatory cytokines exactly where beta cells live. Saturated fatty acids can trigger ceramide accumulation, ER stress, mitochondrial dysfunction, and inflammasome activation inside beta cells.

In human islet experiments, Gerst and colleagues showed something even more interesting: fatty liver may talk to fatty pancreas. The hepatokine fetuin-A, especially in the presence of palmitate, worsened local pancreatic inflammation and impaired glucose-induced insulin secretion, what the authors called beta-cell “glucose blindness” (Gerst 2017, PMID 28791439).

The beta cell isn’t simply “tired.” It’s sitting in a hostile microenvironment, sensing glucose less clearly, secreting insulin less reliably, and losing the first-phase response that normally catches a meal before glucose climbs.

For South Asians, this is where the story gets dangerous. If beta cells are already fewer or more vulnerable, the “Fragile Engine” we’ve covered before, then pancreatic fat may not need to be massive to matter. A small ectopic spillover, in the wrong organ, at the wrong time, may close the recovery window earlier.

Here’s the staggering thing about the literature: the definitive 2025 scoping review of ethnic differences in adipose tissue dysfunction found 31 studies on ectopic fat in South Asians. Twenty-six focused on liver fat. Only three examined pancreatic fat.

Three studies. For a population where lean diabetes is the defining clinical mystery.

There is a single intervention paper from Misra and Dutta in 2025 measuring pancreatic fat fraction in Asian Indian patients with diabetes. Metformin lowered fetuin-A and liver stiffness markers but did not significantly lower MRI-measured hepatic or pancreatic fat fraction; their prior dapagliflozin work did report reductions in hepatic and pancreatic fat. Either way, the point is not that we have the therapy settled. The point is that we barely have the measurement literature.

Outside South Asian cohorts, the strongest mechanistic clue comes from the Newcastle/Taylor diabetes-remission work. In the original 2011 Diabetologia study, 8 weeks of severe energy restriction normalized fasting glucose, improved hepatic insulin sensitivity within a week, dropped liver fat dramatically, and reduced pancreatic triglyceride while beta-cell function recovered (Lim/Taylor 2011, PMID 21656330). The later DiRECT mechanistic analysis found that remission required liver and pancreas fat reduction, but depended on whether beta cells still had capacity to recover (Taylor 2018, PMID 30078554). That last clause matters for South Asians: if the Fragile Engine starts with fewer or more vulnerable beta cells, pancreatic fat may close the recovery window earlier.

The pancreas is being silently injured by ectopic deposition that no routine clinical screening tool detects. MRI-PDFF can measure it, and modern reviews argue fatty pancreas disease is often labile, potentially reversible, but most patients will never be offered that scan.

This is the depot where the Overflow Tank story most directly meets the Fragile Engine story. It should have been studied to exhaustion in South Asians. It hasn’t been. That gap bothers me more than any other in this piece.

Epicardial Fat

Around the Heart

Wrap your heart in a fat blanket. That’s epicardial adipose tissue (EAT) — the fat layer that sits directly on the surface of your coronary arteries. Pericardial fat sits one layer outside that. Both communicate paracrinely with the vessel wall.

The old way of thinking about EAT was simple: extra padding. A passive energy reservoir. The newer literature is much more interesting. Healthy EAT behaves partly like brown or beige fat, metabolically active, rich in fatty-acid oxidation, thermogenic, and locally protective for the myocardium. But under chronic metabolic stress, it can “whiten”: the adipocytes enlarge, mitochondrial beta-oxidation and UCP-1-like thermogenic behavior fall, and the tissue starts secreting TNF-α, IL-6, and profibrotic signals instead (Li 2023).

That matters because EAT has no clean wall separating it from the heart. It sits between the myocardium and visceral pericardium and shares microcirculation with the underlying cardiac muscle (Wu 2017). When EAT becomes inflamed, its secretome can diffuse directly into the coronary vasculature and myocardium.

That’s vasocrine toxicity at the vessel wall, not belly fat that happens to sit near the heart.

Adams 2016 found South Asians had higher epicardial fat volume than Caucasians (103 vs 86 cm³). But the more interesting finding came from MASALA: South Asians had the lowest pericardial fat of five ethnic groups, yet the strongest association with coronary calcium. The same gram of pericardial fat may be more dangerous in South Asians than in any other group studied.

Separate echocardiographic work found EAT thickness above 5 mm associated with left atrial enlargement, higher left ventricular mass, and abnormal diastolic function even when BMI was similar (Goel/Mookadam 2010).

This depot likely contributes to atrial fibrillation, coronary microvascular dysfunction, HFpEF-like diastolic stiffness, vulnerable plaque, and the premature coronary disease that impacts South Asian 10 - 15 years earlier than their European peers. It is the convergence point with the Lp(a) story we covered earlier, the genetic risk that 1 in 4 South Asians carries from birth meets ectopic fat at the vessel wall, and the result is the lipid-rich, low-attenuation, vulnerable plaque that calcium scores miss.

Renal Sinus Fat

The Kidney’s Hidden Burden

Your kidneys sit in a fatty cushion called the renal sinus. This is not ordinary padding. The renal sinus is the kidney’s hilum, the crowded doorway where the renal artery, vein, lymphatics, nerves, and collecting system pass through. When fat expands in that small space, it can mechanically compress low-pressure venous and lymphatic channels, raise intrarenal pressure, impair sodium handling, and activate the RAAS/sympathetic systems that drive hypertension.

That’s why renal sinus fat is a kidney story, not an obesity story. In the Framingham Heart Study, “fatty kidney” was associated with hypertension and chronic kidney disease even after adjusting for BMI or visceral fat (Foster 2011, PMID 21931075). Chughtai’s MRI study found renal sinus fat associated with stage II hypertension and the number of antihypertensive medications a patient required, independent of intraperitoneal fat (PMID 20837881).

Mechanistically, this is the organ version of a crowded plumbing cabinet. The pipes aren’t only inflamed, they’re physically squeezed.

There is exactly one study comparing renal sinus fat between South Asians and White Europeans (Lin 2024, n=93). One. The provocative finding was that under glucose regulation, South Asian patients lost renal sinus fat while Europeans gained it. We have no idea if that replicates.

Renal sinus fat is probably part of the answer to why South Asians develop kidney disease at lower BMI and at lower diabetes severity than other groups. It is the bridge between the Overflow Tank and what the Zinda framework calls the Undersized Filter.

Perivascular Fat

The Empty File Cabinet

Perivascular adipose tissue (PVAT) is fat surrounding your blood vessels. Healthy PVAT is actually protective, it releases adiponectin, nitric oxide, hydrogen sulfide, and other relaxing signals that help the vessel dilate and stay quiet.

Diseased PVAT flips the signal. It loses its anti-contractile effect, secretes IL-6, TNF-α, MCP-1, resistin, and PAI-1, recruits macrophages, lowers endothelial nitric oxide, and pushes inflammation from the outside of the artery inward. This is why PVAT may be the fat depot closest to the actual plaque rupture event.

In non-South-Asian cohorts, cardiac CT can now detect this biology. Inflamed coronary arteries change the adjacent perivascular fat so it becomes more water-rich and less lipid-rich; that shift appears as higher pericoronary fat attenuation on CT. In CRISP-CT, a high fat attenuation index predicted cardiac mortality above standard coronary CT risk features (PMID 30170852). This is the imaging future of the Overflow Tank: not just “how much fat is there,” but “is the fat around this artery inflamed right now?”

In South Asian populations, there is no published data. None. A population with documented vascular vulnerability, earlier endothelial dysfunction, higher Lp(a) prevalence, premature heart disease, has zero studies on the fat depot most directly involved in vascular inflammation. This is one of the largest single gap in South Asian adipose research.

The Subcutaneous Paradox

Here’s something that should change how we talk to patients.

In MASALA, the largest study of South Asian Americans, visceral fat was strongly associated with cardiovascular disease risk. Pericardial fat was strongly associated. Hepatic fat was strongly associated.

But…Subcutaneous fat was inversely associated. (Mongraw-Chaffin 2017)

South Asians with more healthy subcutaneous fat had less cardiovascular risk.

The fat under your skin, when it’s working, is protective. It’s the metabolic buffer that absorbs surplus calories before they spill ectopically. Patients with healthy expandable subcutaneous depots are protected. Patients whose subcutaneous capacity has hit its ceiling, or is constitutively low, cannot buffer, and the spillover begins.

Thus the clinical goal is not “less fat.” The goal is the right fat in the right place, expanding healthy storage capacity may be as important as reducing total adiposity.

It also explains why some South Asians who lose weight aggressively without resistance training end up more metabolically broken than they started. They’ve shrunk their healthy buffer (subcutaneous) faster than they’ve reduced their toxic depots (visceral, hepatic, pancreatic). They ended up with the same total body fat, redistributed unfavorably.

How Do We Actually See the Overflow Tank?

If BMI is the wrong map, how do we know where the fat actually went?

The honest answer is that we can see pieces of the Overflow Tank today, but not yet in one clean, routine clinical picture. Some tools are cheap and imperfect, others, such as full body MRIs, are precise but expensive, and a few are already hidden inside scans patients get for other reasons, waiting for AI to extract the signal.

Think of assessment in layers.

The first layer is the cheap signal layer. This is where most patients should start: waist circumference, waist-to-height ratio, blood pressure, triglycerides, ApoB, HDL, ALT and GGT, fasting glucose, fasting insulin, HbA1c, grip strength, family history. None of these directly measure pancreatic or muscle fat. They tell you whether the storage system is starting to fail.

A South Asian patient with BMI 23, waist-to-height ratio above 0.5, triglycerides creeping up, ApoB elevated, ALT in the high-normal range, and a father with diabetes isn’t “normal weight and fine.” That patient is already showing smoke from an internal storage fire. These markers don’t diagnose anything by themselves, they raise suspicion, which is what we need.

The second layer is practical imaging. This is where medicine is already useful, if we ask the right questions.

DEXA estimates visceral fat and measures lean mass, especially appendicular lean mass. It won’t tell you pancreatic fat, but it shows the thin-fat pattern clearly: normal weight, low muscle, high trunk fat.

FibroScan with CAP estimates liver fat and liver stiffness; current MASLD pathways increasingly use non-invasive tests like FIB-4, VCTE/FibroScan, ELF, and MR-based tools to risk-stratify patients (EASL-EASD-EASO 2024). Standard liver ultrasound can catch obvious fatty liver but misses milder disease and tells you nothing about pancreas, muscle, or heart.

For many South Asian patients, this layer is enough to change the conversation. If the DEXA shows low muscle and high visceral fat, or the FibroScan shows fatty liver at a “normal” BMI, the BMI argument is over. The body has already told you where the surplus is going.

The third layer is precision imaging. This is where MRI-PDFF matters. PDFF stands for proton density fat fraction, a way of quantifying the percentage of fat inside an organ. It’s best established for liver fat, but with the right protocol and reader it can also quantify pancreatic fat; reviews now describe PDFF applications well beyond the liver, including pancreas, muscle, marrow, and visceral/subcutaneous adipose tissue (PMID 35142615).

This is the scan I wish we had more often in high-risk South Asian patients: liver fat, pancreatic fat, visceral fat, muscle composition, and sometimes renal sinus fat in one biologically coherent map.

CT is also useful, especially when it has already been done for another reason. Abdominal CT can estimate visceral and subcutaneous fat, and AI-based body-composition tools are moving this toward clinical implementation (Muller 2024).

Cardiac CT can quantify epicardial or pericardial fat.

Coronary CTA may eventually tell us whether the fat around an artery is inflamed, not only whether plaque exists.

That’s the future version of this framework: the Overflow Tank measured by biological activity, not by volume alone.

The fourth layer is still emerging. Full-body MRI, opportunistic CT body composition, AI-assisted segmentation, perivascular fat attenuation, renal sinus fat quantification, and multi-depot risk maps are not yet routine medicine. But they are coming as more diagnostic companies such as Function health offer them for collapsing costs.

note on full body MRIs: many of the full body MRI scans can be reassessed for ectopic fat. If you have had full body MRIs done, it may be worth keeping the DICOM images and sending them to either another radiology center or even plugging them into an LLM to help assess them (not a medical recommendation).

And when they arrive, South Asians may be one of the populations where they matter most, because the standard external markers have failed us for so long.

The practical takeaway is simple. You don’t need to chase every scan, you need to stop letting BMI be the final answer.

If you’re low-risk, start with waist, labs, blood pressure, and strength. If there are high-prior flags, add DEXA and liver assessment. If there’s lean diabetes, strong family history, premature heart disease, fatty liver at low BMI, or unexplained metabolic dysfunction, the question becomes whether advanced imaging is worth pursuing: MRI-PDFF for liver and pancreas, CT-derived body composition if a CT already exists, or cardiac imaging when the cardiovascular story justifies it.

The Overflow Tank isn’t always visible from the outside, but it leaves clues. Our job is to stop ignoring them.

What to Actually Do

If the framework is “the surplus has nowhere to go and lands in the wrong depots,” the levers fall into three categories.

Shrink the surplus at the source. Optimize diet. Reduce refined carbohydrates, fructose, and ultra-processed foods; be cautious with high-energy refined fats in a low-oxidative-capacity phenotype.

Eat protein.

Eat in a compressed window (8–10 hours) if it helps you reduce late-night substrate load. None of this is glamorous.

All of it points in the same direction: less hepatic de novo lipogenesis, lower overnight insulin exposure, and less surplus fuel available to spill into ectopic depots. Direct pancreatic-fat imaging data for time-restricted eating in South Asians does not exist yet, so don’t oversell it.

Expand the safe storage compartment. This is what most South Asian patients don’t hear from their doctors. Resistance training is the single most important intervention. not for aesthetic reasons, but because building skeletal muscle expands the body’s largest glucose sink and partially reverses the lipodystrophy-spectrum signature in adipose tissue. Train hard, train consistently, eat enough protein (1.2–1.6 g per kg of body weight).

For patients who cannot mount an adequate response, pioglitazone, an old, cheap medication that expands subcutaneous storage capacity, may be uniquely well-suited to South Asian biology and worth discussing with your doctor, though it deserves more direct trials in our population.

Reopen the dispersal route. This is the repeated story. Zone 2 cardio rebuilds oxidative capacity over months. HIIT improves mitochondrial biogenesis. Cold exposure and the β3-agonist mirabegron recruit brown adipose tissue (Boon’s 2020 South Asian RCT showed both the deficit and a partial response).

Medication-wise GLP-1 agonists are extremely potent here, and possibly SGLT2 inhibitors, semaglutide, tirzepatide, dapagliflozin, empagliflozin, preferentially reduce visceral, hepatic, and pancreatic fat.

These tools work especially well in South Asian patients when paired with resistance training to prevent the muscle loss that otherwise comes with rapid weight loss on these drugs.

If you’re a patient and you remember nothing else, remember this: lift heavy things, eat enough protein, eat in a window, and ask your doctor about your pancreatic and hepatic fat, not just your weight. GLP-1 agonists and possibly SGLT2 inhibitors. If you can get a single MRI-PDFF scan in your life that quantifies hepatic and pancreatic fat, that scan will tell you more about your metabolic future than ten years of BMI charts.

If you’re a clinician, the practical translation is: in any South Asian with two or more high-prior flags (BMI ≥23 plus family history; lean diabetes in a parent; premature cardiovascular event in a sibling; vegetarian with substrate gaps), stop using BMI as a stop sign. Order waist circumference, ApoB, fasting insulin, HMW adiponectin if you can get it, GGT, triglycerides. Consider FibroScan or MRI-PDFF where available. Look at the muscle. The Overflow Tank starts running long before the lab values cross conventional thresholds.

A Reality Check on Ectopic Fat Research

I want to be honest about how thin the evidence base is for the depots that may matter most.

We have thousands of papers on South Asian diabetes prevalence. We have a respectable number on hepatic fat. We have growing literature on visceral fat. We have a single recent landmark study on intramuscular fat.

For pancreatic fat, in a population where lean diabetes is the defining clinical mystery, we have three ethnic-comparison studies and one intervention paper.

For renal sinus fat, we have one comparison study with 93 patients.

For perivascular fat, we have nothing.

This isn’t a niche complaint. The South Asian diabetes and cardiovascular epidemic affects nearly two billion people, about 1 in 4 humans alive today. The mechanism most likely to explain why our beta cells fail at lower BMI than any other major population is sitting in three studies. The fat depot most directly involved in vascular inflammation, which probably matters most for why our coronary vessels fail early, has zero South Asian studies at all.

The Zinda research mission is, in part, to push these gaps. To advocate for SA-specific multi-depot imaging studies. To push for pancreatic-fat measurement in any large SA cardiometabolic cohort. To document the cases, the lean South Asian thirty-somethings who develop diabetes that the standard frameworks can’t predict, until the pattern becomes impossible to ignore.

Until that work exists, the framework you’ve just read is the best honest answer I can give to the question “where does South Asian fat go, and why does it cause so much trouble?”

It goes where the substrate we’ve discussed over the course of this blog forces it to go, and where the limited subcutaneous capacity allows it to land. The depots that get the least attention may turn out to matter most.

That’s the Overflow Tank.

-Omar

Dr. Omar Saleem is a double board-certified physician dedicated to health optimization, especially within the South Asian community. He runs Zinda, A South Asian Health Initiative, building the framework for South Asian precision medicine.

Disclaimer: This post is for informational purposes only and does not constitute medical advice. Always consult your physician before making changes to medications or supplements.

A post by made the rounds last week making a sharp point: if mechanistic reasoning alone were enough to understand medicine, drugs wouldn’t fail in >90% of clinical trials. The mountain of preclinical evidence is never sufficient. You need clinical data.

That resonated…as it’s a balance that we at Zinda have been trying to grapple and contend with as we build a new mechanistic framework for the South Asian phenotype, but evidencing it through data can be a barrier.

Our thesis from the beginning was that the reason much of the current framework, its measures and treatments don’t fit the puzzle and the reason many diets don’t work is due to a lack of mechanistic understanding rather than sufficient mechanistic understanding.

A few months ago, we wrote the most in-depth piece this Substack has published: a deep dive into adiponectin, the most abundant hormone most doctors never measure. We called it the Adiponectin Deficit, the missing metabolic brake. We described how South Asians carry 25 - 40% less of this protective signal from birth, how prior research has found it depleted in cord blood before a baby’s first feeding, and how it leaves our fat cells unable to send the one message that tells the rest of the body to stay metabolically calm.

At the time, we had mechanistic evidence. We had population-level comparisons. What we didn’t have was a large study mapping adipokine profiles directly to clinical outcomes, diabetes, dyslipidemia, hypertension, within a South Asian American cohort.

Now we do.

Grab some chai.

The Study

Title: Adipokines and Cardiometabolic Risk in South Asian Americans: Findings from the MASALA Study
Authors: Uttarwar, S., Shah, N.S., Kanaya, A.M., Gadgil, M.D.
Journal: American Journal of Preventive Cardiology, 2026

Researchers at UCSF and Northwestern analyzed 891 South Asian American adults from the MASALA cohort, the study we come back to again and again on this Substack, measuring three adipokines (adiponectin, leptin, resistin) and two composite indices, then testing how each one tracked with prevalent hypertension, dyslipidemia, and diabetes. They adjusted for many major measured confounders: age, gender, education, income, BMI, visceral fat area, diet quality, physical activity, smoking, alcohol, and inflammatory markers (TNF-α and CRP).

This is not a study comparing South Asians to Europeans. This is a study asking: within our own population, among nearly 900 of us, what do these fat-cell signals actually predict?

The cohort tells a familiar story before the adipokines even enter the picture. Mean BMI: 26., not in the obese range. Yet 73.5% had dyslipidemia. 40.3% had hypertension. 25.3% had diabetes. A population that looks metabolically “fine” by the numbers on the scale is carrying a staggering burden of cardiometabolic disease underneath.

The Overflow Tank at work, once again.

What Adiponectin Predicted

Here’s where the Adiponectin Deficit stops being a framework and starts being measurable clinical risk.

For every one standard deviation increase in adiponectin, the odds of dyslipidemia dropped by 35% (OR 0.65, 95% CI: 0.54–0.78). That held across the entire cohort, men and women, after adjusting for BMI, visceral fat, lifestyle, and inflammation.

But the finding that was quite surprising was the gender split.

In women, each SD increase in adiponectin was associated with 46% lower odds of diabetes (OR 0.54, 95% CI: 0.37–0.76). a powerful protective signal.

In men? The association was flat. OR 1.01. Adiponectin predicted nothing about diabetes in South Asian men in this cohort.

The gender interaction was statistically significant (p = 0.02). This wasn’t noise.

Why the Gender Split Matters

The gender split is one of the most interesting findings in the paper. In this cohort, adiponectin’s inverse association with diabetes appeared in women but not in men. The authors discuss hormone profiles, fat distribution, and adipocyte biology as plausible explanations, but those remain interpretations rather than findings directly proven by this dataset.

The biological logic is suggestive: estrogen promotes subcutaneous fat storage (the safer kind) and may enhance adiponectin expression, while androgens favor visceral deposition, which suppresses it. South Asian women, when their adiponectin is intact, may get a metabolic shield that South Asian men don’t experience the same way.

Think of it this way: the Adiponectin Deficit may hit the same population differently depending on sex. In women, restoring that brake could have an outsized effect. In men, the damage may be routed through other pathways, visceral inflammation, intramyocellular fat, mechanisms that adiponectin alone can’t fully capture.

Which also invites further investigation on menopausal impact on South Asian women, blunting much of the protective estrogen effect.

This is why precision medicine can’t be one-size-fits-all, even within our own community. The same phenotype, the same ancestry, the same deficit, but the clinical expression diverges by sex.

What Leptin Didn’t Predict

Here’s what surprised the researchers (and shouldn’t surprise readers of this Substack): leptin showed no significant association with any cardiometabolic outcome after adjustment.

In other populations, African Americans in the Jackson Heart Study, mixed cohorts in MESA, leptin has been linked to glycemic progression. In South Asians, once you account for BMI and visceral fat, leptin tells you nothing more than what the scale already told you. It reflects total adiposity, not the specific adipose dysfunction that drives our risk.

The adiponectin-to-leptin ratio, which has been proposed as a sensitive marker of metabolic inflammation, similarly showed no independent associations. The signal is in the adiponectin. The ratio doesn’t add power in this population.

The Resistin Paradox

And then there’s the finding that doesn’t fit neatly into any framework: higher resistin was associated with lower odds of diabetes in men (OR 0.63, 95% CI: 0.44–0.89).

This is unexpected. Resistin is generally considered pro-inflammatory, it promotes insulin resistance in animal models and has been linked to metabolic dysfunction in several cohorts. Yet in South Asian men in this study, after full adjustment, higher levels tracked with less diabetes.

The authors flag this as unusual and largely unreported elsewhere, with the possible exception of a Canary Islands study on insulin resistance. They hypothesize it may reflect unique aspects of fat partitioning in South Asian men, including higher intramyocellular fat deposition, or unmeasured genetic factors that modulate resistin’s role differently in our population.

It’s a messy result. It complicates the tidy story that adiponectin is the only signal that matters. But that messiness is part of the science. The AR index, notably, smooths this paradox out, the composite doesn’t show the same inverse pattern, suggesting that combining resistin with adiponectin may filter noise that resistin alone introduces. If anything, the resistin finding is another argument for composite metrics over single-analyte readings.

A New Metric Worth Watching

This study introduces something we haven’t discussed on the Substack before: the Adiponectin-Resistin (AR) Index, a composite score first proposed in 2011 that balances adiponectin (protective) against resistin (inflammatory). Notably, the AR index has previously been linked to acute coronary syndrome specifically in South Indian men.

The AR index was associated with 36% higher odds of dyslipidemia overall (OR 1.36, 95% CI: 1.15–1.62). And in women, a higher AR index tracked with 83% higher odds of diabetes (OR 1.83, 95% CI: 1.27–2.77).

The authors note something subtle: the AR index associations mirror adiponectin’s in magnitude but in opposite direction, and unlike resistin alone, the index doesn’t show the paradoxical inverse association seen in men.

This raises the possibility that the index is essentially capturing adiponectin dysfunction in a different mathematical form, the missing brake expressed as a ratio.

Why does this matter? Because composite indices may eventually give clinicians (we’ve seen this with renal function in BUN/Creatinine ratios and lipids with HDL ratios) a more clinically actionable score than any single adipokine. We aren’t there yet. But the architecture for an adipokine-based risk score, one calibrated to our biology, is starting to take shape.

The Zinda Reading

Let’s place this where it belongs in the framework.

We’ve built the Fragile Engine (beta-cell reserve running closer to redline from birth), the Overflow Tank (subcutaneous fat capacity that saturates early, spilling into visceral depots), and the Signal Fire (visceral fat broadcasting IL-6 that jams insulin signaling).

The Adiponectin Deficit sits between the Overflow Tank and the Signal Fire. It is the reason the spillover becomes inflammatory in the first place. When healthy fat cells produce adiponectin, they suppress TNF-α and IL-6. They activate AMPK. They degrade ceramides. They tell the system to stay calm.

When that signal is constitutively low, as it is in South Asians from birth, the Overflow Tank doesn’t just fill. It ignites.

What this MASALA study adds is clinical anchoring: in a cross-sectional cohort of 891 South Asian Americans, higher adiponectin was associated with lower odds of prevalent dyslipidemia overall, and in women, with lower odds of prevalent diabetes. That does not prove causality, but it strengthens the case that the Adiponectin Deficit is not just mechanistic theory. It has a measurable clinical footprint in this population.

And the sex-specific findings suggest something important about intervention strategy, not from this study directly, but as a clinical extrapolation we think is worth stating. If adiponectin’s protective association is stronger in women, then interventions known to support adiponectin signaling, visceral fat reduction, resistance training, omega-3 supplementation, and in some cases pharmacologic approaches like GLP-1 agonists or TZDs…may carry a stronger metabolic return in South Asian women than in men, where additional pathways likely need to be addressed simultaneously.

What This Doesn’t Tell Us

The authors are appropriately careful. This is cross-sectional, a snapshot, not a movie. We can’t say higher adiponectin caused less diabetes. Residual confounding and model-specification artifacts remain possible. And while MASALA recruited participants with heritage from India, Pakistan, Bangladesh, Sri Lanka, and Nepal, making it more diverse than previous pilot work, the cohort is still drawn from two US cities and may not represent the full diaspora.

But the direction is consistent with everything we’ve covered. SHARE/SHARE-AP showed the baseline deficit. The Pune Maternal Nutrition Study showed it in cord blood. Now MASALA shows the clinical footprint.

The next step, and the authors say this explicitly, is longitudinal: following adipokine profiles forward in time to see if they predict incident ASCVD and diabetes. That study, when it comes, will tell us whether adipokine profiling should become standard in South Asian preventive care.

I suspect it will.

The Adiponectin Deficit was always the quietest piece of the Zinda Framework. No dramatic inflammatory cascade. No depleted repair crew. Just a missing signal, a letter that never got sent, leaving the rest of the system to fend for itself. Adpiocytes tend to have such effect, quietly impacting the body in ways we still have yet to fully realize.

Now we have numbers attached to that silence. And they are loud enough to hear.

— Omar

Dr. Omar Saleem is a double board-certified physician dedicated to health optimization, especially within the South Asian community. He runs Zinda, A South Asian Health Initiative, building the framework for South Asian precision medicine.

A new study in the Journal of the American Heart Association study shed valuable insights on prediabetes in South Asians in the US.

At age 45, South Asian men in the US have a prediabetes prevalence of 30.7% by study criteria (meaning we use fasting glucose between 100–125 mg/dL for everyone in the study).

White men the same age? 3.9%.

That 3.9% may feel low compared to national headlines (one would think this is higher considering the Standard American Diet (SAD)), and it is. Reason is this cohort was restricted to adults free of cardiovascular disease at baseline, which skews healthier than the general population.

The point isn’t the absolute numbers. It’s the ratio.

An eightfold divergence, in men who by almost every behavioral measure in this same study are doing better than their peers.

About the Study

Researchers from Northwestern and UCSF combined two landmark US cohort studies, MASALA (South Asian adults, a study we have referred to many times on this Substack) and MESA (White, Black, Chinese, and Hispanic adults), modeling clinical and behavioral risk factors across repeated exam cycles spanning midlife, from age 45 to 55, using approximately 2,700 participants.

This isn’t social media nutrition research. It’s the most thorough, detailed study on cardiac risk done on the diasopora to thsii day; repeated clinical examinations, labs, vitals, dietary assessments, used to ask a precise question: do South Asian adults develop cardiovascular risk factors earlier than other groups, and does that trajectory differ by gender?

The findings at age 45:

The good:

• Highest diet quality scores of all groups, South Asian men scored 65.7, women 67.6 on the Alternative Healthy Eating Index, leading every other group by a substantial margin

• Lowest alcohol use

The bad:

• Highest prediabetes prevalence of all five racial and ethnic groups, in both men and women

• Highest hypertension prevalence compared with White, Chinese, and Hispanic adults, only Black adults were comparable

• Leading dyslipidemia rates among men compared with White, Chinese, and Black men

By age 55, the divergence sharpens.

South Asian adults had the highest probability of developing diabetes of any group.

South Asian men were nearly three times as likely to develop diabetes by 55 as White men. South Asian women saw prediabetes jump 18.5 points, from 17.6% to 36.1%, nearly double the increase of any other group in the study.

The authors named it themselves, and then offered an explanation that implicates not just physiology, but biography: "worse clinical risk factors despite a greater prevalence of protective behaviors" may stem from lifestyle exposures that preceded the study period entirely.

The lifestyle paradox isn’t a footnote. It’s the plot.

The Zinda Reading

This is where the Fragile Engine and the Overflow Tank do their quiet, relentless work.

A South Asian body at 45 is not a caucasian body at 45.

Beta-cell reserve runs smaller from birth, and subcutaneous fat storage saturates earlier. When the overflow goes visceral, into the liver and surrounding organs, the metabolic signal changes entirely. Visceral fat doesn’t just sit there. It behaves like an endocrine organ, pushing inflammatory signaling (IL-6 among others as we discussed here last month), that worsens insulin resistance even when the person eating the meal has the best diet score in the room.

This is why diet quality alone cannot move the needle the same way. The Fragile Engine was already running closer to redline before the fork and knife ever came into the picture.

But the paper goes further than biology. The authors offer an explanation that implicates not just our physiology but our biography.

Most middle-aged South Asian adults in the United States are immigrants. Many arrived eating the way people actually eat at home, fried snacks, sweets, high-fat dairy, limited structured exercise. Over years of assimilation, habits shifted. Better diets. More movement. The MASALA study itself found that women who integrated into American culture had more favorable metabolic profiles than those who maintained strict dietary and lifestyle separation (below).

So what we’re measuring at age 45 is not a lifetime of good behavior. In many cases, it’s a recent conversion. And the Fragile Engine doesn’t care that you started eating well at 38. It remembers the decades before.

The damage isn’t always happening now. Sometimes it happened earlier, in childhood, in the subcontinent, in the decade after immigration before the habits shifted. By the time a South Asian patient walk into a clinic at 45 with excellent diet scores and a prediabetes diagnosis, the story that produced that number may be 20 years old.

What the Guidelines Still Miss

Current ACC/AHA guidelines acknowledge South Asian ancestry as a cardiovascular risk-enhancing factor, but they don’t operationalize what that means for earlier metabolic screening in a way that actually matches this burden. Lp(a), ApoB testing, earlier fasting insulin, HOMA-IR, HbA1c tracked against lower thresholds, none of this is routine. South Asian ancestry is a flag in the guidelines. It hasn’t yet become a protocol.

The infrastructure for better care exists, but it’s uneven. SAHELI suggests culturally adapted programs can improve behaviors, even if cardiometabolic risk-factor changes versus written education were modest, meaning we may need earlier timing, higher intensity, or different targets (waist/visceral adiposity, insulin resistance), not just ‘better advice’.

A Note on What This Study Didn’t Say

The authors were careful on generalization of this data, as we should be. MASALA participants were recruited largely from Indian backgrounds, from two US cities. This is not the full South Asian diaspora. The study also couldn’t use genetically inferred ancestry or biological sex data, which limits mechanistic conclusions.

But the direction of the signal is clear. And it’s been pointing the same way for years, in MASALA, in UK Biobank, in Yajnik’s foundational thin-fat phenotype work. This isn’t a new alarm. It’s the same alarm, getting louder.

The question is no longer whether it’s ringing.

The question is whether anyone is listening, and whether we’re acting before the decade of drift becomes irreversible.

— Omar

Feedback on topics always welcome!

At Zinda, we don’t care about the hype. We care about the phenotype.

Nothing has garnered hype like GLP-1. Super bowl level hype.

For the South Asian community however, GLP-1s may be the most important medication, almost a miracle. It’s not just about fitting into a wedding outfit; it’s about correcting a fundamental evolutionary mismatch.

Lets get into it.

In our previous deep dives, we’ve explored the “Thin-Fat” Paradox, how South Asians suffer from metabolic disease at lower body weights than our Western counterparts. We’ve discussed our “Thrifty Genotype”, an evolutionary adaptation for starvation that has become a liability in the age of abundance. And over the last month delved into the South Asian gut, how its lining, microbiota and axis form a circuit incongruous to a diaspora.

Today, we are connecting those dots, all seemingly leading toward GLP-1s and why they could be metabolic correctors ideal for the specific bottlenecks in the South Asian phenotype.

GLP-1s 101

Before we dive into the South Asian specifics, let’s strip away the brand names and look at the molecule fundamentally.

GLP-1 (aka Glucagon-like Peptide-1) is an incretin hormone naturally produced in your gut after you eat. Like most peptides, they are signaling molecules, messengers who instruct the target cell/organ to do something. In the case of GLP-1s, it communicates between the gut and the rest of the body.

When you eat a meal, GLP-1 travels through your system to coordinate a complex physiological response:

1. In The Brain: It binds to receptors in the hypothalamus to shut down “food noise” that constant mental chatter asking “What’s for dinner?” while you’re eating lunch.

2. In The Stomach: It slows gastric emptying, keeping you physically fuller for longer.

3. In The Pancreas: It primes the beta-cells to release insulin, but crucially only when glucose is elevated. This “glucose-dependent” mechanism is why it rarely causes dangerous lows (aka hypoglycemia), unlike older drugs (though risks increase if combined with insulin or sulfonylureas).

4. In The Liver: It suppresses glucagon secretion from pancreatic alpha cells, thereby stopping your liver from dumping stored sugar into your bloodstream unnecessarily.

For many people, this reads like weight loss. For South Asians, it can function more like metabolic triage, because the bottleneck is earlier, and the margin for error is smaller.

Resistance, Not Deficiency

When we talk about metabolic health, we obsess over insulin. We track spikes, we fear resistance, and we measure fasting levels. But insulin is just the soldier; it follows orders. We are slowly learning the real commanders are the incretins, hormones like GLP-1 that dictate how your body handles a meal.

Now, you might assume that because South Asians get diabetes earlier and more aggressively, we simply lack these hormones. The reality is the exact opposite.

Research comparing healthy young South Asians to Caucasians found a fascinating paradox: in response to sugar, South Asians actually secrete significantly higher levels of GLP-1.

Why?

Think of it as a scream for help. Your body “senses” the metabolic struggle, the insulin resistance in your liver and muscles, and the gut pumps out extra GLP-1 to force the pancreas to respond. But just like we are insulin resistant, we appear to be GLP-1 resistant.

Research strongly supports a “Compensatory Scream” hypothesis. Sleddering et al. (2014) found that healthy young South Asians secreted ~45% more GLP-1 (AUC) than matched Caucasians during a glucose challenge, yet still exhibited higher insulin resistance. This appears specific to our phenotype; Chong et al. (2022) showed that Indians produce significantly more GLP-1 than Chinese or Malays, directly correlating with metabolic dysfunction. Essentially, while the gut is working overtime to stimulate insulin (Misra, 2020), it is fighting a losing battle against systemic defects.

The signal is loud, but the body isn’t listening, a mismatch that suggests a distinct form of “GLP-1 resistance.”

This is why “natural” methods sometimes hit a wall and why pharmacological GLP-1s (which provide doses far higher than nature) can be so effective. They provide a signal loud enough to finally break through that resistance barrier.

Genomic Blind Spots

Research into the pharmacogenomics of GLP-1 agonists in South Asian populations is still in its infancy, especially as this is critical in understanding nuances of hyper-responders and poor responders. A large-scale genome-wide analysis identified a variant in the ARRB1 gene that is associated with an enhanced glycemic response to GLP-1 agonists. However, this variant is almost non-existent in individuals of Asian descent. Conversely, a common variant in the GLP1R gene was linked to a reduced response, but its specific frequency and impact within South Asian populations have not been clearly established.

The significant underrepresentation of South Asians in major clinical trials for these medications is a major obstacle to understanding the role of genetic factors in treatment response and a mission driven goal for Zinda.

A Systemic Shield

One of the most important discoveries in recent years is that GLP-1 receptors are not just found in the pancreas or gut. They are ubiquitous, acting as a “systemic shield” for organs that are particularly vulnerable in the South Asian phenotype.

• The Heart (Endothelial Repair): South Asians have some of the highest rates of premature cardiovascular disease. GLP-1 receptors line our blood vessels and the heart itself. Studies show that activation of these receptors improves endothelial function (the flexibility of blood vessels) and reduces arterial stiffness, often independent of weight loss.

• Systemic Inflammation (The hs-CRP Connection): Chronic, low-grade inflammation is a hallmark of our phenotype, often visible in elevated hs-CRP levels even in “thin” individuals. GLP-1s appear to directly downregulate inflammatory cytokines. This is crucial because inflammation is the spark that often ignites the fuel of insulin resistance.

• The Brain (Neuroprotection): Emerging research suggests GLP-1s reduce neuroinflammation. Given the links between insulin resistance and cognitive decline (often called “Type 3 Diabetes”), this offers a potential protective mechanism against neurodegenerative conditions like Alzheimer’s, which share metabolic roots with diabetes.

Why We Need to Rest, Not Whip

We have previously discussed the “Beta-Cell Fragility” of the South Asian phenotype. If the pancreas is a fuel tank, we are born with a smaller tank.

For decades, the standard treatment for diabetes in South Asia has been Sulfonylureas, older drugs that squeeze the pancreas to pump more insulin. In our framework, this is a mistake. It’s like whipping a tired horse; it works for a mile, but the horse collapses sooner.

GLP-1 receptor agonists work differently. They don’t just squeeze; they optimize.

• They Rest the Beta-Cell: They only stimulate insulin when blood sugar is high, preventing the “burnout” that leads to early insulin dependence.

• Pancreatic Offloading: By aggressively targeting visceral fat (the specific belly fat South Asians store), GLP-1s lighten the “trailer” significantly more effectively than Metformin.

• Preservation: The goal isn’t just to lower A1c today. It’s to stop the beta cells from dying off so you don’t need injected insulin 10 years from now.

• They Target the “Overflow”: The South Asian metabolic crisis is driven by ectopic fat, fat stored in the liver and pancreas because our subcutaneous (under skin) storage is limited. GLP-1s are exceptionally good at mobilizing this specific, dangerous visceral fat.

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The Silent Epidemic

If there is one organ that defines the South Asian metabolic struggle, it is the liver.

South asians have some of the highest rates of MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease), often occurring in people who look “thin” or have a normal BMI. Recent studies in South Indian cities found a staggering 40% prevalence of fatty liver, much of it in non-obese individuals. This is “Lean MASLD,” and it is a silent killer. Because our subcutaneous fat storage (the safe fat under your skin) is genetically limited, any excess energy spills over almost immediately into the liver.

For South Asians, the liver becomes a bottleneck. Once it is clogged with fat, it becomes insulin resistant, pumping out sugar even when you are fasting, driving the cycle of diabetes.

This is where the every new generation of GLP-1s has shown leaping progress:

• Semaglutide (Ozempic/Wegovy): Proven to significantly reduce liver fat, effectively “de-clogging” the filter.

• Tirzepatide (Mounjaro/Zepbound): This is a “dual agonist” (targeting GLP-1 and GIP). Early data, such as the SURPASS-3 MRI substudy, suggests it is even more potent for liver health, potentially halting the progression to fibrosis (scarring).

  

• Retatrutide (The Future): I like to call this the liver GLP. This upcoming “triple agonist” (GLP-1, GIP, and Glucagon) is highly anticipated. In Phase 2 trials, it has shown the ability to resolve fatty liver in >85% of patients in just 48 weeks, with most patients dropping to normal (≤5%) levels. That is mind blowing as we have alwys assumed much of liver steatosis took years to improve. For a population prone to liver disease, this could be revolutionary.

Note: We will be doing a dedicated, comprehensive deep dive into MASLD and the South Asian Liver next week. Why this happens, why and how to screen early, much more... Stay tuned.

The Mitochondrial Connection

At Zinda, as most regular readers already know, we view metabolic health through the lens of bioenergetics, specifically, the mitochondria, our cellular engines. The South Asian “starvation-adapted” engine as we discussed in a previous Chai Shots post, is designed for efficiency, not capacity. When we flood it with modern “fuel oversupply” (processed carbs, seed oils), the engine gridlocks.

Emerging science suggests GLP-1s may help unclog this gridlock. They don’t just suppress appetite; studies indicate they may stimulate mitochondrial biogenesis, helping the body build more engines to burn through the lipid overload in our muscle cells.

The Muscle Trap

However, there is a critical nuance that we cannot ignore.

If you are South Asian, you are likely already battling sarcopenia (low muscle mass). It is a hallmark of our phenotype. GLP-1 medications cause weight loss, but without intervention, up to 40% of that loss can be lean muscle.

If you take these drugs and do not lift heavy weights, you risk becoming a smaller, weaker version of the “Thin-Fat” phenotype, lower weight on the scale, but a disastrously low metabolic rate and higher relative body fat.

Non-negotiables for GLP-1s:

1. Strength is Non-Negotiable: You must engage in resistance training to preserve the “thin” (muscle) while stripping the “fat”.

2. Protein Prioritization: Our traditional diets are often protein-deficient. On these medications, appetite drops, making it even harder to hit protein targets. Conscious, high-protein intake is medicine.

3. Know Your Liver Status: Before starting, understand your baseline. If you have “Lean MASLD,” these medications may be doubly effective for you, acting as both metabolic correction and liver therapy.

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A note on stigma

Something I encounter with many South Asians patients is apprehension stemming from rumors, stories and stigma around these medication. It almost feels they are cheating physiology. For South Asians, GLP-1s are not “cheating.”

In our community, there is often a heavy stigma attached to medication, viewing it as a failure of willpower or a sign of weakness. We need to kill this narrative. Using a GLP-1 to correct a genetically entrenched resistance is no more “cheating” than wearing glasses to correct poor eyesight. It is a tool to level a playing field that evolution tilted against us.

Furthermore, we must shift our mindset from reactive to proactive.

When to Have the Conversation

It can be difficult to know when to move from lifestyle-only to medical intervention. Based on the South Asian phenotype specific metrics we have established so far, you might consider asking your doctor about the GLP-1 class earlier if you meet these criteria:

• Waist-to-Height Ratio: Is your ratio >0.5 despite a “normal” BMI?

• Fasting Insulin: Is it consistently high (>10 uIU/mL), or is your HOMA-IR elevated?

• Liver Health: Do you have MRI or Ultrasound evidence of fatty liver, or elevated ALT levels?

• HbA1c Trend: Is your A1c drifting up year over year, even if pre-diabetic?

• Family History: Is there a strong family history of early T2D or heart disease?

If you check multiple boxes, the metabolic bottleneck may already be present.

Too often, we wait for the crash, the heart attack, the diabetes diagnosis, or the kidney failure, before we act.

At Zinda, we argue for radically proactive metabolic defense, and urge physicians to consider GLP-1s much earlier than they would in other populations. If biomarkers (high insulin, fatty liver, rising HbA1c) show mitochondria are struggling, these tools should be considered now to preserve your organ health, rather than waiting 10 years when the damage is irreversible.

They are not a magic wand, but they are a powerful catalyst.

They work best when placed into the a South Asian focused framework, impeccable nutrition, heavy resistance training, and a deep understanding of your own biology. Why biological first principles matter.

-Omar

Welcome back to Chai Shots, a series where we distill the latest science on South Asian health optimization.

In previous editions, we’ve been building a map of the South Asian metabolic phenotype. We’ve talked about the Fragile Engine (our smaller pancreatic beta-cell reserve), the Overflow Tank (our limited capacity to store fat safely), and the Adiponectin Deficit (the missing metabolic brake).

Today, we are adding two critical new pieces to this puzzle, courtesy of research published just this past year. If you’ve ever wondered why heart disease seems to strike the South Asian diaspora so aggressively, often decades earlier than our neighbors, these two papers provide deep insight.

It turns out we aren’t just fighting a fragile engine. We are fighting a system that is constantly overheating (inflammation) while running with a depleted pit crew (repair cells).

Grab some chai.

Paper No. 1: The Signal Fire (IL-6)

• Title: Ethnic differences in the association between interleukin-6 and the risk of type 2 diabetes

• Authors: Henson, J. et al.

• Journal, Year: eBioMedicine (The Lancet), 2025

  Understanding why inflammation drives diabetes faster in South Asians.

What They Found:
We have known for a while that Type 2 Diabetes is an inflammatory disease. But this study clarifies how that inflammation differs for us. The researchers found that South Asians have significantly elevated baseline levels of Interleukin-6 (IL-6) compared to White Europeans.

The study established that each standard deviation (SD) increase in IL-6 was associated with a 47% higher risk (HR 1.47; 95% CI 1.32–1.64) of developing type 2 diabetes in the fully adjusted model for the entire cohort.

Why It Matters:
Think of Il-6 as a “signal fire.” In the short term (like during exercise), it’s good, it mobilizes energy. But when it’s chronically elevated at rest, it’s a distress signal. It tells your body it’s under attack.

For South Asians, this chronic IL-6 elevation is likely coming from that “overflowing” visceral fat we’ve discussed. This fat isn’t just sitting there; it is biologically active tissue pumping out inflammatory signals. This constant background noise of inflammation desensitizes your insulin receptors. It effectively “jams” the signal between your insulin and your cells, forcing your already Fragile Pancreas to work double-time to compensate.

Paper No. 2: The Missing Mechanics (Vascular Regenerative Cells)

• Title: Vascular Regenerative Cell Deficiencies in South Asian Adults

• Authors: Krishnaraj, A., Verma, S., et al.

• Journal & Year: Journal of the American College of Cardiology (JACC), 2024

Why our blood vessels age faster.

What They Found:

The researchers looked at Endothelial Progenitor Cells (EPCs). Think of these cells as your body’s “road repair crew.” When a blood vessel gets damaged (by high sugar, pressure, or inflammation), these cells rush in to patch the pothole and heal the lining.

The study found that South Asians have markedly lower frequencies of these regenerative cells compared to White Europeans. Specifically, South Asian participants had 23% fewer pro-angiogenic progenitor cells (measured as ALDH^hiSSC^midCD14⁺CD163⁺ cells), even after adjusting for age, BMI, and glucose levels.

Furthermore, the cells we do have are less functional, they are essentially “tired mechanics.” This deficit was observed even in South Asians without established cardiovascular disease, suggesting it is an intrinsic vulnerability rather than just a consequence of illness. It fundamentally challenges the idea that our heart risk is solely due to lifestyle, pointing instead to a compromised biological repair system.

Since we can’t easily measure these “repair crew” cells directly yet, keeping an eye on markers like hs-CRP (inflammation) and microalbumin (vessel leakage) can serve as a practical proxy for this hidden damage.

The South Asian Connection:
This explains the “accelerated aging” we see in South Asian heart health.
In a typical body, damage happens, and repair happens. It’s a balance.
In the South Asian body, we have a Double Hit:

1. High Damage: The elevated IL-6 and insulin resistance cause constant wear and tear on the vessel walls.

2. Low Repair: The repair crew (EPCs) is understaffed and overwhelmed.

   

The result? The potholes don’t get fixed. Plaque builds up faster. Arteries harden earlier.

The Burn and Crash Model

When we integrate these findings into our Zinda Framework, the full picture of our metabolic risk emerges not as a list of symptoms, but as a sequential chain of events:

1. Fragile Engine: We begin with a smaller beta-cell reserve.

2. Overflow Tank: Subcutaneous fat capacity is limited, causing early visceral spillover.

3. Signal Fire: This visceral fat releases excess IL-6, causing chronic inflammation that blocks insulin signaling.

4. Repair Deficit: When blood vessels are damaged by this inflammation, we lack the regenerative cells (EPCs) needed to fix them efficiently.

This isn’t a defect; it’s a mismatch. Our biology is optimized for a low-inflammation, high-activity environment, and it is colliding with a modern world that offers neither.

Why Zone 2 Works (A Deeper look at The Physiology)

A great way to fix this is zone 2 cardio. Yes, we’ve mentioned it a few times and countless times do we hear this said. But why? Intentionality is vital.

To understand why Zone 2 cardio is non-negotiable for our phenotype, we have to look at the source of the static. The Signal Fire isn’t just abstract inflammation, it is a physical distress signal originating from overflowing visceral fat. This tissue is not inert energy storage. It’s biologically active, pumping out cytokines like IL-6 that desensitize your insulin receptors and jam the communication lines between insulin and your cells.

Because of this the phenotype’s tendency to accumulate this specific type of fat earlier and at lower body weights, we create a much longer and pronounced period of inflammation than other populations.

Zone 2 cardio, performed at 60 - 70% of your maximum heart rate, functions as the drainage mechanism for this reservoir of visceral fat. Unlike high-intensity intervals which primarily burn glycogen, Zone 2 intensity maximizes fat oxidation and upregulates mitochondrial transporters like CPT1A. These transporters act like gates, allowing lipids to move into the mitochondria to be burned. By draining the fuel source of the signal fire, we lower the baseline “background noise” of chronic IL-6.

This creates a critical distinction between “good” and “bad” inflammation.

The chronic IL-6 from visceral fat is a distress signal indicating the body is under attack. However, the acute release of IL-6 during exercise is a healthy metabolic trigger.

The goal of Zone 2 is to silence the chronic noise so that the body can once again “hear” the acute, healthy signals of exercise and insulin, effectively unclogging the jammed signaling pathways.

And thats Zone 2.

-Omar

Dr. Omar Saleem is a double board-certified physician dedicated to health optimization, especially within the South Asian community. He runs Zinda - A South Asian Health Initiative, building the framework for South Asian precision medicine.

Over the past year at Zinda, we’ve been methodically dismantling the “South Asian Phenotype.”

We started with The Engine, our smaller pancreatic beta-cell reserve. We explored The Overflow Tank, our limited capacity for safe subcutaneous fat storage. And last week, in Part I: The Migrant Biome, we documented the ecological collapse that happens in our digestive tract when we move West.

We know the biome collapses. We know the metabolism fails. But how does a change in bacteria translate into diabetes?

In the human body, organ systems don’t operate in silos. They communicate. And the most critical conversation for metabolic health happens between two entities: your Gut Microbiome and your Mitochondria.

For South Asians, this conversation many times goes silent, and much earlier in life. Or worse, it turns toxic.

If we view the South Asian phenotype through first principles, we aren’t “broken.” We are suffering, and borrowing - from the engineering side of my family here - a System Compatibility Error. We are running Scarcity Software on Abundance Hardware.

Today, in Part II, we follow the toxins from the gut to the engine. We explore the Gut-Mitochondria Axis, and why fixing it requires reconnecting this.

The “Prius” Engine or Haplogroup M

Let’s recap the hardware.

As we discussed in Chai Shots 003, South Asian mitochondria are unique. Evolutionarily, we are dominated by Haplogroup M (specifically sub-lineages like M2, M3, and M5), a lineage that phylogeographic studies confirm emerged from the earliest migrations into the subcontinent.

Unlike European mitochondria (Haplogroup N), which are “loosely coupled” and waste energy as heat to survive cold climates, evolutionary models suggest that South Asian mitochondria are tightly coupled.

This “efficiency hypothesis” posits that because we evolved in heat and cyclical famine, our engines were designed to waste nothing. They squeeze every molecule of ATP out of every calorie.

We are running a Toyota Prius (hyper-efficient, low waste), [and no this is not a pun] in a world designed for Hummers (high waste, high consumption).

In a famine, the Prius wins.

But in the modern world of endless calories, the Prius battery charges too fast. It overheats and creates a “Traffic Jam” of electrons. This traffic jam leads to oxidative stress, forcing the cell to lock its doors, what we call Insulin Resistance.

This is the “flooded engine” we described in previous posts, intramyocellular lipid accumulation that jams the metabolic machinery.

The Operating System

Now, recall the ancestral South Asian gut we profiled in Part I.

Lets build further on that here. Before migration or Westernization, our microbiome was dominated by Prevotella species (specifically P. copri).

Prevotella is the ultimate scavenger. It possesses a vast library of enzymes (CAZymes) designed to break down complex, fibrous plant tissues that humans cannot digest alone.

It extracts energy. It turns lentils and coarse grains into Short-Chain Fatty Acids (SCFAs) like Butyrate.

Lets call this the Ancestral Synchronization:
For thousands of years, these two systems worked in perfect harmony. The Gut (The Harvester) squeezed maximum energy from a low-calorie diet, and the Mitochondria (The Hoarder) ensured none of that energy was wasted.

It was a masterpiece of biological efficiency…Until it was upended by migration.

The Great Decoupling

Then comes the “6-Month Cliff” we described last week.

When a South Asian migrates to the West, or undergoes dietary acculturation by adopting a “Westernized Vegetarian” diet (even amongst those living in South Asia), the Prevotella colonies collapse. Research on South Asian migrants shows that this ecological collapse happens rapidly, with “industrial” bacteria like Bacteroides replacing the ancestral guilds.

This isn’t just a change in bugs. It’s a communications blackout, cutting the lines in many ways.

The signals that the gut sends to the mitochondria shift from protective to destructive. There are three specific ways this axis breaks down:

1. The Lost “Burn” Signal (Butyrate Depletion)

Your mitochondria don’t decide to burn fat on their own, they wait for chemical signals. One of the strongest signals comes from Butyrate (which we mentioned above0, a short-chain fatty acid produced when gut bacteria ferment fiber.

Butyrate travels from the gut to the liver and muscle, where it tells mitochondria to upregulate beta-oxidation (fat burning). It lubricates the gears of the engine.

When we suffer the “Enzymatic Extinction,” losing the microbes that digest fiber, butyrate production flatlines. The mitochondria never receive the memo to burn fat.

The Traffic Jam worsens. The engine is already prone to backing up; without the butyrate signal to open the exhaust vents, lipids accumulate inside the muscle cells.

2. The “Toxic” Signal (Metabolic Endotoxemia)

As we introduced in Part I, the loss of the Bifidobacterium and diversity shield leads to Leaky Gut. Now we see where that leak leads.

Toxins from bacterial cell walls, known as Lipopolysaccharides (LPS), leak into the bloodstream.

LPS is a direct mitochondrial poison. While acute exposure causes sepsis, leaky gut creates a chronic, low-grade trickle known as metabolic endotoxemia. It binds to TLR4 receptors on your cells and shuts down mitochondrial respiration.

As if that wasn’t enough…

The South Asian Multiplier (The Adiponectin Paradox)
This inflammation has a specific casualty: Adiponectin.
As we explored in our deep dive on Adiponectin And Clinical Blind Spots, South Asians already have constitutively lower levels of this “guardian angel” hormone, often 25-40% lower than Caucasians from birth.
Adiponectin burns fat and sensitizes us to insulin.

But here is the main issue. LPS toxicity actively suppresses its production. We start with a lower reserve, and the toxic gut signal depletes what little we have. We lose our primary metabolic defense.

3. The “Blockade” Signal (BCAAs)

We touched on this in Part I: the dysbiotic gut becomes a factory for Branched-Chain Amino Acids (BCAAs). Here is the mechanism.

While dietary protein provides BCAAs, a dysbiotic, Westernized gut becomes an internal factory that overproduces them. A landmark study published in Nature Medicine linked elevated circulating BCAAs directly to insulin resistance, independent of obesity. The association is particularly strong in Asian populations.

High levels of BCAAs in the blood activate a nutrient-sensing switch called mTOR, which actively blocks insulin signaling in muscle tissue.

Your gut bacteria are literally manufacturing insulin resistance.

The Unified Equation

When we put this together, the “South Asian Metabolic Syndrome” stops looking like a mystery and starts looking like a mechanical inevitability. This is why we’ve spent weeks breaking down each part first and rebuilding from the ground up with the South Asian phenotype in mind.

We have a High-Efficiency Engine (Mitochondria) being driven by a Corrupted Operating System (Dysbiotic Gut).

No Fiber → No Butyrate → Lipid Accumulation

Leaky Gut → LPS Leak → Adiponectin Crash → Inflammation

Dysbiosis → BCAA Overproduction → Insulin Blockade

The body responds exactly as programmed: it stores the excess energy as visceral fat (The Overflow Tank) and protects the cells by rejecting glucose (Insulin Resistance). This is the same conclusion we reached in previous posts, the South Asian body is executing ancient survival code that no longer matches the environment.

Over the coming weeks, my goal on this Substack, is to bring together these different concepts while adding further building blocks so that we build out a holistic model for South asian health optimization.

Re-Establishing the Connection

So how do we get them talking again?

We cannot change our mitochondrial genetics (though as we mentioned in the Vanishing Engine on Sarcopenia, many gene therapies are coming) , nor should we. Efficiency is a gift if managed correctly. We must fix the inputs.

1. Reboot (Fiber, But Carefully)

We can’t just dump Metamucil into a dysbiotic gut. That causes bloating and discomfort because of the “Enzymatic Extinction,” we lack the bacterial machinery to digest it.

How to fix it?

We need cellular fibers, the intact structures found in various foods:

• Whole lentils (dal with the skin)

• Unpolished millets (bajra, jowar, ragi)

• Fibrous vegetables (okra, bitter gourd, drumstick)

• Resistant Starches: Cooked and cooled rice or potatoes. The cooling process changes the starch structure, allowing it to bypass digestion and feed the microbiome directly, significantly increasing butyrate production.

A great nutritionist here can do wonders (even well crafted chatGPT prompt or Claude skill (something I am collecting together).

We need to re-introduce the substrates that feed the Prevotella guilds, slowly rebuilding the butyrate factories. Start slow to monitor for GI tolerance. Increase gradually over 4-6 weeks. Let your gut ecology adapt.

2. Manual Override (Zone 2 Cardio)

If the chemical signal (butyrate) is missing, we must use a mechanical signal.

How to fix it?

Zone 2 Cardio, steady state, conversational pace, 3-4 hours per week.

This specific intensity forces the mitochondria to burn fat even without optimal chemical signals. It mechanically clears the “Traffic Jam” of electrons, reducing the back-pressure that causes insulin resistance. This is the same recommendation we made in previous posts, the intervention architecture for South Asian metabolic health requires this aerobic foundation.

You cannot out-lift a flooded engine. You must first drain it.

3. The Fermentation Bridge

We need to patch the leaky gut to stop the LPS poisoning.

How to fix this? Traditional fermented foods.

• Homemade dahi (curd)

• Idli/dosa batter fermented overnight

• Kanji (fermented carrot/beetroot water)

• Achaar (traditional pickles with live cultures)

These provide the Lactobacillus and Bifidobacterium strains that reinforce the gut lining, physically blocking the toxins from reaching the mitochondria.

Note: Commercial “probiotic” yogurts often lack the strain diversity and colony counts of traditional preparations. Some are great and do have these colonies, please refer to the ingredients section of the product for this. Source from home fermentation whenever possible.

We’re moving away from the idea that South Asians are simply “prone to diabetes” because of laziness or bad luck.

We are bio-energetic machines operating in the wrong environment.

The Gut-Mitochondria axis is the dashboard. By controlling the inputs, fiber for the gut, Zone 2 for the mitochondria, fermentation for the barrier, we can make significant strides in changing that trajectory.

That is what we will cover in part III. Why GLP-1s may be the most important medication for south asians.

This is what we mean by recalibration. It’s not fighting your biology, but understanding it well enough to work with it.

— Omar

We often think of migration as a change of address. A new city, a new climate, new neighbors.

But biologically, it is a much more profound event…closer to a change of species.

Within months of arrival in the West, the internal ecosystem you inherited, the trillions of bacteria that co-evolved with your ancestors over millennia, begins to collapse. And with it, a cascade of dysfunction that helps explain why we face diabetes, heart disease, and autoimmunity at rates that defy every standard guideline.

We have explored the genetic angles of the South Asian paradox in previous posts: the fragile engine of our beta cells, the ghrelin dysfunction that strips our muscle, and the adiponectin deficit that makes every calorie dangerous. But genetics alone cannot explain the velocity of the change. Genes take generations to shift. Our health often deteriorates within a single generation of arrival.

The missing variable, or one big oen, is the gut microbiome. And its collapse is faster, and more reversible, than anyone realized.

The 6-Month Cliff

The loss of your ancestral microbiome doesn’t take decades. It takes months.

Landmark studies tracking immigrants reveal that significant displacement of native gut bacteria occurs within the first 6 to 9 months of residence in the West. In rural South Asia, the gut is dominated by Prevotella species; bacteria exquisitely adapted to break down the complex fibers in lentils, millets, and traditional vegetables into Short-Chain Fatty Acids (SCFAs), like butyrate.

Butyrate is not just fuel for the gut lining; it is an epigenetic signal. It works by inhibiting Histone Deacetylases (HDACs), effectively “switching off” the genes responsible for inflammation. When we lose Prevotella, we lose this critical chemical brake on our immune system.

Upon migration, Prevotella is rapidly displaced by Bacteroides, bacteria that thrive on animal proteins, fats, and refined sugars. While Prevotella may not disappear entirely, this represents a functional extinction of our dominant metabolic guild. The “keystone” species responsible for maintaining your gut barrier and feeding anti-inflammatory pathways are marginalized.

The substrate they depended on, the dal, the unpolished rice, the fibrous saag, has been replaced by ultra-processed foods that now constitute nearly 60% of daily calories in the standard Western diet.

Losing The Good Stuff

While Prevotella is the workhorse of digestion, Bifidobacteria are the guardians of the gut barrier. Research confirms that the traditional Indian microbiome carries significantly higher levels of Bifidobacterium, sustained by plant fibers and traditional fermented dairy, homemade dahi, lassi, idli, dosa, achaar, kanji.

In the West, this population crashes, contributing to a broader loss of overall microbial diversity.

The reasons are straightforward: beneficial bacteria need specific fibers to survive. When we swap whole dals for refined flour, we starve them. And the “yogurt” we replace dahi with is often pasteurized and standardized into weak monocultures that don’t colonize, and frequently loaded with sugar that feeds harmful bacteria instead.

When diversity drops, the gut lining weakens.. Bacterial toxins (lipopolysaccharides [LPS in above image]) escape into the bloodstream, triggering the chronic low-grade inflammation that drives insulin resistance. This is the same metabolic endotoxemia we discussed in the context of the flooded engine, except now we see where the flood originates.

As much as I love Straus…we may need to reprioritize.

The Mechanism: The False Alarm (TLR4)
These escaped toxins don’t just float around; they dock onto Toll-Like Receptor 4 (TLR4) on your immune cells. This receptor is designed to detect severe bacterial infections. When activated by a leaky gut, it tricks your body into thinking it is fighting septic shock.

The body responds by initiating a “war protocol”: it raises systemic inflammation and blocks insulin receptors in muscle and fat cells. Why? To keep blood sugar high so the immune system has fuel to fight the “infection.” This is one powerful mechanism by which a leaky gut drives Type 2 Diabetes, even in thin individuals.

“Westernized Vegetarian”

Many of us retain our vegetarian identity in the West, we may think this protects us.

It doesn’t. Not automatically.

The quality of the vegetarian diet often shifts dramatically. We replace complex, cellular fibers from traditional foods with “acellular” refined carbohydrates, white flour, polished rice, sugar. Worse, we introduce a flood of Omega-6 rich vegetable oils common in processed Western foods.

A “Westernized Vegetarian” diet, high in refined carbs and seed oils, low in complex fiber; can be ecologically worse for the South Asian microbiome than a moderate omnivorous diet. It creates fermentable substrate for gas-producing bacteria (the bloating we all know too well) without feeding the species that protect our metabolic health.

Enzymatic Extinction

Perhaps the most alarming finding is the loss of CAZymes, the molecular “scissors” our bacteria use to break down plant fibers.

Studies on South Asian Canadians show that second-generation immigrants often completely lack the genes required to degrade specific traditional fibers. This means even if you try to revert to a high-fiber ancestral diet later in life, your gut may no longer possess the machinery to process it efficiently.

This creates a vicious cycle. We avoid fiber because it causes discomfort, further starving the few remaining beneficial bacteria.

Dysbiosis and The Metabolic Mismatch

How does this connect to diabetes?

Dysbiotic gut bacteria (specifically certain strains of P. copri and Bacteroides) are prolific producers of Branched-Chain Amino Acids (BCAAs). As detailed in this pioneering metabolic research, elevated serum BCAAs are a potent driver of insulin resistance.

Recent research points to specific strains of Prevotella copri and Bacteroides as culprits here. It is important to note the nuance: P. copri is not universally “bad,” some strains found in traditional rural diets are beneficial. However, the specific strains, as seen in the Danish study above, that tend to thrive in the Westernized gut are frequently linked to BCAA production and insulin resistance.

The westernized South Asian gut becomes a factory for these metabolites, effectively blocking insulin signaling in your muscles and driving visceral fat storage, even if you aren’t overeating.

Second Generation Gets Hit Worse

The most profound impact is seen in the second generation.

First-generation immigrants often retain a “transitional” microbiome, a shadow of their ancestral gut that provides some residual resilience. But Gen 2, born in the West, faces something worse: complete extinction of ancestral heritage microbes from birth.

Born into sterile hospital environments, often via C-section (which bypasses the critical seeding of maternal vaginal flora), and exposed to higher rates of antibiotics in early childhood, Gen 2 children possess a microbiome nearly indistinguishable from the general Western population.

They have the South Asian genome. But the Western microbiome. From day one.

The Mechanism
Our immune cells rely on specific ancestral bacteria (our “Old Friends”) to train a specialized squadron of immune cells called Regulatory T-Cells (Tregs). Tregs are the peacekeepers; their job is to tell the immune system when not to attack.

Without early exposure to diverse microbes, the immune system fails to produce enough Tregs. It remains “uneducated” and trigger-happy.

This mismatch is driving an explosion of autoimmunity in younger generations:

• Inflammatory Bowel Disease (IBD): Once vanishingly rare in South Asia, conditions like Crohn’s and Ulcerative Colitis are skyrocketing in the diaspora. In Canada, South Asian immigrants now have one of the fastest-growing rates of IBD in the country, often presenting with more aggressive disease than Caucasians.

• The Skin-Gut Axis: Eczema and psoriasis are often the first visible signs of this. These aren’t just “skin conditions,” they are external signals of a gut barrier that has lost its integrity.

• Asthma & Allergies: Asthma rates in diaspora children have surged, often surpassing their non-immigrant peers.

Gut-Brain Connection

As we already know well about the Gut-Brain Axis, a mention on its impact.

The gut produces roughly 90% of your body’s serotonin, the neurotransmitter that regulates mood, sleep, and gut motility. This process depends heavily on microbial metabolites.

When the gut is inflamed and dysbiotic, something shifts. Pro-inflammatory signals commandeer the pathway that makes serotonin and divert it toward producing neurotoxic compounds instead. The result is a double blow: less serotonin for your brain, plus inflammatory metabolites that cross the blood brain barrier.

This helps explain why South Asian immigrants, already facing acculturation stress, family separation, and discrimination, may have a lower biological threshold for depression and anxiety. One in five US South Asians reports experiencing a mood disorder in their lifetime. The gut isn’t the only factor. But it is a significant one that rarely gets discussed.

Reclaiming the Internal Ecosystem

The situation is urgent, but not hopeless.

Understanding that our health issues are ecological rather than just genetic gives us a new lever for change.

1. Feed the guild. Prioritize complex, cellular fibers, whole mung beans, steel-cut oats, fibrous vegetables. Not “whole wheat” flour.

2. Revive the Bifido-Shield. Don’t rely on sweetened store bought yogurt. Reintroduce traditional fermented foods, homemade 24-hour fermented dahi, idli/dosa batters fermented naturally, kanji.

3. Filter the oils. Eliminate high Omega-6 vegetable oils in favor of traditional fats (ghee, mustard oil) or olive oil.

A Note on Reversibility: Reclaiming your biome is possible, but reversibility has limits. Some microbial extinctions in the second generation can be permanent. This makes early intervention, especially for children, critical.

Migration changed our biology. It is up to us to adapt our lifestyle not just to fit the country we live in, but to respect the ancient ecosystem we carry within us.

But this is only part of the story.

In Part II, we will follow where these gut toxins travel next, directly to your mitochondria, the power plants of every cell in your body. And we will explore why fixing the gut might be the first step to fixing your energy, your metabolism, and your longevity.

This is Part I of a three-part series on the South Asian gut. As always any feedback is greatly appreciated. Please share with those you think would enjoy this.

-Omar

Goal remains the same…South Asian health optimization.

In Part I, we mapped the architecture of South Asian sarcopenia: the fetal programming that sacrifices muscle for fat, the dissociated mitochondria running hot, and the hormonal axes that compound it all. We established that muscle is not merely mechanical tissue but a metabolic organ.

The question now is what to do about it.

What follows is a comprehensive structure on how we can approach it.

The Intervention Architecture

If the South Asian body is built for conservation, storing fat, minimizing muscle, rationing energy, then the intervention strategy must be designed to override these defaults. It must be aggressive, multimodal, and sustained.

Consider how we approach dyslipidemia in South Asians which we touched a bit on Chai Shots earlier this month. We do not tell a patient with Lp(a) of 150 nmol/L to “just eat better.”

We recognize that the genetic architecture is set, that lifestyle alone, while necessary, cannot overcome the magnitude of the inherited risk.

We layer interventions: diet modification, exercise, and pharmacology working in concert. We monitor biomarkers. We titrate aggressively.

Sarcopenia in South Asians demands the same approach. The upregulated myostatin signaling suppressing hypertrophy, the developmental programming favoring fat over muscle, the mitochondria running hot but failing to clear lipids, these are not lifestyle problems with lifestyle solutions. They are genetic headwinds requiring metabolic intervention.

The current clinical approach, ”lift weights, eat protein,” is analogous to telling someone with familial hypercholesterolemia to reduce saturated fat. It is not wrong. It is woefully insufficient.

What follows is a comprehensive architecture built on three pillars:

• exercise programming (not generic, but South Asian-specific)

• peri-exercise optimization (what you do before and after matters as much as the training itself)

• pharmacological support (the interventions that address what lifestyle cannot).

This is not a menu of options. It is a layered framework that begins with non-negotiable foundations and builds upward toward targeted enhancement.

Foundation Layer: South Asian-Specific Exercise Programming

1. Volume and Frequency

Meta-analyses show resistance training at 70-85% of one-repetition maximum produces the greatest gains. However, for South Asians fighting myostatin-mediated suppression, the volume must exceed generic guidelines.

• Target: 3 - 4 sessions/week.

• The Reasoning: The signal must be louder to overcome the genetic noise. If you train infrequently, the conservation-programmed body simply reverts to baseline. You must present a constant demand that makes muscle maintenance a survival priority.

2. Compound Movements First

The largest glucose sinks in the body are the legs, glutes, and back. Squats, deadlifts, rows, and presses help build this as a core.

• The Reasoning: These muscles, when developed, create the metabolic runway we lack. Isolation exercises (like bicep curls) have their place, but they cannot substitute for the systemic anabolic signal that compound movements generate.

3. Time Under Tension & Eccentrics

Moving weight is not enough. The muscle must experience sustained mechanical tension to trigger the mTOR pathway.

• The Tactic: Controlled eccentrics (lowering phase), pauses at the bottom, and deliberate tempo.

• The Reasoning: Rushing through sets with momentum defeats the purpose. You must mechanically stress the tissue to signal to a conservation-programmed body: this expensive tissue is needed for survival.

4. Velocity Training (The Spark Plug)

Sarcopenia begins with motor neuron death, specifically the fast-twitch Type II neurons. If you never ask them to fire, they atrophy. Asians usually have significantly less Type II (fast-twitch) muscle fiber density compared to other populations..

• The Tactic: Move weights fast. The concentric phase (lifting) should be explosive. Consider “velocity days” with lighter loads (50-60% 1RM) moved with maximum speed.

• The Reasoning: Traditional “slow and controlled” lifting builds tension but misses the neural component. Explosive movement keeps the “spark plugs” (motor neurons) firing, preventing the neural disconnect that precedes muscle loss.

5. Capillary Density: The Last Mile

South Asian muscle often shows lower capillary density. You can flood the bloodstream with nutrients, but if the “last mile” infrastructure is sparse, the muscle starves.

• Intervention: Heat therapy (Sauna: 15-20 mins at 170-190°F, 3-4x weekly).

• The Reasoning: We have discussed the engine (mitochondria) and the fuel (lipid overflow), but not the road. Sauna use is one of the few interventions that stimulates angiogenesis (new blood vessel growth) independent of mechanical load, building the infrastructure for future training.

  • This reinforces the nitric oxide interventions discussed below, citrulline and beetroot are not merely for “the pump.” They are for vascular recruitment, opening collateral pathways to reach under-perfused tissue.

  • Additionally, heat therapy (sauna, 15-20 minutes at 170-190°F, 3-4 times weekly) is one of the few interventions that stimulates angiogenesis, the growth of new capillaries, independent of mechanical load. For the sarcopenic patient who cannot yet train intensely, sauna builds the infrastructure that will eventually support training.

6. Zone 2 for Metabolic Flexibility

By far my favorite…because it rewards patience and consistency. And I want to spend some time on the nuances here as Zone 2 spans a broad definition.

Resistance training alone does not clear the intramyocellular lipid trap. For that, you need aerobic work that preferentially burns fat.

Zone 2 cardio (heart rate 60-70% of maximum, conversational pace, 3-4 hours weekly) remains the foundation for this population. Lower baseline muscle mass and metabolic dysfunction make high-intensity work riskier, Zone 2 offers benefit without the same injury risk or stress load. More importantly, Zone 2 specifically trains fat oxidation pathways and is the only intensity that that upregulates MCT-1 transporters, the machinery that clears lactate. Since metabolically inflexible individuals often run with elevated baseline lactate, Zone 2 addresses this dysfunction directly in a way HIIT cannot. As capacity develops, higher-intensity work can be layered in.

The training stimulus requires nutritional support. Protein intake of 1.6-2.0 g/kg/day of ideal body weight, far higher than the 0.8 g/kg RDA designed for sedentary populations, is the threshold for supporting muscle protein synthesis in a body fighting innate headwinds geneticall. The lower recommendations (1.0-1.2 g/kg) are insufficient when starting from sarcopenic baseline.

Critical to understand: older or insulin-resistant muscle becomes “deaf” to protein signals. You need to exceed a threshold to trigger growth. Leucine, the amino acid that most potently activates the mTOR pathway governing muscle growth, must reach approximately 3.0g per meal to reliably stimulate muscle protein synthesis.

Here is the math based on traditional South Asian diets to provide sufficient protein for muscle building:

Food Source Amount Needed for 3g Leucine Whey protein isolate 1 scoop (25g) Chicken breast 120g (one palm-sized portion) Paneer 200g Greek yogurt 400g Dal (lentils) ~2.5 cups thick / ~9 bowls typical Rice + dal combined Still insufficient without fortification

The reality is that atypical bowl of dal contains roughly 0.5g of leucine which is not nearly enough. To hit the leucine threshold from dal alone, you would need to eat over 2.5 cups of thick lentils or nearly 9 bowls of typical homemade dal (almost a full cooker worth!!) in a single sitting. This is not a cultural judgment; it is a mathematical reality. For the vegetarian South Asians, supplementation is a necessity.

This is where cultural dietary patterns often collide with physiological need. Plant-based South Asian diets can provide adequate protein, but they require intention, combining rice with dal, emphasizing paneer and yogurt, adding whey or EAAs to meals. The casual vegetarianism that many families practice is not automatically sufficient for someone trying to build metabolic reserve.

Peri-Exercise Optimization: What Happens Before and After

Read more

There is a scene that repeats itself in clinics across the world, in SF, NYC, in Leicester, in Dubai, in Bangalore, so often that it has become almost invisible. A South Asian man, let us call him Raj, sits on an examination table. The paper beneath him crinkles. The fluorescent light hums. The doctor, who is usually kind, usually competent, usually pressed for time, glances at a chart and delivers the verdict: BMI of 24, blood pressure acceptable, cholesterol within range. “You’re healthy,” the doctor says. “Keep doing what you’re doing.”

Raj buttons his shirt. He feels relieved. He should not.

A little over a year ago, I started this blog to understand what I was seeing in my own family.

An uncle who was on top of his health, yet, had a heart attack way too young. A family history littered with cardiovascular disease, stroke, early diabetes among those athletic and active. As a physician, it made little sense to me, until I started reading…and then it made even less sense. The literature rarely covered us. The studies weren’t designed for us. The answers I was looking for didn’t exist.

So I went looking myself. And what I found was an area somewhat undiscovered, but rarely addressed, especially for those of us in the diaspora, where the compounding effects of ancestry and environment collide in ways no one is tracking.

One in four.

That is how many of us there are. South Asians constitute roughly a quarter of the world’s population. We are not a minority in any meaningful sense. We are, by sheer arithmetic, one of the largest coherent biological populations on Earth.

And yet the medicine we receive was not built for us.

The reference ranges on our lab work, the BMI charts on clinic walls, the dosing guidelines in pharmaceutical inserts, all calibrated on bodies in Western nations.

When these protocols are applied to us, they do not merely underperform. They mislead. They harm. They kill, sometimes, while telling us we are fine.

You know this already. You have watched it happen. There is a particular grief in seeing your family members fall, one by one, to diseases that were “managed” but never prevented. In hearing “your numbers look good” while sensing that something is wrong. In knowing that the medical system sees you but does not see the specific body you inhabit.

We are entering an extraordinary moment in medicine. The age of precision is arriving. n=1 care, gene therapies, treatments targeted not to populations but to individuals. Continuous monitoring, computational biology, interventions calibrated to your specific genome and metabolism. For the first time in history, we can move beyond the average.

But here is the cruelest irony: even this revolution threatens to leave us behind. The new tools, the wearables, the biomarker panels, the advanced diagnostics, still interpret your data against thresholds derived from bodies that do not share your biology. You can wear the devices, run the panels, book the scans, and still be told a story about yourself that is not true. A more expensive lie. A more granular lie. But a lie nonetheless.

The technology exists to see you clearly. What has been missing is the will to recalibrate.

We are not waiting for the system to notice us.

The traditional path runs through decades of trials that excluded us, guidelines that will arrive too late for our parents, acknowledgment that may never come. We are building something else.

Interpretation that begins with South Asian biology as the baseline, not the exception.

Synthesis that connects your data streams through a lens that actually applies.

Medicine that at default, assumes you are unique, and that your uniqueness has a context shaped by ancestry, by evolution, by the specific body you inherited.

This is what precision medicine was always supposed to be. We are building it for us, because no one else will.

Here is what we are working toward:

A new framework for South Asian health. Research that should have existed decades ago. Tools that give you the perspective on your own biology that you deserve, not as an afterthought, not as a subgroup analysis buried in an appendix, but as the foundation.

We are working with some of the best physicians in this space to make it happen. More on this very soon.

What started as a problem I was solving for my own genetics, is a problem one in four face around the world.

This is bigger than a blog. This is the beginning of something we should have had all along.

At zinda.health you will find tools and calculators that give a true picture of South asian health, with targets that actually are normal for our bodies. Our hope is to provide more tools and research which will always be available and published on this Substack.

This is Zinda. The word means “alive.”

It is what we intend for you to be.

One in four human beings will not wait quietly to be noticed.

One in four. Irreducible. Finally, fully seen.

Welcome.

-Omar

Due to the depth and detail of this article, I have decided to split it into two parts. First dives into foundational knowledge of how the south asian muscle works and the why. Part 2 will focus on interventions and protocols.

Secondly, I have some big news (some hints hidden in the post) on what is coming soon as we work on building a new framework for South Asian health and optimization.

Would love your feedback on these, as always!

In 2004, two scientists stood side by side in Pune, India, and posed for a photograph that would quietly revolutionize how we think about South Asian metabolism.

Dr. Chittaranjan Yajnik, an Indian diabetologist, and Dr. John Yudkin, his British collaborator, had identical BMIs: 22.3 kg/m². By every standard measure, they were metabolically equivalent. The photograph told a different story. When body composition was measured, Yajnik, the thinner-appearing of the two, carried 21.2% body fat. Yudkin carried 9.1%.

Same BMI. More than double the fat. The Yajnik-Yudkin Paradox, as it came to be known, captured something clinicians treating South Asian patients had intuited for decades: we are not built the same.

But here is what that famous photograph did not show, what no photograph could show: the corresponding poverty in Yajnik’s muscle tissue. The fat that his body composition analysis revealed was not merely present; it had displaced something. And that something, the lean mass that should have been there, the contractile tissue that burns glucose and generates power, was conspicuously, dangerously absent.

This is the story of that absence. Of how South Asians, from the moment of our first breath, are predisposed toward a peculiar form of metabolic fragility: abundant fat wrapped around insufficient muscle, a physiology optimized for surviving famine that now kills us in the age of plenty.

If you’ve been following our map-building project, the mitochondria, the beta cells, the adipocytes, the hormonal axes, this is where another critical piece snaps into place. Sarcopenia is not merely one more problem to add to the list. It is the structural foundation upon which all the other problems rest.

It is also a story about what we can do to rewrite this inheritance.

The Organ You Didn’t Know You Had

Before we go further, a reframe is necessary. When most people hear “muscle,” they think of the gym, of strength, aesthetics, the ability to lift heavy things. This is a catastrophic misunderstanding.

Muscle is not primarily a mechanical tissue. It is a metabolic organ, the largest in the human body, and arguably the most consequential for metabolic health. Skeletal muscle is responsible for approximately 80% of insulin-stimulated glucose disposal. When you eat carbohydrates, the vast majority of that glucose should be pulled into muscle tissue. If the muscle isn’t there, or isn’t functioning properly, that glucose has nowhere to go. It stays in the bloodstream, drives compensatory insulin secretion, and eventually overwhelms the system. The pancreas fails not only because it is inherently weak, but because the tissue that should be absorbing its signal has atrophied.

But muscle does more than absorb glucose. It is an endocrine organ, secreting a family of signaling molecules called myokines that regulate metabolism, inflammation, and even cognition throughout the body. Interleukin-6 (IL-6), released during muscle contraction, improves insulin sensitivity and mobilizes fat. Irisin converts metabolically inactive white fat into thermogenic brown fat. Brain-derived neurotrophic factor (BDNF) supports neuroplasticity and cognitive function. When muscle contracts, it is not merely generating force, it is broadcasting hormonal signals that coordinate systemic health.

This reframes sarcopenia entirely.

Losing muscle is not just “getting weak.” It is organ failure, the progressive loss of a tissue that regulates glucose, modulates inflammation, and communicates with every other organ system in the body.

When a South Asian loses muscle mass, they are not just losing strength. They are losing the metabolic buffer that protects them from diabetes, the inflammatory regulator that protects them from cardiovascular disease, and the glucose sink that their fragile beta cells depend on.

The liver fails visibly; we call it cirrhosis. The kidney fails measurably; we track creatinine and GFR. But muscle fails silently, over decades, and we have no routine screening for it. By the time weakness becomes apparent, the metabolic damage is already done.

This is the organ we need to protect.

Born Different

The thin-fat paradox does not begin in middle age. It does not begin in the sedentary years of desk work and evening sweets. It begins in the womb.

The Pune Maternal Nutrition Study (as we discussed last week) documented something remarkable: Indian newborns, compared to white Caucasian babies born in the UK, averaged nearly 800 grams lighter at birth. They had thinner arms and legs, visibly less muscle. But their subscapular skinfolds, the fat deposits on their backs, were preserved. Fat was protected. Muscle was sacrificed.

This is not pathology. This is programming.

The body of a South Asian infant emerges into the world with clear metabolic priorities: store energy, conserve resources, prepare for scarcity. These are the instructions written into our developmental biology by millennia of agricultural subsistence, seasonal famine, and vegetarian diets that provide adequate but not abundant protein. The instructions make sense in a world of periodic hunger. They become a liability in a world of constant abundance.

Skeletal evidence spanning 11,000 years reveals that South Asians have consistently demonstrated lower bone breadth relative to height compared to other populations. This is not recent. This is ancient. We carry a body plan that was optimized for a different era, an era when being metabolically “efficient” meant survival.

The problem is that metabolic efficiency, in the modern context, translates to a simple and devastating reality: we build muscle poorly, store fat readily, particularly in visceral depots that we’ve previously called The Overflow Tank—and develop diabetes at BMIs that Western medicine considers normal.

The Genetic Blueprint for Less

If the thin-fat phenotype is written into our developmental programming, it is also encoded in our DNA.

At the center of muscle regulation sits a gene called MSTN, located on chromosome 2q32.2. This gene produces myostatin, a protein whose name translates, roughly, to “muscle stopper.” Myostatin acts as a molecular brake on muscle growth. When myostatin signaling is disrupted, the results are dramatic: Belgian Blue cattle, with their famous double-muscling, carry myostatin mutations. So did a German child identified in 2004 who, at five years old, could hold seven-pound weights horizontally with his arms extended.

South Asians do not carry the dramatic loss-of-function mutations that produce these exceptional cases. We carry something more subtle and more insidious: evidence of genetic selection near the MSTN gene that appears to favor reduced muscle mass. In North Indian populations, MSTN variants have been directly associated with lower lean body mass. The A55T polymorphism (rs1805065), common in Asian populations, is linked to both reduced muscle mass and obesity predisposition.

What does this mean in practice?

But myostatin is not the only genetic brake. The ACTN3 gene, sometimes called the “speed gene,” produces alpha-actinin-3, a protein concentrated in fast-twitch muscle fibers that enables explosive power. The R577X polymorphism (rs1815739), which results in complete absence of this protein, is more prevalent in South Asian populations. Carriers have reduced fast-twitch fiber function: less explosive strength, less hypertrophy potential, and potentially accelerated age-related muscle loss in the very fibers that matter most for metabolic health.

The consequences cascade outward. Muscle tissue is not merely structural. It is the body’s largest glucose sink, the primary site where insulin-mediated glucose disposal occurs. Less muscle means less metabolic runway. Less runway means the pancreas must work harder to clear circulating glucose. And the South Asian pancreas, it turns out, is also starting from a position of disadvantage.

The “fragile beta-cell hypothesis“ proposes that South Asians possess reduced pancreatic beta-cell reserve, the insulin-producing capacity that buffers metabolic stress. This may result from intrauterine undernutrition, genetic predisposition, or both. If you remember, we described this as The Fragile Engine, the 4-cylinder motor, but here in the contex t of muscle. The IDF’s recent recognition of Type 5 Diabetes has begun to validate this understanding institutionally. The implication is stark: we arrive in adulthood with smaller muscles to absorb glucose and weaker pancreases to manage it. Two strikes before we’ve even begun.

The Flooded Engine

Now we come to the level of the cell, in the the mitochondria. Here, too, the South Asian story is one of dysfunction. But the nature of that dysfunction is more nuanced than simple deficit.

A landmark multi-ethnic study (highly recommend reading full study and something we may dive deeper into) examining muscle biopsies from older adults in Singapore, the UK, and Jamaica found that sarcopenia, regardless of ethnicity, is characterized by a profound transcriptional signature of mitochondrial dysfunction. The genes responsible for oxidative phosphorylation are downregulated. The master regulators of mitochondrial biogenesis PGC-1α and its partner ERRα, are suppressed. This is the end-stage picture: the cellular machinery winding down.

But the beginning of the story is different. Research by Dr. Sree Nair demonstrated something counterintuitive: insulin-resistant South Asians often show preserved or even enhanced mitochondrial capacity compared to Caucasians. The engine isn’t weak. It isn’t lazy. It is flooded.

This is what we call the dissociation hypothesis. Studies on South Asian muscle reveal a paradox, the mitochondrial machinery is present and working furiously, but it is overwhelmed by the lipid overflow characteristic of our phenotype. There’s a disconnect between insulin signaling and fuel oxidation. The mitochondria are gridlocked, not idling.

This creates the intramyocellular lipid trap. In a trained athlete, fat stored inside muscle cells is rapidly mobilized and burned. In the typical South Asian phenotype, that fat accumulates faster than it can be cleared. The mitochondria are working, but they cannot oxidize the lipid fast enough to keep up with the influx. The fuel backs up. And when fat sits inside a muscle cell without being burned, it becomes toxic, converting into harmful intermediates like diacylglycerols (DAGs) and ceramides that directly impair insulin signaling.

Your cells are steeped in fuel they are desperately trying to burn. It is not a power failure, it is a traffic jam at the cellular level. This explains why we are thin-fat: we are burning energy, but inefficiently, with much of it lost to futile cycling rather than productive work.

Over time, this chronic overload leads to burnout. The transcriptional downregulation documented in sarcopenic muscle, the suppression of PGC-1α, the reduced expression of electron transport chain complexes, is not where the story begins. It is where the story ends, after years of the flooded engine running at redline.

What does this look like functionally? Perturbed NAD+ metabolism, disruptions in both the biosynthesis and salvage pathways of nicotinamide adenine dinucleotide, the essential cofactor that mitochondrial respiration depends upon. NAD+ sits at the crossroads of energy metabolism and cellular repair. When NAD+ levels fall, as they do with age, metabolic disease, and chronic overload, the consequences ripple outward: reduced ATP production, impaired DNA repair, accelerated cellular senescence. Sarcopenic muscle consistently shows depleted NAD+, the molecular signature of an engine that has finally given out.

For South Asians, the mitochondrial story layers onto all the other stories. We begin with less muscle. That muscle contains mitochondria that may be genetically predisposed toward tight coupling, the kind we’ve previously called The Prius Problem: excellent fuel economy under normal conditions, but hitting capacity quickly when demand spikes. Then we flood those tightly-coupled mitochondria with lipid overflow from our constrained adipose tissue. Chronic hyperinsulinemia and inflammation compound the damage.

The engine is not merely small. It is drowning.

The Hormonal Conspiracy

The assault on South Asian muscle extends beyond genetics and mitochondria into the endocrine system, the network of hormones that orchestrate growth, repair, and metabolism.

Consider growth hormone and IGF-1, the anabolic signaling axis that promotes muscle protein synthesis. In South Asian men, this axis is frequently suppressed by high levels of circulating free fatty acids and intramuscular fat infiltration, direct consequences of the thin-fat phenotype. Obesity, even at normal weight, creates a hormonal environment hostile to muscle growth.

The adipokine profile compounds the problem. Adiponectin, the “good” fat hormone that enhances insulin sensitivity and supports muscle health, is consistently lower in South Asians than in other populations, a phenomenon we explored in depth in The Silent Letter. Resistin, which promotes insulin resistance and impairs muscle anabolism, is elevated. The fat tissue that South Asians accumulate preferentially is not metabolically neutral, it is actively antagonistic to muscle.

Even ghrelin, the “hunger hormone” that typically stimulates growth hormone release and promotes anabolism, behaves paradoxically. South Asian men demonstrate lower fasting ghrelin levels compared to BMI-matched Europeans, the same phenomenon we explored in The Ghrelin Paradox. This may be an adaptation to chronic adiposity, but it blunts the muscle-building signals tied to food intake and removes the protective “brake” on beta cell insulin secretion.

And in women, menopause delivers an additional blow. The loss of estrogen increases oxidative stress, accelerates mitochondrial dysfunction, and promotes fat infiltration into muscle tissue. The South Asian woman navigating menopause is contending not merely with universal hormonal changes, but with those changes superimposed on an already compromised muscular foundation.

The Liver-Muscle Axis

The metabolic web extends beyond adipose tissue to involve another organ that has become emblematic of South Asian metabolic dysfunction: the liver.

Non-alcoholic fatty liver disease (NAFLD) and sarcopenia are not merely co-travelers. They are co-conspirators. A meta-analysis examining this relationship found that Asians with NAFLD had nearly double the odds of sarcopenia (OR≈1.97), whereas in Western populations, this link was weak or absent.

The mechanism is bidirectional. A fatty liver pumps out inflammatory cytokines and releases excess free fatty acids into the bloodstream, both of which impair muscle protein synthesis and accelerate breakdown. Simultaneously, sarcopenic muscle loses its capacity to dispose of glucose effectively, worsening insulin resistance and driving more fat accumulation in the liver. Each organ’s dysfunction amplifies the other’s.

This liver-muscle crosstalk may be particularly impactful in South Asians because we arrive at the table with both organs already under stress. The “TAFI” phenotype, thin arms, fatty liver, insulin resistance, is not an aberration in this population. It is, increasingly, the norm.

Diagnosis in a Population Built Different

Here is a case we see far too often (and what inspired this Substack initially): a 55-year-old South Asian man walks into your office. His BMI is 23. His waist-to-hip ratio is elevated. His fasting glucose is 105 mg/dL, prediabetic by some criteria, “almost fine” by others. You measure his grip strength, and it is adequate. His leg muscle mass, quantified by DXA, appears normal.

By conventional criteria, he does not have sarcopenia. And this is where conventional criteria fail.

Studies from India have demonstrated that prediabetic and diabetic South Asians often show normal leg muscle mass but significantly reduced strength compared to healthy controls. Function declines before mass. The muscle is present but incompetent, unable to generate force or efficiently contract. Measuring mass alone misses the disease entirely.

The emerging consensus for diagnosing sarcopenia in South Asians recommends requiring two of three criteria: low mass, low strength, or poor physical performance, all measured against South Asian-specific reference values.

Grip strength and chair-stand tests become as important as DXA scans.

The question shifts from “how much muscle?” to “how well does the muscle work?”

And the clinician must remain alert for “normal-weight obesity”, the patient whose BMI registers in the healthy range while their body composition tells a different story. Central adiposity, fatty infiltration of muscle, and insulin resistance can coexist with a scale readout that reassures everyone in the room except the patient’s metabolism.

The Cystatin C Correction: There is a diagnostic trap specific to sarcopenic patients that deserves attention here. Creatinine, the standard marker for kidney function, is a byproduct of muscle breakdown. A sarcopenic South Asian has low muscle mass, which means low creatinine production. This artificially inflates their eGFR (estimated glomerular filtration rate), potentially masking significant kidney disease behind a “normal” result.

The fix: demand Cystatin C. Unlike creatinine, cystatin C is produced by all nucleated cells and is independent of muscle mass. If a patient has “normal” creatinine-based eGFR but elevated cystatin C, you have uncovered sarcopenic kidney misinterpretation, and potentially caught kidney dysfunction that would otherwise have been missed until much later. For the thin-fat South Asian patient, cystatin C is the truth-teller.

What Comes Next

We have mapped the problem: the fetal programming that sacrifices muscle for fat, the genetic architecture that limits hypertrophy, the mitochondria that hit capacity at lower thresholds, the intramyocellular lipid trap that paralyzes what muscle remains, and the hormonal conspiracy that compounds it all. We have established that muscle is not a mechanical tissue but a metabolic organ, and that losing it is a form of organ failure that precedes and predicts the cascade of cardiometabolic disease.

The question now is what to do about it.

In Part II, we will build the intervention architecture: South Asian-specific exercise programming, peri-exercise optimization, the supplement layers that support mitochondrial function, and the emerging pharmacological approaches that address what lifestyle cannot. We will move from diagnosis to action, from understanding why we are built different to engineering a different outcome.

-Omar

This article is for educational and informational purposes only and does not constitute medical advice. The information presented reflects current research and should not replace consultation with qualified healthcare providers. Individual treatment decisions, particularly regarding prescription medications, peptides, and supplements, should be made in partnership with your physician based on your specific circumstances.

If you’ve been following lipid management guidelines, you’ve probably heard about PCSK9 inhibitors, the “miracle drugs” that cut LDL-C by 50-60%. Repatha, Praluent, and the newer siRNA agent inclisiran have transformed cardiovascular prevention.

So here’s the uncomfortable question to ask: What if this entire therapeutic strategy was optimized for the wrong population?

Lipids are heavily genetics driven, and this is something we’ll explore through research.

Two studies published in the past six months suggest exactly that, lets dive in.

Yes…Grab some chai.

The PCSK9 Pump Problem

A Mendelian randomization study from The Lancet Regional Health – Southeast Asia examined the “proteomic architecture” of lipid metabolism across ancestries. The headline finding: PCSK9’s effect on LDL-C is 57% weaker in South Asians compared to Europeans.

The numbers are striking. The beta coefficient for PCSK9’s effect on LDL-C was 0.37 in Europeans versus just 0.16 in South Asians (95% CI: 0.11–0.21). This isn’t a subtle difference, it’s a fundamentally different relationship between the protein and the lipid.

The study identified why. In Europeans, PCSK9 functions like a master pump, genetically encoded variation in PCSK9 strongly predicts LDL-C levels and cardiovascular outcomes. Block the pump, solve the problem.

In South Asians, the pump is still there, but it’s not the main driver. Instead, three alternative pathways emerge as more impactful:

CELSR2 — This gene showed novel causal association with coronary artery disease specifically in South Asians, with strong Bayesian colocalisation evidence (PPH4 >80%) across multiple lipid fractions. (see table below)

ANGPTL3 — Its causal role in South Asian dyslipidemia was confirmed, with strong colocalisation with all lipid fractions except HDL-C.

Lp(a) — The genetic wildcard that keeps showing up in South Asian cardiovascular research, with confirmed colocalisation with LDL-C and total cholesterol.

The Genetics Deep Dive

This is where it gets interesting for those who’ve had pharmacogenomic testing or are considering it. One of my favorite areas to write about.

PCSK9 Variants: Population-Specific Effects

The R46L variant (rs11591147) is the poster child for PCSK9 loss-of-function genetics. According to research published in The New England Journal of Medicine, in Europeans:

• Carriers have ~15% lower LDL-C

• 47-50% reduced risk of coronary heart disease

• Enhanced response to statin therapy

• Lower Lp(a), lower VLDL particle concentrations, lower inflammatory markers

The problem for South Asians: R46L is rare in Asian populations. Studies in Chinese populations found zero carriers of this protective variant. The allele frequency is approximately 3.2% in Europeans but <1% in South Asians, meaning this genetic “get out of jail free card” is largely absent in our population.

Other protective PCSK9 loss-of-function variants (Y142X, C679X) are similarly rare or absent outside European and African-American populations.

SOmething to think about. If you’re South Asian and your PCSK9 inhibitor isn’t hitting targets as expected, this may (stress on may) explain why. The genetic variants that predict excellent response are underrepresented in our population.

The 1p13 Locus: CELSR2/SORT1

The chromosome 1p13 locus is one of the strongest genetic signals for LDL-C and CAD in GWAS studies. The key variant is rs12740374, which:

• Creates a C/EBP transcription factor binding site

• Alters hepatic expression of SORT1 (sortilin-1), affecting VLDL secretion and LDL clearance

• The minor (protective) allele increases SORT1 expression up to 10-fold

Here’s what makes this South Asian-relevant: The C4D Consortium found that the effect size of SORT1-related variants on CAD was significantly lower in South Asians than Europeans. What’s protective in Europeans may be neutral, or potentially harmful, in South Asians due to different linkage disequilibrium patterns and gene-environment interactions.

The Lancet SEA study specifically identified CELSR2 as having novel causal relevance in South Asians, with strong colocalisation across LDL-C, HDL-C, total cholesterol, and non-HDL-C. This suggests the entire hepatic lipid handling apparatus at this locus may function differently in our population.

Key SNPs to know at this locus:

• rs12740374 (primary causal variant)

• rs629301 (CAD risk haplotype)

• rs599839, rs646776, rs660240 (all in strong LD)

LPA Gene Variants: The Lp(a) Story

Lp(a) genetics are notoriously complex, but here’s what matters clinically:

KIV-2 Repeat Number: The number of Kringle IV type-2 repeats in the LPA gene is inversely correlated with Lp(a) levels. Fewer repeats = smaller apolipoprotein(a) isoform = higher Lp(a) = higher risk. This is ~90% heritable and determines your lifetime Lp(a) trajectory.

rs10455872 (intronic SNP) and rs3798220 (causes amino acid change I4399M in the protease domain): These are the two most commonly tested Lp(a)-associated variants. According to the Journal of the American Heart Association, in Europeans, they:

• Tag small apo(a) isoforms

• Predict elevated Lp(a)

• Associate with 1.47x and 1.68x increased MI risk, respectively

• Combined genotype score shows 4.87x risk with two or more variant alleles

But here’s an interesting point for SAs (and something that illustrates precision therapy eloquently)

rs3798220 does NOT predict elevated Lp(a) in South or East Asians. A study published in Atherosclerosis examining this variant across ethnicities found:

• The variant allele frequency in Indian CAD cases was only 0.15%

• In Asians carrying rs3798220, there was no association with small KIV-2 alleles or elevated Lp(a)

• The haplotype structure is different, the same SNP sits on a different genetic background

This has major implications: Commercial genetic tests using rs3798220 and rs10455872 to predict Lp(a) risk will generate high rates of false negatives in South Asian populations.

For rs10455872 specifically: According to recent comprehensive reviews, the minor allele is absent or extremely rare in East Asian and South Asian populations. If you’re South Asian and tested “negative” for Lp(a) risk variants, you still need to actually measure your Lp(a) level.

What to do: Get your Lp(a) level measured directly (in nmol/L, not mg/dL for accuracy). Don’t rely solely on genetic proxies developed in European populations.

ANGPTL3: The Emerging Target

ANGPTL3 inhibits lipoprotein lipase and endothelial lipase, increasing circulating triglycerides and LDL-C. Loss-of-function mutations cause familial combined hypolipidemia, remarkably low levels of all lipoproteins with no apparent pathology.

Key SNPs:

• rs6690733 — The C allele increases ANGPTL3 expression and is associated with higher TC and LDL-C and increased ischemic stroke risk

• rs12563308 — The C allele is protective, associated with lower TC and LDL-C

The Lancet SEA study confirmed ANGPTL3’s causal role in South Asian dyslipidemia with strong genetic evidence. This is significant because ANGPTL3 inhibition works regardless of LDL receptor function, it’s a fundamentally different mechanism than statins or PCSK9 inhibitors.

Evinacumab (Evkeeza) is already FDA-approved for homozygous FH. Given the weaker PCSK9 effect in South Asians, ANGPTL3-targeted therapies may prove particularly relevant for our population.

Lp(a): Same Test, 2x the Risk

The INTERHEART study and subsequent analyses published in the Journal of the American Heart Association confirmed what cardiologists have suspected: elevated Lp(a) confers substantially higher MI risk in South Asians compared to Europeans.

Same biomarker. Same laboratory cutoff. Completely different clinical meaning.

Lp(a) matters. Siginificantly.

A thirty-year study published in JAMA this week showed very high Lp(a) levels were associated with 30-year risk of cardiovascular disease among healthy women.

According to the National Lipid Association, the prevalence of elevated Lp(a) (>50 mg/dL) is higher in South Asians (~25%) versus Europeans (~20%), but prevalence alone doesn’t explain the risk differential. There’s something about how Lp(a) interacts with South Asian vascular biology that amplifies its atherogenic potential, possibly related to our tendency toward smaller coronary vessels, higher inflammatory burden, and different lipoprotein composition.

2026 is be a big year

Especially for treatments that matter for South Asians

The next 12-18 months will be transformative for Lp(a). According to the American College of Cardiology and recent updates in Pharmacy Times:

Pelacarsen (antisense oligonucleotide) — The phase 3 Lp(a)HORIZON trial has enrolled 8,325 patients with established CVD. Lowers Lp(a) by ~80%. Results expected early 2026.

Olpasiran (siRNA) — Phase 3 OCEAN(a) trial (NCT05581303) has completed recruitment of over 7,200 patients. Phase 2 showed 94% Lp(a) reduction. Results expected December 2026.

Lepodisiran — Phase 2 ALPACA data showed >90% Lp(a) reduction with a single 400 mg dose, persisting for over 360 days. Phase 3 ACCLAIM-Lp(a) trial currently enrolling 12,500 participants.

Muvalaplin — Oral Lp(a) inhibitor showing 86% reduction in phase 2. Yes, oral.

The critical question.

Will these drugs show the same efficacy across ancestries? The genetic architecture differs significantly. Early data suggest efficacy isn’t dramatically affected by baseline isoform size or common LPA SNPs, encouraging, but real-world South Asian representation in these trials matters.

What This Means for Treatment

If you’re South Asian with dyslipidemia, the standard algorithm may be insufficient.

The precision approach:

1. Get Lp(a) tested directly. Not negotiable. Don’t rely on genetic proxies, the SNPs don’t work in our population. It’s a one-time test (levels are genetically fixed), and if elevated, it fundamentally changes your risk calculus.

2. Push harder on ApoB. ApoB captures all atherogenic particles, LDL, VLDL remnants, and Lp(a). Given our alternative drivers, ApoB may be a more meaningful target than LDL-C alone. Consider a target <60 mg/dL if high risk, <80 mg/dL for primary prevention.

3. Don’t abandon PCSK9 inhibitors, but manage expectations. 57% weaker doesn’t mean zero effect. These drugs still work; they just may not be the home run they are in Europeans.

4. Watch the ANGPTL3 space. Given the confirmed causal role in South Asian dyslipidemia and the PCSK9-independent mechanism, this pathway may prove particularly relevant.

5. Consider advanced lipid testing. LDL particle number, ApoB, Lp(a), oxidized phospholipids, these give a more complete picture than standard lipid panels.

The proteomic architecture of lipid metabolism isn’t uniform across humanity. We evolved under different dietary pressures, different infectious disease burdens, different metabolic demands. The genetic variants that protect Europeans from heart disease are often rare or absent in South Asians. The SNPs used to predict drug response don’t work in our population. The effect sizes of therapeutic targets differ by 50% or more. Yet we still barely have SNPs and other omic structures that can be harnessed for south asians, especially the diaspora underrepresented in populations.

The playbook is being rewritten. We’re the authors now. Make sure you’re reading the right edition.

-Omar

This is educational content. Work with your physician on any medication decisions. If you found this useful, please share it with a family member who should know their Lp(a) status or would be interested in learning more about their body. We are also working on building something for the South Asian diaspora. More on this next week!

References

It turns out this may be a hypothesis gaining momentum.

In April 2025, the International Diabetes Federation formally recognized Type 5 diabetes, a distinct phenotype characterized by profound insulin deficiency with preserved insulin sensitivity, arising from pancreatic underdevelopment due to chronic undernutrition. Twenty to twenty-five million people worldwide. Sixty-five percent in South and Southeast Asia. Last month, they have solidified this with a working group and concrete recommendations.

Many misdiagnosed as Type 2, started on metformin for insulin resistance they don’t have, while their actual problem, beta cell failure, goes unaddressed.

This isn’t new science. It’s institutional recognition of what the fragile engine framework already predicted: that the dominant South Asian diabetes phenotype is a secretion problem, not a resistance problem. And the test that distinguishes between them, C-peptide, remains almost universally ignored in diaspora clinical settings.

Seventy Years in the Wilderness

The history behind this matters, because it shows how long this knowledge has been available, and ignored; validating what we are working towards here.

Type 5 diabetes was first identified in 1955 in Jamaica by physician Hugh-Jones, who called it “J-type diabetes.”

Clinicians in India, Bangladesh, Ethiopia, and across sub-Saharan Africa subsequently described the same pattern: young, lean patients with severe hyperglycemia who didn’t fit the autoimmune profile of Type 1 or the insulin-resistant profile of Type 2.

In 1985, the WHO formally recognized it as “malnutrition-related diabetes mellitus.” Then, in 1999, they removed the classification due to “lack of evidence”; not because the patients disappeared, but because the research infrastructure to study them properly didn’t exist in the regions where they lived.

For twenty-six years, millions of patients with a distinct metabolic disorder were administratively erased. Clinicians in South Asia and Africa continued seeing them. The textbooks said they didn’t exist.

Dr. Meredith Hawkins, who now chairs the IDF Type 5 Working Group, first encountered these patients in 2005 while teaching at global health meetings. Doctors from multiple countries described patients with “an unusual form of diabetes,” young and thin, suggesting Type 1, but for whom insulin treatment was ineffective and sometimes fatal. “Malnutrition-related diabetes is more common than tuberculosis and nearly as common as HIV/AIDS,” Hawkins noted, “but the lack of an official name has hindered research and treatment.”

Her 2022 metabolic studies finally characterized the phenotype precisely: Type 5 patients showed lower insulin secretion than lean non-diabetics AND Type 2 diabetics, but higher insulin sensitivity than Type 2s. They respond well to insulin. They just can’t make it.

Seventy years from first identification to formal re-recognition. That’s the timeline when your population isn’t the default research subject.

The critical distinction: Type 5 patients are insulin-deficient like Type 1, but not from autoimmune destruction. They’re lean like Type 1, but don’t develop ketoacidosis. They don’t respond to metformin like Type 2, because they don’t have insulin resistance. They need insulin support, but giving them high-dose insulin (as you would Type 1) can cause fatal hypoglycemia because they retain insulin sensitivity.

This is why misdiagnosis kills. The treatment for each type is different, and applying the wrong one doesn’t just fail, it harms.

“But I Grew Up in Houston…Does This Apply to Me?”

Here’s where I need to make an important distinction, because the Type 5 framing can be misleading for some readers.

Type 5 diabetes specifically refers to the malnutrition-driven phenotype, pancreatic underdevelopment from chronic undernutrition during childhood. If you grew up in the US, UK, Canada, or the Gulf with adequate nutrition, you (likely) don’t have Type 5 in the strict sense.

But you may still have an insulin-deficient phenotype. And here’s why:

The fragile engine isn’t just a consequence of malnutrition. It appears to be a population-level characteristic.

The autopsy data showing 45% fewer large islets in Indian versus American pancreases wasn’t drawn exclusively from malnourished individuals. This reduced beta cell reserve appears to be a baseline feature of South Asian physiology, present even in well-nourished populations.

Three mechanisms explain why this applies to diaspora South Asians who grew up with plenty to eat:

1. Intergenerational epigenetic programming

Your beta cell capacity may have been shaped not by your own nutritional history, but by your mother’s, or your grandmother’s. Yajnik’s research showed that even UK-born Indian babies to well-nourished mothers still exhibit the thin-fat phenotype, higher body fat percentage, higher cord blood insulin, lower adiponectin. The developmental programming doesn’t reset in a single generation. The metabolic memory of scarcity travels across generations, even when the scarcity itself is gone.

2. Inherent islet architecture

There appear to be genetic factors (as we discussed in Chai Shots #003) affecting beta cell mass and islet organization that are more prevalent in South Asian populations, independent of any nutritional programming. This isn’t “damage” from malnutrition, it’s population-level variation in pancreatic reserve, likely shaped by millennia of evolutionary pressure in environments where caloric efficiency was advantageous.

3. The mismatch problem

Even without frank undernutrition, a metabolism optimized for lower caloric intake collides with Western dietary abundance. Your beta cells may have adequate capacity for a traditional South Asian diet but insufficient reserve for the caloric load of a standard American one. The engine isn’t broken, it’s just being asked to tow a trailer it wasn’t built for.

Think of it this way:

• Type 5 = the extreme, malnutrition-driven end of the spectrum

• SIDD = the broader insulin-deficient phenotype that includes Type 5 but also affects well-nourished diaspora South Asians

• The fragile engine = the underlying population-level characteristic that predisposes us to insulin deficiency regardless of personal nutritional history

The practical implication is the same: if you’re South Asian, whether you grew up in Chennai or Chicago, you cannot assume that your diabetes (or even prediabetes) is the insulin-resistant, metformin-responsive type. You need C-peptide measured to know what you’re actually dealing with.

It comes down to C-Peptide

C-peptide is cleaved from proinsulin in a 1:1 ratio when your pancreas secretes insulin. Unlike insulin itself (which is cleared rapidly and variably by the liver), C-peptide circulates with a stable half-life. It’s the direct readout of what your beta cells are actually producing.

Low C-peptide = your pancreas can’t make enough insulin => SIDD/Type 5 phenotype = needs secretagogues, GLP-1 agonists, or early insulin support

High C-peptide = your pancreas is overproducing insulin to compensate for resistance = classical insulin-resistant phenotype = metformin appropriate

This is not subtle. It isbinary information that changes the entire treatment approach. And yet in Western clinical practice, C-peptide is almost never ordered at diabetes diagnosis. The assumption is Type 2, the prescription is metformin, and if glucose doesn’t improve, the dose goes up. Two years later, A1c is 8% and by the time proper treatment has started, retinopathy in the eyes and worsening kidney function have done their damage.

The test exists. It’s cheap. It’s available. It’s just not being used; because (most) physicians managing our care were trained on populations where insulin-deficient diabetes is the exception, not a plurality.

If you’re South Asian living in the US, UK, Canada, or the Gulf, the physician managing your metabolic health almost certainly wasn’t trained on the INSPIRED data. They don’t know CIRDD exists. They’ve never heard of Type 5. They see a lean patient with elevated glucose and reach for metformin, because that’s what the guidelines say, because the guidelines were written for different bodies.

The Larger Pattern

We’ve spent the past year at Grasshopper Medicine building a framework piece by piece, the Fragile Engine, the Overflow Tank, the Ghrelin Paradox, the adiponectin deficit. Each piece pointed in the same direction. South Asian metabolic disease is driven by beta cell failure occurring earlier and at lower BMI than Western models predict, compounded by adipocyte dysfunction that removes the protective signals those fragile beta cells need.

The IDF’s recognition of Type 5 diabetes, and the INSPIRED study’s identification of SIDD and CIRDD as dominant South Asian phenotypes, is institutinal validation of this framework. The world is catching up to what the physiology already told us.

But validation doesn’t automatically translate to changed practice, especially not in diaspora settings where the research hasn’t penetrated. That translation is what we’re building; a clinical infrastructure that treats South Asian bodies as South Asian bodies, not as European bodies with inexplicably worse outcomes.

Seventy years from first identification to official recognition. The fragile engine finally has its diagnosis. Now comes the work of making sure the people who need to know actually learn it.

If you’re South Asian with diabetes and have never had C-peptide measured, you may want to look into it.

Happy New Year!

-Omar

Consider Terra Australis Incognita. For centuries, mapmakers drew a massive, non-existent continent at the bottom of the globe simply because philosophers believed the world needed “balance.” They assumed that for the Northern Hemisphere to exist, an equal mass must exist in the South.

Then there was the Island of California. For over a hundred years, maps depicted California as detached from the American mainland, floating on its own. It was a fiction born of wishful thinking and bad data, yet it persisted because it was easier to copy the mistake than to survey the coast.

And perhaps most striking reminder, the Mountains of Kong. From 1798 to the late 1800s, maps of Africa showed a massive mountain range stretching across the continent. It never existed. Mapmakers simply drew it there to fill a blank space they didn’t understand, preferring a detailed lie to an honest void.

Now consider a man who inherits a vast estate but has never walked its grounds. He knows it only by the old surveyor’s charts, boundaries drawn by someone else, for someone else, long ago. The land has shifted. The river has moved. The forest has grown where the meadow was marked. But he trusts the map because it is the only map he has.

This is the position of South Asian patients in modern medicine.

The reference ranges were drawn for other populations. The diagnostic thresholds were calibrated on different bodies. The treatment protocols were optimized for different metabolisms. And yet we trust them; because they are the only maps we have.

At Grasshopper Medicine, we decided to walk the grounds.

We started on this journey twelve months ago, and over the past year, we’ve been building a new framework for understanding South Asian physiology, not by importing conclusions from research that excluded us, but by returning to first principles. We started at the smallest scale and worked outward. Organelles. Cells. Tissues. Organ systems. Each layer examined on its own terms before asking how it connects to the next.

The logic is simple: you cannot build a house on a borrowed foundation. If the baseline assumptions are miscalibrated, everything downstream, diagnosis, risk stratification, intervention, inherits that error.

What emerges is not a picture of a population that is mysteriously sicker. It is a picture of a population whose biology was never properly mapped in the first place.

In the coming year, we go deeper. Build an architecture and framework that is actionable. We’re also working on building something truly powerful that brings what we have done to the millions around the globe.

The goal is and remains optimizing south asian health. And we can do this through a precision medicine protocol rooted in South Asian biology, designed to intervene before the cascade becomes irreversible.

We are drawing a new map. Building our own surveys, as we are all cartographers now.

-omar

On the Substack, we’ve spent the last few weeks building out a map of the South Asian metabolic phenotype with beta cells, ghrelin, mitochondrial efficiency, genotypes.

Today we add another layer: adiponectin.

You’ll need some chai for this as this will be the most in-depth piece we have done so far.

TL;DR

• South Asians reach the same diabetes risk at BMI 23.9 that White Europeans reach at BMI 30; a six-point gap that standard charts completely miss. The question is why our bodies cross metabolic thresholds so much earlier.

• Adiponectin is a big part of this, the most abundant hormone you’ve never heard of, secreted by healthy fat cells to keep metabolism in sync. It tells your liver to stop dumping glucose, tells your muscles to accept fuel, activates AMPK (the master energy switch), and suppresses inflammation. When it falls, the orchestra descends into chaos.

• South Asians have constitutively low adiponectin from birth, independent of obesity. MASALA study data shows our levels run 15-30% lower than White populations at matched BMI. This isn’t something we develop; it’s something we’re born with, written into ADIPOQ gene variants that affect both production and multimerization.

• There’s no adiponectin pill (we discuss why), but there’s a three-part intervention framework: (1) activate PPARγ to drive transcription (omega-3s, curcumin, TZDs in refractory cases), (2) bypass the missing signal by activating AMPK directly (HIIT, berberine, metformin), and (3) rehabilitate the sick adipocyte itself (GLP-1 agonists, SGLT2 inhibitors, resistance training, weight loss that preserves muscle).

• The practical approach: recalibrate your thresholds (BMI ≥23, waist ≥90cm men / ≥80cm women), request the right tests (fasting insulin, apoB, consider adiponectin), target visceral fat not just weight, and advocate for yourself, the clinical guidelines were built on European cohorts and systematically underestimate your risk.

You know the story. Your uncle, the one who walked five miles a day, never touched alcohol, wore the same 32-inch waist he had at his wedding, had a heart attack at 54. Your mother’s fasting glucose crept past 100 despite her being “thin.” Your cousin, a competitive swimmer in college, developed Type 2 diabetes before his 40th birthday. The doctor said his BMI was “normal.”

In South Asian families, we’ve learned to expect this.

We joke darkly about the “desi tax,” the sense that our bodies operate by different rules, that the metabolic dice are loaded against us.

What we haven’t been told is why.

The answer, or at least a central piece of it, is a hormone called adiponectin. And if you’ve never heard of it, you’re not alone. Most physicians don’t measure it. Most medical schools barely mention it. But understanding adiponectin may be the single most important thing you can do to make sense of why South Asian bodies fail in the specific ways they do, and what we can actually do about it.

The Paradox in the Exam Room

Picture this scene, repeated thousands of times daily across clinics in London, Toronto, Houston, and Mumbai:

A mid 30s South Asian man sits on an exam table. His BMI is 24.5, squarely “normal” by the chart on the wall. His total cholesterol is 195. His doctor smiles, tells him everything looks great, and suggests he come back in a year.

What the chart doesn’t show: this man has the visceral fat distribution of someone 50 pounds heavier. His liver is quietly accumulating fat. His fasting insulin is elevated, his pancreas is already working overtime to maintain normal glucose. Inside his fat cells, a silent inflammatory cascade is suppressing the very hormone that could protect him.

Five years later, he’ll be diagnosed with diabetes. Seven years after that, he’ll have his first cardiac event. His doctor will be surprised. He shouldn’t be.

A landmark UK study of 1.47 million people quantified what South Asian families have observed for generations: we reach the same Type 2 Diabetes risk at BMI 23.9 that White Europeans reach at BMI 30. That’s not a rounding error. It’s a six-point gap, the difference between “you’re fine” and “you need intervention now.”

Using standard BMI cutoffs, approximately 36% of South Asians with undiagnosed diabetes are told they’re healthy.

The question is: what makes our bodies cross the threshold so much earlier?

The Hormone That Should Be Protecting You

For most of medical history, we thought of fat as storage. Passive. Inert. A depot that expands when you eat too much and shrinks when you don’t. End of story.

We were completely wrong.

When I was in training as a medical resident, a mentor once told me that that we probably only know 10-15% of what the adipocyte actually dose. That we would find it to be consequential in ways unimagined. That stuck with me and was an inspiration. Not only into adipocytes, but to constantly think that there is always something we may not know, and a big reason for this Substack.

So what is the adipocyte?

The adipocyte, or the fat cell, is an endocrine organ. It synthesizes and secretes dozens of bioactive molecules called adipokines that communicate with your liver, muscle, pancreas, brain, and blood vessels. Your fat tissue isn’t just sitting there. It’s talking to the rest of your body constantly.

Think of adipocytes as sending messages.

Some letters are distress signals: “Help! I’m stressed, I’m hypoxic, I’m inflamed, send backup!” These are the pro-inflammatory cytokines like IL-6, TNF-α, and resistin. When your fat tissue is unhealthy, these letters dominate.

Other letters are status reports: “All systems normal. Metabolism running smoothly. Keep the gates open.”

Adiponectin is the most important of these protective letters.

It circulates at remarkably high concentrations 3 to 30 μg/mL, roughly 0.05% of your total serum protein. No other adipokine comes close to this abundance. Evolution invested heavily in adiponectin, which tells us its functions are fundamental to survival.

What Adiponectin Actually Does

When adiponectin binds to its receptors (AdipoR1 in muscle and brain, AdipoR2 in liver), it triggers a cascade that touches almost every aspect of metabolic health.

AMPK Activation: Adiponectin is one of the most potent physiological activators of AMPK, the master energy sensor. When AMPK switches on, your cells increase glucose uptake, ramp up fatty acid oxidation, and improve mitochondrial function. It’s the signal that says “burn fuel efficiently.” This, as we will learn further, it is of paramount importance in both metabolic function and mitochondrial functiona.

Hepatic Glucose Suppression: In the liver, adiponectin puts the brakes on gluconeogenesis. Less inappropriate glucose dumping into your bloodstream means less demand on insulin secretion to clean it up.

Insulin Sensitization: Through both AMPK-dependent and independent pathways, adiponectin makes your tissues more responsive to insulin. The doors to glucose entry stay open.

Ceramide Degradation: This one is underappreciated. Adiponectin receptors have intrinsic ceramidase activity, they directly break down ceramides, which are toxic sphingolipids that impair insulin signaling. Adiponectin doesn’t just improve insulin sensitivity through signaling; it physically removes one of the molecular species that causes resistance.

Anti-Inflammatory Effects: Adiponectin suppresses TNF-α and IL-6 while promoting anti-inflammatory cytokines. It keeps the immune system from attacking your own metabolic machinery.

Mitochondrial Biogenesis: Through the AMPK-PGC-1α axis, adiponectin drives the creation of new mitochondria. More mitochondria means more capacity to process energy without backing up.

When adiponectin is abundant, it acts like a skilled conductor keeping an orchestra in sync.

When adiponectin falls, the orchestra descends into chaos. Your liver ignores insulin’s signals. Your muscles become resistant. Inflammation rises. Fat accumulates in places it doesn’t belong; your liver, your pancreas, threaded through your muscle fibers. Your mitochondria, starved of the signal to burn efficiently, begin to sputter and produce reactive oxygen species instead of clean energy.

The Isoform Problem

One complexity worth understanding: adiponectin doesn’t circulate as a simple molecule. It assembles into multimeric complexes:

• trimers (low molecular weight)

• hexamers (medium molecular weight)

• large multimers of 12-18 subunits (high molecular weight, or HMW)

The HMW form is the most biologically active. It correlates most strongly with insulin sensitivity and cardiovascular protection. Women have higher HMW concentrations than men, which may partially explain sex differences in metabolic disease timing.

When adipose tissue becomes dysfunctional, HMW adiponectin falls first, the ratio shifts toward less active isoforms before total adiponectin even drops. A “normal” total adiponectin can mask significant early dysfunction if HMW has already cratered. This is the same pattern we see elsewhere and discussed previously: HOMA-IR missing beta cell decline, BMI missing visceral adiposity. The standard measurement hides the signal.

Note to physicians reading this: If you’re going to test (and in metabolically complex patients, you should consider it), HMW adiponectin is ideal. It’s not widely available, but total adiponectin is still informative, especially when it’s low in someone who appears lean or metabolically “normal” by conventional criteria. That discordance itself is diagnostic.

The Reference Range Problem

Here’s where precision medicine meets its limits, and where the research imperative for South Asian populations becomes acute.

Standard adiponectin reference ranges, typically cited as 2-20 μg/mL for total adiponectin, are derived from mixed or predominantly European cohorts. When your doctor orders this test (if they order it at all), the lab report will flag values as “normal” or “abnormal” based on these population norms.

For South Asians, this is worse than useless. It’s actively misleading.

A 2008 Diabetes Care study revealed something that should have rewritten clinical practice: researchers compared insulin-resistant versus insulin-sensitive women in both South Asian and Caucasian groups. In Caucasians, the expected pattern held, where insulin-resistant women had markedly lower adiponectin than insulin-sensitive women. The biomarker tracked the disease.

But in South Asians, there was no significant difference in adiponectin between insulin-resistant and insulin-sensitive individuals. A South Asian woman could have profoundly dysfunctional glucose metabolism and still show adiponectin levels indistinguishable from her metabolically healthy counterpart.

The relationship was decoupled.

This finding has been replicated across multiple studies, in Indian teenagers, British South Asians, and migrant populations in Singapore. Adiponectin simply doesn’t correlate as cleanly with insulin resistance, BMI, or cardiometabolic variables in South Asian populations as it does in Europeans. The biomarker relationship that defines the reference ranges doesn’t hold for us.

And yet, and this is critical, when adiponectin does drop in South Asians, the consequences are steeper. A 2013 cross-ethnic Canadian study found that ethnicity significantly modified the relationship between HMW adiponectin and HOMA-IR. For every decrease in HMW adiponectin concentration, South Asians showed a greater increase in insulin resistance compared to Europeans. At the same absolute adiponectin level, South Asians had higher HOMA-IR.

The practical implications are disorienting:

• A South Asian with “normal” adiponectin by European standards may already be functionally deficient relative to what their physiology requires

• The same absolute value means something different depending on ethnicity; 9 μg/mL in a South Asian is not metabolically equivalent to 9 μg/mL in a European

• The threshold at which metabolic risk accelerates may be entirely different, and no one has systematically defined it

What’s missing from the literature, and what would constitute a genuine advance in South Asian precision medicine, is foundational work that simply hasn’t been done:

1. Ethnic-specific reference ranges. No major study has systematically derived South Asian-specific optimal ranges or cutoffs for metabolic risk prediction. We’re using a European genotype/phenotype ruler to measure a South Asian body.

2. Population-specific risk thresholds. At what adiponectin level does metabolic risk accelerate in South Asians versus Europeans? The inflection point that should trigger intervention may be entirely different. A South Asian at 7 μg/mL might warrant the same concern as a European at 4 μg/mLl, but we don’t know, because the studies haven’t been powered to answer this.

3. Whether the relationship truly differs or just appears to. Is adiponectin genuinely “decoupled” from insulin sensitivity in South Asians, or are we measuring the wrong form? Perhaps HMW percentage, or a specific multimer ratio, or adiponectin receptor sensitivity matters more in our population. The tools to fractionate and characterize exist, they just haven’t been systematically deployed.

4. Why the difference emerges so early. South Asian infants at 3-6 months , as we talk about below, already show lower adiponectin than European infants despite smaller body size. This isn’t acquired dysfunction, it’s developmental programming. Understanding the genetic and epigenetic drivers could reveal intervention windows that current medicine doesn’t even know to look for.

This gap exemplifies a broader problem. Even sophisticated tools like Function Health panels, full-body MRIs, and continuous glucose monitors interpret their findings against reference populations that don’t include us in representative numbers. You can spend thousands on the most advanced testing available and still receive results calibrated to someone else’s physiology.

The adiponectin test exists. Any commercial lab can run it. But without South Asian-specific interpretation, without knowing what “optimal” means for our population, we’re flying partially blind even when we measure the right thing.

This is a research imperative, not an academic curiosity and something I am genuinely passionate to help further in my role as a physician (stay tuned for something in this regard). One quarter of the global population is South Asian. The diabetes and cardiovascular epidemic unfolding across India, Pakistan, Bangladesh, and the diaspora is not adequately explained by lifestyle alone. We need our own reference ranges, not because we’re asking for special treatment, but because the current ones are systematically wrong for us. THis remains the most important imperative of our generation.

Until that research exists, clinicians working with South Asian patients should interpret adiponectin results with appropriate skepticism. A “normal” value provides less reassurance than it would in a European patient. A “low-normal” value warrants concern. And the trend over time may matter more than any single measurement, a declining adiponectin in a South Asian patient, even within the “normal” range, should prompt intervention.

Born Different

Here’s where it becomes specific to South Asians.

South Asians have 25-40% lower circulating adiponectin than Caucasians. Not because we’re more obese, this gap persists after adjusting for BMI, total body fat, age, sex, and lifestyle factors.

The SHARE/SHARE-AP study in Canadian populations quantified it: South Asian adiponectin levels of 9.35 μg/mL versus 12.94 μg/mL in Europeans. That’s not a subtle difference.

That gap represents nearly 1.5 standard deviations in most cohorts; not a slight shift, but a fundamentally different physiological baseline.

But here’s what makes this truly concerning: the dose-response relationship is steeper for us.

For each unit decrease in HMW adiponectin, South Asians show greater increases in HOMA-IR than Europeans (p=0.040 for interaction). We get less of the protective signal, and each decrement costs us more in terms of insulin resistance. Even at similar adiponectin levels, the South Asian curve sits at a worse metabolic position, reinforcing the idea of a different physiological baseline, not just a shifted mean.

Less adiponectin. Greater sensitivity to its absence. Double hit.

This is not a lifestyle problem. It is constitutional.

The evidence goes deeper still, to a finding that reframes everything we think about metabolic destiny.

In 2015, the Pune Maternal Nutrition Study documented something remarkable. Indian newborns compared to European newborns showed lower birth weight and lower lean mass, but higher percentage body fat for their size, the thin-fat phenotype already established in utero.

The original Pune data showed preserved truncal fat in lower birth weight babies. More recent body composition studies using precise methods like pea-pod plethysmography in normal birth weight Indian infants haven’t always replicated absolute fat preservation to the same degree. But the core finding persists: higher adiposity relative to lean mass, and lower cord blood adiponectin.

These weren’t premature babies or cases of intrauterine growth restriction. These were full-term, apparently healthy infants already metabolically programmed differently.

And their cord blood? Higher insulin. Lower adiponectin.

Think about what this means. Before a South Asian baby takes its first breath, before the first taste of formula or rice cereal, before the first birthday party (laden with gulab jamun ofcourse!) the metabolic signature is already written. Central adiposity and adiponectin deficiency aren’t things we develop through poor choices. They are part of our developmental architecture.

This pattern has been confirmed in multigenerational Indians in Surinam, in Pakistani children in the UK Born in Bradford cohort, in migrant Indians across Canada and the United States. The thin-fat phenotype travels with us. It is inherited not just genetically but epigenetically, written into how our genes are expressed, passed from mother to child through the intrauterine environment.

When your grandmother tells you that “our family has sugar,” she’s not wrong. She’s just describing the phenotype without the mechanism.

The Fat That Lies

There’s a reason the uncle with the 32-inch waist had a heart attack. It wasn’t the fat you could see. It was the fat you couldn’t.

The clinical term, as we have discussed previously, is “TOFI”, thin outside, fat inside. Or “metabolically obese, normal weight.” But these sterile phrases don’t capture what’s actually happening: an internal geography of fat distribution that makes standard measurements nearly useless.

Imagine two men, both with a BMI of 24. One is Scandinavian. The other is Gujarati. On paper, they look identical. Under an MRI, they are different species.

One of my favorite studies, the MASALA study (Mediators of Atherosclerosis in South Asians Living in America) compared South Asians to Caucasians, African Americans, Latinos, and East Asians. Even after adjusting for BMI, South Asians had more visceral fat (the deep abdominal fat wrapped around organs), more hepatic fat (fat infiltrating the liver), more intermuscular fat (fat marbled through muscle tissue, like a poorly-graded steak), and less lean muscle mass.

The Gujarati man, at BMI 24, is carrying his fat in the worst possible locations. His subcutaneous fat, the pinchable fat under the skin, may be minimal. But his visceral compartment is stuffed. His liver is fatty. His muscles are infiltrated.

This matters for adiponectin because visceral fat is the primary source of the inflammatory signals that suppress adiponectin production. TNF-α, IL-6, resistin (which MASALA also showed to be higher), these cytokines pour out of visceral adipose tissue, creating a local inflammatory environment that directly inhibits adiponectin synthesis. The more visceral fat you carry, the lower your adiponectin falls.

But the arrow runs both directions. Low adiponectin doesn’t just result from visceral fat accumulation, it promotes further visceral storage. Without adequate adiponectin signaling, insulin resistance worsens, and hyperinsulinemia preferentially drives fat into visceral and ectopic depots rather than metabolically safer subcutaneous sites.

The adipocyte loses its signal to expand healthily; instead, existing cells hypertrophy and new fat spills into the liver, the muscle, the viscera.

This is why the relationship is a vicious cycle rather than a simple cause-and-effect. And for South Asians, both the thin-fat phenotype and constitutively low adiponectin appear to emerge together from the same developmental programming, present from infancy, written into the architecture before lifestyle has any chance to intervene. We don’t acquire visceral fat and then lose adiponectin. We enter the world with both vulnerabilities already in place, each poised to worsen the other.

South Asians enter this cycle at much lower total body weights than other populations.

The MASALA study revealed a striking pattern: South Asians have higher intermuscular fat (fat marbled through muscle tissue) and hepatic fat (fat infiltrating the liver) compared to every other ethnic group studied including Whites, Chinese Americans, African Americans, and Latinos. This held true even after adjusting for BMI. The fat isn’t just in the wrong anatomical compartment; it’s infiltrating the organs themselves.

[Great interview on this below with Dr. Alka Kanaya who led the MASALA study.]

There’s a cellular layer too. South Asian adipocytes are hypertrophic, at the same BMI, our fat cells are physically larger than Caucasian fat cells. This isn’t just a curiosity. Hypertrophic fat cells are stressed fat cells. They outgrow their blood supply and become hypoxic. They trigger the unfolded protein response, a cellular stress alarm. They cannot produce adequate adiponectin because they are too busy trying not to die.

The thin-fat phenotype isn’t about being thin. It’s about carrying a normal amount of fat in catastrophically distributed ways, in cells that are already exhausted.

Here’s where it gets dark: the adipocyte itself has mitochondria. When those mitochondria fail, overwhelmed by lipid influx, hypoxic from adipocyte hypertrophy, damaged by ROS, the adipocyte’s ability to produce adiponectin declines further.

Less adiponectin → less mitochondrial biogenesis → more mitochondrial dysfunction → less adiponectin.

The fat cell is both the source of the problem and a victim of it. (More on that below).

The Genetic Inheritance

The story deepens at the level of DNA.

The ADIPOQ gene, located on chromosome 3q27, encodes the adiponectin protein. Variations in this gene, what we call single nucleotide polymorphisms, or SNPs, help explain why adiponectin levels vary so dramatically between individuals and populations.

Several SNPs are significantly more common in South Asian populations:

rs1501299 (+276 G/T): In the Chennai Urban Rural Epidemiology Study, the TT genotype conferred 1.65-fold higher obesity risk. This variant sits in an intron, affecting how the gene is regulated rather than the protein itself.

rs822396 (-3971 A/G): In North Indian populations, the GG genotype associates with 3.6-fold higher Type 2 Diabetes risk. That’s not a modest increase, it’s the difference between a 10% and a 36% lifetime probability.

rs2241766 (+45 T/G): The G allele is more common in diabetic versus non-diabetic Punjabis (29% vs 21.5%, OR 1.49), and this same variant is associated with coronary artery disease susceptibility specifically in South Asian and European populations—but not in East Asians.

Broader meta-analyses show these SNPs have variable effects across ethnicities, sometimes protective in Caucasians, risk-conferring in South Asians. This variability is precisely the point: population-agnostic guidelines derived from European cohorts systematically miss genetic risks that behave differently in our background.

What’s critical to understand: these variants aren’t destiny. They’re conditional. In a traditional rural setting with high physical activity, lower glycemic load, and energy scarcity, these SNPs may remain silent; the environment never pulls the trigger. But in a sedentary urban context with refined carbohydrates and chronic caloric surplus, the same genotype becomes a landmine. That 3.6-fold diabetes risk from rs822396 GG isn’t inevitable; it’s what happens when the modern environment unmasks a genetic vulnerability that was neutral for millennia.

This reframing matters because it returns agency to the equation. You can partially recreate the “masking” environment through lifestyle, not perfectly, but meaningfully.

Perhaps most fascinating is a gene-nutrient interaction involving the ADIPOQ 276G allele. South Asian carriers of this variant show reduced omega-3 fatty acid levels in their serum. Omega-3s are natural ligands for PPAR-γ, the nuclear receptor that drives adiponectin transcription.

So this variant creates a double bind: a gene that produces less adiponectin, housed in a body that retains fewer of the nutrients needed to stimulate that gene.

This has direct clinical implications. Omega-3 supplementation for South Asians carrying this variant isn’t generic “heart health” it’s targeted correction of a specific gene-nutrient mismatch.

When your family seems to “run diabetic” or “have heart problems,” this is part of what you’re inheriting. Not fate, exactly, but a set of biological constraints that require specific countermeasures.

The Energetic Frame: When the Mitochondria Struggle

There’s one more layer to this story, and it’s the one that ties everything together.

In our practice, we have recently been integrating to view metabolic dysfunction through the lens of what we call Energy Resistance; the idea that biological systems must resist electron flow to do useful work, but excess resistance creates friction, heat, and damage.

Think of your mitochondria as power plants. Electrons flow from the food you eat down a series of protein complexes, and that flow drives the production of ATP, cellular energy. Some resistance in this system is necessary; it’s what allows the energy to be captured rather than dissipated. But too much resistance means the electrons back up, leak out, and form reactive oxygen species, molecular shrapnel that damages proteins, membranes, and DNA.

South Asians show signs of high intrinsic energy resistance. Our VO2max (maximal oxygen uptake) is lower. Our skeletal muscle oxidative capacity is reduced. We have fewer mitochondria per muscle cell, and the ones we have may be running tightly coupled, efficient in the Prius sense, hitting capacity quickly rather than having headroom to spare.

Adiponectin, in this framework, functions as a conductance signal. When adiponectin binds its receptors and activates AMPK, it’s essentially telling the system: open the gates, let the electrons flow, build more mitochondria, burn the fuel. It lowers resistance. It enables efficient energy production. Through the AMPK-PGC-1α axis, it drives mitochondrial biogenesis, the creation of new mitochondria to handle the load.

The chronic hypoadiponectinemia of South Asians means we’re running our metabolic machinery with the brakes partially engaged. The electrons back up. The reactive oxygen species accumulate. The inflammation rises. And the very fat cells that should be producing adiponectin become too stressed to make it.

Here’s where it gets dark: the adipocyte itself has mitochondria. When those mitochondria fail, overwhelmed by lipid influx, hypoxic from adipocyte hypertrophy, damaged by ROS, the adipocyte’s ability to produce adiponectin declines further.

Less adiponectin → less mitochondrial biogenesis → more mitochondrial dysfunction → less adiponectin.

The fat cell is both the source of the problem and a victim of it.

You feel this as afternoon fatigue despite adequate sleep. As the heaviness after a meal that seems out of proportion to what you ate. As the difficulty building muscle despite consistent training. As the sense that your body is working harder than it should to do basic things.

This isn’t weakness or laziness. It’s bioenergetic constraint. And it requires specific interventions.

Bringing It Together

If you’ve been following this newsletter, certain patterns should be emerging.

We’ve talked about beta cells that have lower reserve and burn out faster—the fragile engine that redlines under chronic demand. About ghrelin that’s suppressed when it should be pulsatile, removing a brake on insulin secretion and a growth hormone stimulus that should be protecting lean mass. About mitochondria that are efficient but hit capacity quickly, backing up electrons and triggering resistance. About subcutaneous fat that overflows early into visceral depots because the tank is smaller to begin with.

Adiponectin touches all of these.

It protects beta cells directly and reduces the hepatic glucose load that exhausts them. It participates in reciprocal regulation with ghrelin through the gut-adipose axis. It drives mitochondrial biogenesis that would relieve the electron backup. It determines whether adipocytes expand healthily or hypertrophy and overflow.

When adiponectin is adequate, it buffers against all of these failure modes. When it’s constitutively low, as it is in South Asians from birth, every system becomes more vulnerable.

The adipocyte isn’t just another organ in the story. It’s increasingly looking like the upstream node; the source from which many downstream problems flow.

This is why I’m working on a deeper exploration of adipose tissue itself for an upcoming post. The biology of adipocyte expandability. Hyperplasia versus hypertrophy. The “adipose tissue overflow hypothesis.” What it means to have fat tissue that fails at lower thresholds than other populations.

Adiponectin is our window into that adipocyte. When it’s low, it tells us the fat cell is struggling. The question becomes: can we intervene at the source?

What Actually Works

Here’s the uncomfortable truth that explains why adiponectin optimization has remained on the margins of clinical medicine: we can’t give adiponectin directly. The protein is undruggable, the receptor agonists haven’t made it to metabolic trials, and there’s no pill that simply raises levels. The pharmaceutical industry has largely moved on.

This isn’t for lack of trying. Understanding why the direct approaches failed is essential context for the workarounds we’re forced to use.

Why You Can’t Just Give Adiponectin

At first glance, the solution seems obvious: adiponectin is low, so give adiponectin. We do it with insulin, with growth hormone, with EPO. Why not adiponectin?

The answer lies in the molecule’s baroque complexity. Adiponectin isn’t a simple hormone like insulin. It’s a 244-amino acid protein that must assemble into elaborate multimeric structures to function. The basic building block is a trimer, three adiponectin molecules wound together. These trimers then combine into hexamers. And the hexamers further aggregate into high-molecular-weight (HMW) multimers containing twelve to eighteen individual protein chains massive molecular machines that dwarf most circulating hormones.

Here’s the problem: only the HMW form appears to be the biologically active species for insulin sensitization. The trimers and hexamers circulate but don’t produce the metabolic effects we want. And getting a protein to properly assemble into HMW multimers requires specific post-translational modifications, disulfide bonds at the right cysteines, hydroxylation of conserved lysines, glycosylation of those hydroxylysines. These modifications happen in the endoplasmic reticulum of living adipocytes through the action of specific chaperone proteins. You can’t replicate this in a bacterial expression system. Bacterially produced adiponectin lacks these modifications entirely and fails to form proper trimers, let alone the HMW multimers that actually work. Let’s bring back the original diagram:

Even if you could produce properly multimerized adiponectin, you’d face brutal pharmacokinetics. The protein has a half-life of 45-75 minutes—meaning you’d need continuous infusion or frequent injections. It can’t be given orally because digestive enzymes destroy it. The HMW multimers are unstable outside the body, requiring stringent storage conditions that don’t translate well to clinical use. And the C-terminal globular domain—where the active site lives—is notoriously insoluble, complicating large-scale production.

The diverse molecular forms create reproducibility problems that would doom any clinical trial. In vitro and in vivo results vary wildly depending on which adiponectin preparation you use—full-length versus globular, bacterial versus mammalian expression, fresh versus stored. No pharmaceutical company can build a drug development program on such inconsistent biology.

a bit of history before we understand what needs to be done.

The AdipoRon Story

If you can’t give the protein, why not make a small molecule that mimics it? This was the thinking behind AdipoRon, discovered in 2013 at the University of Tokyo through screening a chemical library for compounds that activated AMPK in muscle cells. It was the first orally available adiponectin receptor agonist—a drug you could swallow that would theoretically replicate what adiponectin does.

The animal data looked spectacular. AdipoRon, given orally at 50 mg/kg to genetically obese diabetic mice, reduced plasma glucose levels comparably to adiponectin protein injection. After two weeks, the mice showed markedly improved glucose tolerance, reduced insulin resistance, and better lipid profiles. When put on a high-fat diet, AdipoRon-treated mice lived longer than untreated controls. It appeared to work through both AdipoR1 and AdipoR2, activating the AMPK-PGC1α and PPARα pathways that adiponectin normally engages. The papers proliferated: AdipoRon for diabetes, for fatty liver, for cardiovascular disease, for neurodegeneration, for cancer.

Yet over a decade later, AdipoRon has never entered human clinical trials for metabolic disease.

The reasons are instructive. The binding affinity of AdipoRon to its receptors is relatively weak, dissociation constants of 1.8 and 3.1 micromolar for AdipoR1 and AdipoR2 respectively. In pharmaceutical development terms, this is poor. The concentration needed to activate AMPK in cells (EC50 around 10 micromolar) falls below the threshold that typically justifies advancing a compound through development. Current pharmaceutical go-no-go criteria, as one review put it, “are not in favor of pursuing a candidate with such a low cellular activity.”

There’s also the problem of systemic toxicity testing. Small molecules that activate receptors throughout the body face stricter safety hurdles than topical preparations. This difficulty is evident even in the well-established GLP-1 class, the most famous single receptor activators, where developing oral small molecules has faced far greater toxicity scrutiny than their peptide predecessors.

The one adiponectin mimetic that has reached human trials, a peptide called ADP355, is being tested only as eye drops for dry eye disease, where systemic exposure is minimal. For metabolic indications requiring whole-body effects, no adiponectin receptor agonist has yet convinced regulators or pharmaceutical companies that the benefit-risk profile justifies human testing.

The adiponectin paradox adds complexity: in certain chronic conditions (heart failure, chronic kidney disease, established coronary disease), higher adiponectin levels correlate with worse outcomes.

This may represent compensation, the body upregulating a protective hormone in the face of overwhelming disease, but it gives pharmaceutical companies pause. A drug that raises adiponectin signaling might help early-stage metabolic dysfunction while harming patients with established cardiovascular disease. The heterogeneous responses across disease stages make clinical development treacherous.

The Implication

This history matters because it explains why we’re forced into indirect approaches. The pharmaceutical industry hasn’t ignored adiponectin out of disinterest, billions of dollars were spent chasing it. The biology proved intractable. The protein is too complex to manufacture, the receptor agonists too weak to develop, the clinical variability too dangerous to navigate.

So how do we think about intervention?

We have three strategic options: increase production at the source by making the adipocyte produce more adiponectin; mimic the downstream signal by activating the pathways adiponectin would have activated; or fix the adipocyte itself, addressing the cellular dysfunction that’s suppressing production in the first place. Each approach has different tools and different implications. The most effective protocols combine all three.

Strategy 1: Drive Adiponectin Gene Transcription

Adiponectin production is controlled primarily by PPARγ (peroxisome proliferator-activated receptor gamma), the master transcription factor of adipocyte differentiation and function. If you activate PPARγ, you turn up the adiponectin gene.

This is why thiazolidinediones produce the largest adiponectin increases of any intervention, two to threefold. Pioglitazone is a direct PPARγ agonist. It’s literally pressing the “make more adiponectin” button at the genetic level. The trade-offs (fluid retention, bone density concerns, weight gain) mean they’re not first-line for everyone. You’re activating a powerful switch with broad downstream effects. But for severe, refractory cases with dangerous metabolic trajectories, they remain a tool worth considering.

For most patients, we look for gentler PPARγ modulators. Omega-3 fatty acids (EPA and DHA) are PPARγ agonists that activate the receptor enough to drive adiponectin translation without the full adipogenic program. This is why therapeutic-dose omega-3s have metabolic effects beyond “heart healthy fats.” They’re actually modulating nuclear receptor signaling in the adipocyte.

The gene-nutrient interaction we discussed earlier makes this especially relevant: ADIPOQ variants that reduce adiponectin production are also associated with lower omega-3 levels. Correcting the nutrient deficit removes a brake on a gene that’s already underperforming.

Curcumin (a derivative of haldi (turmeric)) (in bioavailability-enhanced forms as the key is absorption) also acts as a PPARγ modulator, with the added benefit of NF-κB suppression, addressing both the transcriptional drive and the inflammatory suppression of adiponectin simultaneously. There’s a certain symmetry in finding that a compound central to South Asian cuisine has therapeutic relevance for our specific metabolic vulnerabilities.

Strategy 2: Bypass Adiponectin and Activate Its Downstream Pathways

If we can’t raise adiponectin adequately, we can ask: what would adiponectin have done? And can we achieve that effect through another route?

Adiponectin’s major downstream effector is AMPK, the master switch for cellular energy metabolism. Anything that activates AMPK independently is essentially doing adiponectin’s job for it.

High-intensity interval training is the most potent physiological AMPK activator we have. The energy depletion during intense intervals triggers AMPK directly in muscle tissue; increased glucose uptake, fatty acid oxidation, mitochondrial biogenesis. HIIT produces larger metabolic benefits than moderate continuous exercise not because it burns more calories, but because it creates the demand signal that low adiponectin fails to provide.

This reframes exercise prescription for the South Asian patient. It’s not about “burning off” dietary excess. It’s about pharmacologically activating a pathway that your adipose tissue isn’t adequately stimulating. The intensity matters more than the duration. A 45-minute moderate treadmill walk is not metabolically equivalent to 20 minutes of intervals with genuine high-intensity efforts.

Disclaimer Reminder: Please consult a trainer or your physician prior to trying these, this is just for education purposes.

Berberine activates AMPK through inhibition of mitochondrial complex I, a different mechanism than adiponectin, but converging on the same master switch. It also appears to specifically promote HMW adiponectin assembly, giving you both the bypass and the source correction. Some trials show efficacy comparable to metformin for glucose control.

Metformin itself works partly through AMPK activation (though its mechanisms are multiple and debated). This may explain why it remains useful in South Asian populations even when it doesn’t address beta cell protection, it’s compensating for the downstream signal that low adiponectin should have provided.

Strategy 3: Fix the Adipocyte Itself

This is the most upstream approach and potentially the most powerful.

Remember: adiponectin falls because the adipocyte is sick. Hypertrophic, hypoxic, inflamed, mitochondrially dysfunctional. If we can restore adipocyte health, adiponectin production should improve as a consequence.

GLP-1 receptor agonists (semaglutide, tirzepatide, soon retatrutide) work here at multiple levels. They reduce caloric intake, yes, but more importantly they preferentially mobilize visceral fat and reduce adipocyte size. Smaller adipocytes are healthier adipocytes; better oxygenated, less inflamed, more functional. The 16-23% adiponectin increases seen with GLP-1 agonists aren’t the primary mechanism; they’re a readout that the adipocyte is recovering.

Recent meta-analyses show greater cardiovascular protection in Asian populations than in White populations (hazard ratio 0.69 vs 0.85), probably because these drugs target the specific adipocyte pathology we carry. If you’ve been told you’re “not heavy enough” for these medications, push back. The weight thresholds were developed for European populations.

SGLT2 inhibitors (dapagliflozin, empagliflozin) increase adiponectin through mechanisms we don’t fully understand; possibly by shifting substrate utilization in ways that reduce adipocyte stress, possibly through effects on visceral fat depots. The fact that the mechanism is unclear doesn’t diminish the clinical relevance: these agents improve adipokine profiles while providing cardio-renal protection, which matters given our accelerated trajectory toward those complications.

Resistance training deserves special mention here. By building skeletal muscle, you’re creating a larger glucose sink, more tissue that can clear glucose from circulation, reducing the demand on insulin secretion, reducing the hyperinsulinemia that itself suppresses adiponectin. South Asians have lower lean mass at every BMI, so muscle isn’t cosmetic, it’s metabolically therapeutic.

Weight loss itself, specifically, fat mass reduction that preserves lean mass, shrinks adipocytes back toward functional size. But the type of weight loss matters enormously. Crash dieting that loses muscle while preserving visceral fat doesn’t fix the adipocyte problem and may worsen it. This is why we emphasize protein-forward nutrition and resistance training during any weight loss intervention.

Synthesizing a Multi-Target Intervention

What emerges from this framework is that no single intervention is sufficient. The patient with constitutively low adiponectin, the typical South Asian metabolic phenotype, needs a strategy that hits multiple nodes: PPARγ activation to drive transcription, direct AMPK activation to bypass the missing signal, adipocyte rehabilitation to fix the source, and glucose sink expansion to reduce downstream burden.

The pharmacologic agents, GLP-1 agonists, SGLT2 inhibitors, potentially low-dose pioglitazone in refractory cases, layer onto this foundation. They’re not substitutes for the lifestyle architecture; they’re amplifiers of it.

This framework also opens the door to thinking about novel approaches. Anything that improves adipocyte mitochondrial function should theoretically help, which brings us to photobiomodulation with near-infrared light (810-850nm), which stimulates mitochondrial Complex IV. But here’s the nuance most discussions miss: melanin absorbs red light. If you have Fitzpatrick skin type IV, V, or VI, common across South Asian populations, visible red light (630-660nm) will be significantly absorbed by your epidermis before reaching deeper tissues.

You need near-infrared wavelengths specifically, which penetrate past the melanin barrier. The one-size-fits-all protocols developed for lighter-skinned populations will underdeliver for us.

[I built out a model of the mitochondrial response to different interventions as above. You can find the full app of the simulation here]

[Working on building a tool to help with this which should be available end of the year (hopefully).]

Cold exposure, which activates brown adipose tissue and may influence white adipocyte function, deserves investigation in this population. Time-restricted eating, compressing the eating window to 8-10 hours, with most calories consumed earlier in the day, may better align nutrient intake with adiponectin’s natural circadian rhythm, which typically peaks in late morning.

The framework gives you a map. The specific interventions are waypoints on that map, not the territory itself.

The Practical Approach

If you’ve read this far, firstly thank you for reading. You now have deeply understand something most South Asians never learn: that the metabolic vulnerability you’ve observed in your family, felt in your own body, and worried about for your children has a mechanistic basis. It’s not destiny. It’s biology, and biology can be addressed. We remain optimistic as always at changing this trajectory.

Recalibrate your thresholds. A BMI of 24 is not “fine” for a South Asian. Neither is a 34-inch waist in a man or a 32-inch waist in a woman. The evidence supports action at BMI ≥23 and waist circumference ≥90cm (men) / ≥80cm (women). If your doctor uses standard cutoffs, educate them, or find a doctor who understands ethnicity-specific risk.

Request the right tests. Standard lipid panels miss qualitative defects common in South Asians (small dense LDL, dysfunctional HDL). Ask for apolipoprotein B, which captures atherogenic particle number. Ask for fasting insulin and calculate HOMA-IR; you may be insulin resistant with normal fasting glucose. HMW adiponectin is ideal but not widely available; total adiponectin is still informative, especially when it’s low in someone who appears lean or metabolically “normal.” That discordance tells you something is wrong at the adipocyte level, even if standard markers haven’t caught up yet.

Target visceral fat, not just weight. The number on the scale matters less than where the fat sits. Interventions that specifically reduce visceral adiposity, GLP-1 agonists, HIIT, Mediterranean diet, deliver more metabolic benefit than the same weight loss achieved through muscle wasting or extreme caloric restriction.

Think mitochondrially, cannot stress this enough. And unfortunately most clinical approaches near completely ignore the mitochondria. If you experience fatigue, poor exercise tolerance, or a sense that your body doesn’t produce energy efficiently, build muscle as expected, you may be encountering the energy resistance that underlies our phenotype. Interventions supporting mitochondrial function, CoQ10, NAD+ precursors, regular high-intensity exercise, adequate sleep, morning light exposure, address the upstream problem.

Advocate for yourself. The clinical guidelines, the BMI charts, the risk calculators—they were built on European cohorts. They systematically underestimate your risk. You are not being hypochondriac when you push for earlier intervention. The data supports you.

Optimism is Paramount

There’s a particular grief in watching your family members fall, one by one, to diseases that were “managed” but never prevented. In hearing “your numbers look good” while sensing that something is wrong. In knowing that the medical system sees you but does not see the specific body you inhabit.

Adiponectin is not the whole story. But it is a crucial chapter, a molecular key that unlocks understanding of why South Asian bodies fail in the particular ways they do. The thin-fat phenotype, the visceral fat accumulation, the insulin resistance at normal weight, the cardiac events that arrive decades too early, adiponectin deficiency runs through all of it.

And if you’ve been following along, you can see how the threads connect: the beta cell under chronic demand, the ghrelin signal gone quiet, the mitochondria running at capacity, the subcutaneous tank that overflows early. Adiponectin sits at the center, the letter that should be keeping all these systems in communication.

In our practice, we’re building a precision medicine protocol that takes these differences seriously. Not as an afterthought or a footnote, but as the foundation. Because until medicine learns to see our specific biology, we have to see it for ourselves.

The metabolic dice may be loaded. But understanding how they’re loaded is the first step toward changing the odds.

Optimism is paramount.

-omar

edited with Claude; Deep research for using Gemini, Manus and Claude

Disclaimer: This post is for informational purposes only and does not constitute medical advice. Always consult your physician before making changes to medications or supplements.

I’m a precision preventative medicine physician focused on South Asian health. I’m also a hospitalist. And this year, I became something I never expected: a builder.

I built 161 apps on Replit and published 47 of them. That apparently puts me in the top 0.5% of users on the platform.

I’m not a software engineer. I’m a doctor who got tired of waiting.

The Problem No One Wants to Talk About

Here’s what I kept running into: the tools we use in medicine, the calculators, the risk scores, the reference ranges, the guidelines, weren’t built for people who look like me. Or my patients.

South Asians have a fundamentally different metabolic profile. This isn’t a minor footnote. It changes everything.

• BMI cutoffs don’t apply. A South Asian at BMI 23 can carry the same metabolic risk as a white individual at BMI 30. The WHO acknowledged this years ago. Most tools still haven’t caught up.

• Visceral adiposity behaves differently. We accumulate fat around organs at lower body weights, often invisible on the outside but deeply dangerous on the inside.

• Beta cell function follows a different trajectory. South Asians tend to have lower beta cell reserve and earlier dysfunction. By the time fasting glucose looks “abnormal” by standard cutoffs, significant damage is already done.

• The biomarkers that matter most aren’t the ones being tracked. Adiponectin, a key marker of metabolic health, is often lower in South Asians, yet almost never measured in standard care.

This isn’t speculation. The research exists. But it takes years, sometimes decades, for evidence to filter into guidelines, then into EMRs, then into the tools physicians actually use. Meanwhile, people are developing diabetes, heart disease, and fatty liver at rates far higher than their neighbors, often while being told their labs look “fine.”

I watched this happen to family members. I felt it in my own health journey. And I saw it every day in my patients.

The Turning Point

In mid-2024, Replit launched their AI Agent. I’d been frustrated with the available tools for tracking my own metabolic health, so I decided to see if I could build something better.

I built a health dashboard with wearable integration. It worked.

So I kept going.

What I Built

My entire clinical practice now runs on tools I built myself:

• A custom website with a built-in AI agent that answers patient questions—not generic FAQ responses, but informed by the specific context of South Asian metabolic health

• Patient intake forms with intelligent verification

• An interactive service menu and dashboards

• A patient education platform that curates content specific to each patient’s visit and concerns

• Biomarker tracking and optimization powered by best-in-class AI tools—tracking the markers that actually matter for our population

Beyond the practice infrastructure, I built tools that solve specific problems:

PracticeOS: an AI-native practice hub for DPC and cash-pay clinics. It handles resource allocation, treatment protocols, HSA information, and acts as a real-time consultant for running a precision medicine practice. It understands the context of what I’m trying to do.

RosterRx: a free scheduling app for hospitalists, now used by multiple groups across the country.

Credential Management agent — an AI agent with Telegram bot that tracks my licenses, certifications, and renewal deadlines so I never have to think about it.

An HSA bundling tool: focused on newer therapies including longevity interventions, helping patients understand what’s actually eligible and how to optimize their spending.

Care Journey: a free charity project providing multilingual AI-powered health guidance for patients in underserved regions who lack access to care.

Why This Matters for South Asian Health

Here’s what I’ve realized: we cannot wait for the system to catch up.

The traditional path looks like this: researchers identify a disparity → studies are funded → data is collected over years → papers are published → guidelines committees convene → recommendations are updated → EMR vendors implement changes → physicians are trained on new protocols.

This takes a decade. Sometimes longer. And at every step, South Asian-specific considerations get diluted, deprioritized, or dropped entirely because we’re a “subgroup” that doesn’t move the needle on population-level statistics.

Meanwhile, South Asians have 4x the risk of heart disease. Type 2 diabetes is reaching epidemic levels in the community, often striking in the 30s and 40s. Fatty liver disease is rampant and underdiagnosed.

We cannot wait.

What I’ve learned this year is that we no longer have to.

The tools to build custom solutions now exist. You don’t need millions in funding. You don’t need a development team. You don’t need to convince a product manager at a healthcare software company that your population matters enough to prioritize.

You can build it yourself. Today.

The Compounding Returns

The returns on this investment have been compounding in ways I didn’t anticipate.

I’ve gotten very good at this. I know exactly how to get what I want from an app now. Each build is faster and more ambitious than the last.

More importantly, it’s pushed me to explore the frontiers of what’s actually possible. Not just “how do I use AI to save time?” but “how do I fundamentally reimagine care delivery for a population that’s been underserved by default?”

I’ve moved beyond chatting with AI in a terminal to building systems where AI functions as an actionable intern, doing the legwork, surfacing the right information at the right time, helping patients understand their health in their own language.

This isn’t about replacing physicians. It’s about amplifying what we can do. It’s about building the tools that should exist but don’t because the market didn’t prioritize them.

What I Want You to Take From This

If you’re a physician: The barrier to building custom tools has collapsed. If you’ve ever thought “I wish this existed,” you can probably build it now. And if you serve a population that’s underrepresented in standard guidelines, whether that’s South Asians, other ethnic groups, or any community with specific needs, you have the power to create something that actually fits.

If you’re a South Asian who cares about your health: Understand that the standard playbook may not apply to you. A “normal” BMI doesn’t mean you’re metabolically healthy. A “normal” fasting glucose doesn’t mean your beta cells are thriving. Advocate for testing that matters, fasting insulin, HOMA-IR, adiponectin, apoB, a real look at visceral fat. Find physicians who understand these distinctions. And know that the landscape is changing. Tools built specifically for our needs are coming, some of them are already here.

For everyone: The biggest lesson from this year wasn’t technical. It was learning to build tools I actually need, creating a framework for what matters, and not building for the sake of building.

I replaced what was probably thousands of dollars in monthly SaaS spend with software that fits exactly how I work. No bloatware. Nothing extra. Just what’s needed.

The Path Forward

Times are changing for doctors. This is one way we stay ahead.

More importantly, times are changing for patients, especially those of us from communities that have been afterthoughts in medical research and tool development.

We don’t have to wait for permission anymore. We don’t have to wait for validation from organizations that move at glacial speed while our families develop preventable disease.

We can build. We can share. We can push the frontier ourselves.

That’s what I intend to keep doing.

If you are a physician wanting to learn more about this, please reach out. Happy to help.

Thank you to Amjad Masad and the team at Replit for building something that made all of this possible. If you’re curious, try it out. You’ll feel it.

We have spent a lot of time on this Substack discussing the unique metabolic challenges South Asians face, specifically the “South Asian Phenotype,” with its paradoxical visceral fat, early onset dysregulation and unique bet-cell structure. This edition of Chai Shots, we want to finally start (slowly) connect the dots, moving beyond the gross observations we’ve discussed to the genetic why that underpins our physiology.

For years, we’ve asked that question. Why does insulin resistance and subsequently type 2 diabetes (T2D) seem to hit South Asians so much harder and earlier? Why are certain medications more useful when tackling this?

I strongly believe much of these answers will become evident through advances in genotyping in the coming years.

Recent literature from 2023–2025 has finally started to hand us some concrete answers. It’s not just “bad genes” or diet; it’s a specific, intricate interplay of mitochondrial efficiency and insulin pathways. For this edition of Chai Shots, I’ve distilled the latest heavy-hitting papers into what you actually need to know. This will likely require a few posts so consider this part 1.

Translating Genotype to Phenotype

A massive study published in Nature Medicine last year (2024) gave us definitive evidence. Looking at over 50,000 British Pakistani and Bangladeshi individuals, researchers identified two specific mechanistic pathways that hit South Asians harder than Europeans [1].

This isn’t just abstract data; this is the biological blueprint of the “Thin-Fat” individual.

1. Beta Cell 2 pPS (Insulin Deficiency)

• The Mechanism: This pathway drives a primary failure in insulin secretion.

• The Phenotype (The Fragile Pancreas): Unlike the typical Western model of robust insulin hypersecretion followed by burnout, South Asians often start with lower beta-cell reserve. You essentially have a smaller tank of gas to begin with.

2. Lipodystrophy 1 pPS (Fat Distribution)

• The Mechanism: This pathway dictates unfavorable fat storage.

• The Phenotype (The Overflow Tank): Your body has a genetic cap on subcutaneous fat storage (the “safe” fat). Once that small capacity is filled, energy spills over into visceral depots (liver, pancreas) almost immediately, causing lipotoxicity at BMIs that doctors typically consider “healthy.”

The Practical Reality: If you have high risk in both these pathways, the data shows diagnosis occurs on average 8.2 years earlier and at a BMI 3 kg/m² lower than those with low risk.

This diagram may explain it better.

What does this mean clinicall? The study notably found that the “Insulin Deficiency” pathway is linked to a poorer response to SGLT2 inhibitors.

If your phenotype suggests early beta-cell failure rather than pure insulin resistance, standard first-line therapies might need a second look.

Exome Associations

The largest Exome-Wide Association Study (ExWAS) for South Asians just dropped a preprint in 2025, and it’s a fascinating in-depth analysis. They analyzed over 54,000 exomes and found some South Asian-specific quirks. (Since this is a preprint, the data is fresh. I will be doing a deep-dive breakdown of this specific paper in a future issue once the peer review settles and we have more granular data.)

However, there are four key findings you need to know now:

1. HNF4A (Pro437Ser): Probably the most interesting finding in this article. A classic “good news, bad news” variant.

   

   • The Good: It actually protects against T2D and diabetic retinopathy.

   • The Bad: It raises LDL cholesterol and increases the risk of heart attacks. This complicates the picture, you might have a patient with “good” blood sugar control who is silently building up coronary risk.

     So this complicates the picture. You might have “good” blood sugar control but silently building up coronary risk due to this specific variant.

   More on how we tackle this below.

2. GP2 (Val429Met / rs78193826): This variant was specifically linked to chronic kidney disease (CKD) risk and beta-cell dysfunction. It highlights that for South Asians, kidney protection needs to be a priority even before diabetes is fully established.

3. CDKAL1 (Pro409Arg / rs77152992): A missense variant strongly associated with T2D risk, likely affecting insulin response.

4. RNF19A: The study identified gene-level predicted loss-of-function (pLoF) variants here associated with T2D, marking it as a novel gene of interest for our population.

Mitochondrial Efficiency Through Genes

We spoke about insulin above and often, but we need to talk about the mitochondrial engine itself.

A 2025 review in Molecular Genetics and Metabolism Reports highlights that this isn’t just about hormones; it’s about energy production.

(As always a shoutout here to the Energy Resistance principle, check out Martin Picard’s recent Huberman episode on this, fascinating discussion. Will be posting about energy dynamics in South Asians later this week.)

While the paper itself is a broad review of mitochondrial mechanics, the connection to the South Asian demographic is hidden in the specific variants discussed, notably A10398G.

This polymorphism is a defining marker of Haplogroup M, the maternal lineage found in a vast majority of the South Asian population (and distinct from European lineages). So, while the paper discusses the mechanism globally, the prevalence makes it a uniquely South Asian problem.

The “Hot Battery” Hypothesis: The A10398G variant alters Complex I of the electron transport chain. Imagine an engine with a loose gasket. This leads to 3 main problems, all of whom we’ve discussed on the Substack previously.

• Inefficiency: It struggles to pump protons efficiently, meaning you generate less ATP (energy) for the same amount of fuel.

• Toxic Exhaust: More critically, this “loose gasket” causes electron leakage, which creates Reactive Oxygen Species (ROS).

• Beta-Cell Burnout: Pancreatic beta cells are famously poor at handling oxidative stress. This constant low-grade ROS production essentially “cooks” the beta cells over decades, leading to early burnout and insulin deficiency.

Nature vs. Nurture? Or Both?

Getting practical now, and a bit real.

A 2024 systematic review in Nutrition Reviews analyzed 15 studies and found 132 significant gene-lifestyle interactions. These were from studies in India, Pakistan and Bangladesh while also including studies on South Asian diaspora in Singapore and Canada (broad!).

What does this mean?

It means your genes aren’t a sentence; they are a susceptibility we can work on improving.

And more importantly, the “South Asian Phenotype” is incredibly sensitive to inputs. The data confirms that lifestyle levers, specifically sleep quality, smoking cessation, and physical activity, pull much harder on the metabolic health of South Asians than other groups. But the review also showed this goes both ways. Interactions with low physical activity, poor sleep, irregular patterns, and smoking significantly elevate obesity and T2D risk in South Asians, while higher fiber intake and activity may mitigate it. So you are truly what you do and eat, using genetics as an excuse is not an option.

Managing the South Asian Genotype

What these studies prove is we need to move beyond generic guidelines. Given the genetic constraints on subcutaneous storage and beta-cell reserve, our management strategy must be aggressive and precise.

1. Screening

Read more

If you have ever felt like your body fights tooth and nail to hold onto every calorie while your friends seem to eat whatever they want, you aren’t imagining things. You are likely fighting a ghost from the past (wayy past your grandparents so dont blame them), a biological program running on an operating system designed for a world that no longer exists.

Today, we are decoding Ghrelin or “hunger hormone”, and its strange, paradoxical behavior in South Asians.

Most people think obesity comes from having too much hunger hormone. But in the South Asian “thin-fat” phenotype as we covered at the beginning of this blog, the story is often the opposite. And understanding this difference is the key to unlocking your metabolic health.

The “Grow” Hormone

lets start with the basics. Ghrelin is often called the “dinner bell” of the body. Produced primarily in your stomach, it travels to the brain to deliver a simple message: “We are empty. Find food.”

But Ghrelin has a secret second job, hidden right in its name. The word comes from the Proto-Indo-European root ghre, meaning “to grow.”

Why? Because Ghrelin is a potent trigger for the release of Growth Hormone (GH).

• The Ideal Cycle: You get hungry (Ghrelin rises) -> This triggers a pulse of Growth Hormone -> GH helps mobilize fat for fuel and protects your muscle mass while you look for food.

  In a healthy metabolism, Ghrelin isn’t just making you eat; it’s trying to keep you lean and muscular. [1] Physiology

  

(We are going to do a full deep-dive on the South Asian Growth Hormone crisis in a future post on GH and sarcopenia (referred below), but for now, just remember this: Hunger and Muscle-Growth are coupled. If one breaks, the other usually follows.)

The South Asian Paradox

Here is where it gets weird.

If you look at a South Asian individual with the “thin-fat” phenotype (normal BMI but higher belly fat/visceral adiposity), you would expect their ghrelin levels to be sky-high, driving them to overeat.

The reality is often the opposite. Research has observed that insulin-resistant individuals (a trait highly prevalent in South Asians) actually exhibit significantly lower fasting ghrelin levels compared to metabolically healthy controls. In studies of South Asian men, acylated ghrelin was found to be lower than in white Europeans of similar BMI, correlating with higher visceral fat and insulin resistance. [2] Ghouri et al., PLoS One

Why? It isn’t a “broken” gene, but a feedback loop. High baseline insulin (common in South Asians) suppresses ghrelin production. Your body knows you have plenty of energy stored as visceral fat, so it lowers the hunger signal.

The Problem:
Even though your baseline ghrelin is low, the system is malfunctioning:

1. The “Deaf” Brain: Despite low ghrelin, the brain often perceives starvation due to Leptin Resistance. You have high fat stores (Leptin), but the signal isn’t getting through. The “Aunty” in your metabolism panics and keeps hoarding energy. [3] StatPearls

2. The Growth Hormone Cost: Because your baseline Ghrelin is chronically suppressed and non-pulsatile, you likely lose that beneficial “Growth Hormone” spike. This is a potential contributor to Sarcopenia (low muscle mass)—a hallmark of the South Asian physique. [4] PMC

Revving a Fragile Engine, Beta-cell and Ghrelin

This “Low Ghrelin” state directly threatens your pancreas.

South Asians are born with “smaller engines”, as we discussed on last week’s post on beta cells. Autopsy studies comparing Indian and American pancreatic tissue found a striking 45% reduction in the proportion of large islets in Indian samples. Large islets are your metabolic “buffer”—without them, you have less margin for error. [5] PMC

Here is how Ghrelin fits in:

• The Brake Pedal: One of Ghrelin’s physiological roles is to suppress insulin secretion. When you are hungry, Ghrelin tells the beta cells: “Stop pumping insulin! We need to release sugar, not store it!” [6] Tong et al., Diabetes

• The Cut Brake Line: In the context of visceral obesity and low fasting ghrelin, this “brake” is weakened.

  The Burnout: Without the Ghrelin brake, your already fragile (and smaller) beta cell reserve is left uninhibited, constantly leaking insulin. You are red-lining a small engine because the rev-limiter has been disconnected.

The Ghost of Famines Past

Why is your biology wired this way? The leading theory is the “Thrifty Gene” Hypothesis, specifically adapted to the Indian subcontinent.

South Asian history is scarred by severe, repeated famines. In that harsh environment, a metabolism that burned energy quickly (high muscle mass) was a death sentence. The survivors were those who could store fat efficiently in the abdomen and survive on very few calories. [7] Research Open World

Warning: This is going to hit hard for some.

Think of your metabolism as the Aunty. The son (unfortunate beta) represents your modern biological reality: “I am full, I don’t need any more.” (This is your low baseline ghrelin).

But the Aunty represents your Genetics. She remembers the famine. She is terrified that if you don’t eat now, you might die tomorrow. She overrides the son, forcing energy into the system and storing it as visceral fat “just in case.”

(Really tried hard on that one.)

The Genetic Nature

This isn’t just behavioral; it’s written in the code.

While specific gene variants like Leu72Met have been studied (caveat: with mixed results), the South Asian phenotype likely faces a genetic “Double Hit”: [8] Frontiers

1. Beta Cell Fragility: Risk variants in genes like TCF7L2 that limit insulin capacity.

2. Hormonal Dysregulation: Epigenetic programming (often from low birth weight) that sets the “starvation” dial to high, prioritizing fat storage over muscle growth.

Now how do we tackle this? We’ll dive deeper below on the protocols we’ve developed to counter this including the melatonin effect, protein and what to eat when breaking fasts in the morning or after a log intermittent fasting session.

Managing Your Ghrelin

Read more

Fair warning: this post has quite a bit about cars considering Lando’s F1 win last weekend.

For decades, the global guideline for Type 2 Diabetes has been the same: Metformin First.

The logic seems sound: “Type 2 Diabetes is a disease of insulin resistance. Metformin fixes resistance. Problem solved.”

But new research suggests that for South Asians, insulin resistance is only half the story and maybe not even the main character. If you follow the standard advice without understanding your specific phenotype, you might be managing your symptoms while letting your organ function slowly degrade.

Here is why the “Fragile Engine” theory matters.

The South Asian Phenotype

To understand diabetes, we have to look at the Beta Cells, the cells in your pancreas responsible for making insulin.

In many populations (like the Latin American phenotype), diabetes is often a result of massive resistance. These individuals often have robust beta cells that work overtime for years, eventually “burning out” from fighting significant obesity.

The South Asian phenotype is different.

South Asians often suffer from a primary secretory defect. Research from the landmark MASALA Study indicates that even at a healthy weight (the “Thin-Fat” phenomenon), South Asian beta cells often have a lower “fuel tank” (reserve) and a lower “top speed” (capacity) compared to other ethnic groups.

You don’t need to be obese to strain this system. You just need to exceed the capacity of a naturally smaller engine.

Now because Lando Norris won F1 this year, we’ll be talking about cars today.

The Car Analogy

The easiest way to understand your metabolism is to imagine a car towing a trailer up a hill.

• The Trailer = Your Body Fat / Insulin Resistance

• The Engine = Your Pancreas (Beta Cells)

The “Volume” Model

THis is the latin american phenotype.

Imagine a massive truck with a V8 Engine. It is towing a huge trailer (obesity). The engine is powerful, but eventually, if the trailer gets too heavy, the engine overheats and fails.

The “Capacity” Model

This is the South Asian Phenotype

Now, imagine a compact sedan with a small 4-cylinder engine. The trailer might be small (normal BMI), but the engine simply isn’t built for towing. It struggles to pull even a light load up the hill.

This is the crux of the problem: The medical system treats the 4-cylinder engine like it’s a V8.

Why Metformin Isn’t Always the “Gold Standard”

Just want to be clear.

Metformin is a great drug. It’s changed lives and improved outcomes. But nuance matters.

In our analogy, Metformin greases the wheels of the trailer.

It improves insulin sensitivity, making the load easier to pull. That helps! But it does nothing to repair, support, or boost the under-powered engine.

If your beta cells are genetically fragile, simply lowering resistance might not be enough to stop them from failing over time. By relying solely on Metformin, you are managing the symptom (high sugar) but not preserving the organ (the pancreas).

The Case for GLP-1s as First-Line

This is why many longevity-focused physicians are pushing to move GLP-1 agonists (like Semaglutide or Tirzepatide) to the front of the line for South Asian patients.

Here is why they fit the “Fragile Engine” better:

1. Pancreatic Offloading: By aggressively targeting visceral fat (the specific belly fat South Asians store), GLP-1s lighten the “trailer” significantly more effectively than Metformin.

2. Beta Cell Support: Unlike older drugs like Sulfonylureas (which “whip” the tired horse to make it run faster), GLP-1s help the beta cells work more efficiently, stimulating insulin only when needed.

3. Preservation: The goal isn’t just to lower A1c today. It’s to stop the beta cells from dying off so you don’t need injected insulin 10 years from now.

It’s about time we codified this change.

If you are South Asian, “Normal” isn’t good enough. The standard ranges on lab tests are often based on Caucasian data, which does not account for the fragile beta cell reserve.

Metformin alone might be bringing a knife to a gunfight. Protect beta cells like they are a non-renewable resource, because they are.

-Omar

Disclaimer: This post is for informational purposes only and does not constitute medical advice. Always consult your physician before changing your medication strategy.

Chai Shots this week was supposed to be on beta-cells and pancreas (we’ll get that to you next week for sure). However, an important development made me switch.

We are currently witnessing a quiet but profound revolution in medicine. For the last century, the “Central Dogma” of medicine has been biochemistry. We view the body as a chemical soup: a collection of receptors, ligands, and proteins bumping into each other. If you have high sugar, we give a chemical (Metformin) to lower it. If you have pain, we give a chemical to block it.

But the winds are shifting. We are moving from the chemical to the physical; from the molecule to the quantum.

And Andrew Huberman’s latest episode with Glen Jeffrey may likely be the spark that lights this movement.

An overdue resurgence in cellular and mitochondrial medicine is forcing us to acknowledge a deeper reality: we are electrical beings before we are chemical ones. The chemical reactions we obsess over are just the downstream results; the flow of energy, electrons and photons, is the cause.

As physicians, we usually spend most days talking, thinking, and explaining primarily biochemistry: hormonal pathways, insulin, glucose, lipids.

But today, for this week’s Chai Shot, we need to talk about biophysics. It’something I have been waiting for years to get into.

A little background: my first love and interest growing up was Russian literature (Chekhov ofc the inspiration for this blog name), second, was Newton and in turn physics. I actually was thinking I would become a physicist when I grew up. Then I met math…and decided on medicine.

Why Physics Matters (and Why Now)

Why is this shift to “Quantum Medicine” happening now? Because we have hit a wall with the chemical model. Chronic diseases are skyrocketing despite our best pharmaceuticals. We are realizing that you cannot chemically force a system that is energetically broken. This is limiting and blinding us to areas of biology that dont fit into the chemical model. Mitochondria are likely the biggest victims of this and why this is now changing.

We are seeing a renaissance in understanding the mitochondrion, not just as a “power plant” that burns food, but as a quantum sensor that interacts with the environment. It senses gravity, magnetism, and most importantly, light.

Martin Picard and Nirosha Murugan are leaders in this with their energy resistance hypothesis and whom I’d recommend to follow. Check out their paper on The Energy Resistance Principle and podcast episode associated with it.

This brings us to the topic of the week: Light as a Metabolic Nutrient.

This is not “New Age” woo-woo. This is hard biophysics.

And this is what brings us to recent discussions, amplified by neuroscientists like Dr. Glen Jeffery on the Huberman Lab, which are bringing this into the mainstream. The idea is simple but radical: we are suffering from a deficit of photons. We are starving for the right frequencies of light while overdosing on the wrong ones (junk LED light).

The South Asian Connection

For South Asians, this shift to biophysics is everything. Our “Paradox,” getting diabetes while skinny, having heart disease with normal cholesterol, makes little sense through a purely chemical lens. We aren’t always eating more calories than our neighbors.

This is further complicated by a cultural habit we know all too well: the avoidance of the sun. For generations, we’ve been told by our elders and society to stay out of the sun, often (and this is unfortunate) to avoid getting darker. While maybe well-intentioned for aesthetics, this advice has been disastrous for our biophysics. It has deepened our photon deficit, starving our mitochondria of the very nutrient they need.

But through a biophysical lens, it makes perfect sense. Our mitochondria are “tightly coupled” nanomotors designed to save energy. When we park these efficient motors in a sedentary, blue-lit world, the electrons don’t just “burn off”; they jam.

Understanding this physics allows us to stop blaming our “bad genetics” and start tuning our engines.

Let’s dive into the quantum machinery of your cells. You’ll need some chai for this as lots of depth here.

It’s About the Water

Dr. Glen Jeffery’s research at UCL has thrust the humble mitochondrion into the spotlight, yes, pun intended. We used to think of mitochondria just as “power plants.” We now know they are also light sensors.

Jeffery compares our modern indoor environment, saturated with blue-heavy LEDs, to “asbestos” for our cells. It’s junk light. It stimulates us but doesn’t nourish us. His research shows that specific wavelengths (deep red and near-infrared) act as a nutrient.

It sounds like sci-fi, but the data is real.

A 15-minute exposure to deep red light was shown to reduce blood glucose spikes by nearly 28%.

But here is where the science gets truly elegant.

Decades ago, researchers assumed mitochondria absorbed red light directly through a specific enzyme called Cytochrome C Oxidase (CCO). In fact, this challenges my own understanding, as in my training, I was taught that light was absorbed in CCO.

But when Jeffery tried to prove it with spectrometry, the absorption profile didn’t match the mitochondria. It matched something else entirely: Water.

It brings to mind David Foster Wallace’s famous commencement speech, This is Water. He tells the story of two young fish swimming along who meet an older fish. The older fish nods and says, “Morning, boys. How’s the water?” The two young fish swim on for a bit, and then eventually one of them looks over at the other and asks, “What the hell is water?”

For decades, science has been the young fish. We were so obsessed with the enzymes and the proteins, the swimming creatures, that we ignored the medium they were swimming in. We ignored the water.

Specifically, the structured nanoscopic water inside the mitochondrial matrix.

Long-wavelength light alters the viscosity of that water. Now imagine ATP synthase, the spinning turbine that produces all your ATP, trying to rotate in thicker or thinner fluid. If the water is viscous (like molasses), the turbine slows down. Change the viscosity back to a fluid state, and you change the speed of the turbine.

Expose mitochondria to the right wavelengths in the red/near-infrared range, and two things happen:

1. ATP production increases almost immediately (the turbine spins faster).

2. The cell begins building more of the electron transport chain itself,

   ”laying more track,” as Jeffery put it.

This isn’t mystical “energy healing.” It’s physics driving biochemistry.

[Check out this interactive mitochondria we made to illustrate this]

The “Prius” Problem

To understand why light therapy is a game-changer specifically for us, we have to look at our engines.

Most of my South Asian patients fit a profile: normal BMI, but high visceral fat, high triglycerides, and early insulin resistance. We call this the “Thin-Fat” phenotype. But why does this happen?

The answer lies 65,000 years in the past.

Mitochondrial DNA (mtDNA) tracks our maternal ancestry (we’ll have more on the specifics of this on a later newsletter). While Europeans largely carry Haplogroup N (adapted for cold), South Asians largely carry Haplogroup M (adapted for heat and famine).

• The European Engine (Haplogroup N/H): Think of this like a Hummer. It’s “loose.” It burns fuel inefficiently and generates a lot of heat (thermogenesis) to survive the cold. It wastes energy.

• The South Asian Engine (Haplogroup M): Think of this like a Toyota Prius. It is “tightly coupled.” It is hyper-efficient. It extracts every ounce of ATP from a calorie because our ancestors faced heat (where excess body heat is deadly) and famine.

In a famine, the Prius wins. In a modern world of endless UberEats and desk jobs, the Prius becomes a liability.

The Traffic Jam

This is where we must layer in the work of Martin Picard, a pioneer in mitochondrial psychobiology. He proposes a concept called Energy Resistance, and it explains the South Asian condition perfectly.

Think of your mitochondria as a club. When the club is at capacity (full of electrons/ATP) and the fire marshal (Reductive Stress) says “no more,” the bouncers close the doors.

• The Problem: Your “Prius” engine is so efficient it doesn’t leak energy. It hits capacity very fast when you are sedentary.

• The Reaction: To prevent the engine from exploding (oxidative damage), the mitochondria signal the cell to stop accepting fuel.

• The Result: The cell locks the doors to glucose. We clinically call this “Insulin Resistance.”

But it is actually Energy Resistance.

Your body isn’t broken; it is protecting itself. The mitochondria are resisting new energy because they haven’t used the old energy. For South Asians, because our engines are “tightly coupled” and don’t waste heat, we hit this Energy Resistance threshold much faster than a European “Hummer” engine would, even at the same calorie intake.

We are chemically resistant because we are electrically full.

Light as The Traffic Controller

This is why I am so excited about Photobiomodulation (PBM).

Red and Near-Infrared (NIR) light targets the very end of that electron chain. Whether by reducing water viscosity to speed up the turbine, or by interacting with copper centers to knock out inhibitory Nitric Oxide, light acts as a traffic controller.

It forces the electrons to move. It clears the jam.

By mechanically accelerating the electron chain, light therapy relieves the “Energy Resistance.” It creates demand, allowing the bouncers to open the doors again, potentially reopening the gates to glucose, without you having to run a marathon (though please, still exercise).

The Fitzpatrick Factor: Why Melanin Changes the Rules

Before you go buy a red light panel on Amazon. You need to understand your skin type, or you will waste your money, or worse, damage your skin. It’s something that hasn’t received much attention after this podcast episode, but is vital to understand.

In dermatology, we use the Fitzpatrick Scale to classify skin based on how it responds to UV light. Most clinical studies on light therapy are done on mice (white fur) or Caucasian humans (Fitzpatrick Types I-III).

South Asians typically fall into Fitzpatrick Types III (Medium/Olive), IV (Light Brown), V (Brown), and VI (Deeply Pigmented).

This matters because melanin is not just a color; it is a biological shield. It is a broad-spectrum absorber of light.

Think of it like “Bioavailability” in Pharmacology.
If you have a patient with poor gut absorption (say, Celiac disease), you know that a standard oral dose of a medication won’t achieve therapeutic levels in the blood. The absorption barrier reduces the bioavailability.
Melanin acts the same way. It is a barrier that reduces the “bioavailability” of photons reaching your mitochondria.

• The Red Light Trap (600nm - 670nm): If you have Fitzpatrick Type V skin, your epidermis absorbs 60-80% of standard red light. The energy gets trapped in the skin surface as heat. It never reaches the deep muscles or liver where your metabolic “traffic jam” is happening. This is great for surface wrinkles, but useless for diabetes or visceral fat.

• The Thermal Risk: Because melanin absorbs this energy as heat, using high-intensity panels can actually cause thermal injury or trigger hyperpigmentation (melasma) in South Asians.

The Solution? The “Optical Window.”

Melanin becomes much more transparent as the wavelength gets longer. This is why we must shift our focus to Near-Infrared (NIR) light (810nm - 850nm). These wavelengths slip past the melanin shield and penetrate deep into the tissue.

Example Protocol

If you want to harness this physics for your longevity, here is one possible specific approach for the South Asian phenotype:

1. Start with the Source (Sunlight): Before any devices, use the sun. And to answer the common question: Yes, we are focusing on the Infrared. While UV is for Vitamin D, nearly 50% of the sun’s energy is Infrared. This is the “nutrient” your mitochondria are starving for.

   • Recommendation: 10-20 minutes of morning sun (before 10 AM). This provides the natural “spectral diet” of Infrared light to prime your mitochondria for the day.

2. Go Near-Infrared (Devices, no endorsement here): If using a device, ignore the visible red light for metabolism. You need 810nm, 830nm, or 850nm. These are the wavelengths that can punch through Type IV-VI skin.

3. Adjust Your Dose (The Multiplier): Because your melanin acts as a filter, fewer photons get through. You need to increase the exposure time to compensate.

   • Fitzpatrick Type III (Medium/Olive): Add 1.2x time.

   • Fitzpatrick Type IV (Light Brown): Add 1.5x time.

   • Fitzpatrick Type V-VI (Brown/Dark Brown): Add 2x time.

   • Example: If a protocol says “10 minutes,” a darker-skinned individual may need 15-20 minutes to get the same therapeutic dose to the mitochondria.

4. Target the “Tank”: Aim the light at your largest muscle groups, your quads and your back. This is where we need to create the glucose sink.

5. Timing is Everything: Do this in the morning (8 AM - 10 AM). Your mitochondria have a circadian rhythm; they are most receptive early in the day.

6. The Stack: Combine PBM with a walk. Light unclogs the jam; movement keeps the traffic flowing.

The Takeaway

We are not just chemical beings; we are electrical ones.

So, get some morning sun, go for a walk and keep those electrons moving.

Disclaimer: This is educational, not medical advice. Always consult your physician before starting new therapies.