The man who showed that fat could silence insulin

For years, type 2 diabetes was seen as a sugar problem: too much glucose in the blood, too little insulin to manage it. Doctors prescribed drugs to lower blood sugar – often without asking why the body had stopped responding in the first place. But underneath lay a defect far more common – and far more dangerous.

“Insulin resistance is not just about diabetes,” says Professor Gerald I. Shulman, who is also Co-Director of the Yale Diabetes Research Center at the Yale School of Medicine. “It is one of the biggest threats to human health in the 21st century. It is driving cardiovascular disease, fatty liver, obesity-related cancer — and probably Alzheimer's disease.”

Shulman, a physician-scientist at Yale University, has spent more than 30 years figuring out how this defect works. He calls it the trap door of metabolism: when insulin is working, glucose slips into muscle cells and is stored as fuel. But when resistance sets in, the door jams shut. Sugar builds up in the blood, fat leaks into places it should not be and the body starts to come apart.

The catch is that most people never feel it happening. Even some young, lean volunteers in Shulman’s studies – seemingly healthy – carried the defect in their muscles.

“Just like hypertension used to be called a silent killer, that is what insulin resistance is.”

By the time blood sugar goes up, the damage may already be done: arteries scarred, livers inflamed, cancer beginning to grow. One in four healthy young adults – lean, fit and outwardly fine – already carry the defect.

This hidden epidemic is what makes Shulman’s work so important – and why he is receiving the 2025 EASD–Novo Nordisk Foundation Diabetes Prize for Excellence. His career has taken one scientific risk after another: threading catheters into dog livers, sliding human subjects into magnetic resonance imagers and chasing obscure lipid fragments most researchers ignored. Each gamble paid off – revealing not just how insulin resistance works but how it might be undone.

Childhood lessons at diabetes camp

Gerald Shulman did not learn about metabolism in a classroom. He learned it in the cabins of a summer camp for children with type 1 diabetes in Michigan. His father was the camp doctor, his mother a nutritionist, and together they taught children how to live with injections, strict diets – and constant risk.

“Every morning the kids lined up outside the cabin. My dad would check their urine for glucose and ketones and then draw up these big pork or beef insulin injections. They hurt, but that is how it was done back then.”

Meals were planned down to the last calorie.

“You would get a card – A through E – depending on your size and activity level. That card dictated how much food was scooped on your plate.”

The risks were always close.

“Once in a while a camper would faint. If they were conscious, orange juice brought them back. Sometimes it meant glucagon or even fluids and insulin in the infirmary.”

For young Shulman, those moments stuck – collapse one minute, recovery the next.

“It showed me how fragile blood sugar is, and how, if you understand the biology, you can change someone’s life in an instant.”

From physics to human metabolism

The camp had shown him how easily blood sugar could tip out of balance. In college, Shulman started asking how the body managed that balance – and why it sometimes failed. His first love was physics, with its neat equations and rules. But metabolism kept pulling him in.

“My true first love was physics. Advanced physics, math – I loved that. But the physiology always stuck with me, the interest in studying metabolism.”

Biochemistry became the bridge between the two.

“Physics is about the universe. Biochemistry is about the body. The same principles apply.”

Medicine gave him a way to connect those principles to real people. What drew him in was how rapidly things could change – molecular switches that make the difference between health and serious illness.

“How is blood sugar regulated? What organs are responsible? And how do we fix it? Diabetes gave me a way to ask those questions.”

To Shulman, insulin resistance was not an abstract concept. It was the key to a global epidemic – and solving it meant bringing together physics and physiology.

Tracking sugar in real time

In medical school, Shulman was not satisfied with blackboard diagrams. He wanted to see metabolism in motion. His PhD studies at Vanderbilt University gave him the tools to do that. By threading catheters into the portal and hepatic veins of dogs, he could track glucose flowing in and out of the liver, minute by minute.

“We could really look at everything going on in the liver: measure what was coming in and what was going out and interpolate what was happening inside the cell.”

The timing was perfect. Scientists had just discovered that somatostatin could shut down both insulin and glucagon.

“Suddenly we could hold insulin and glucagon steady while raising glucose alone – showing that high blood sugar by itself puts the brake on the liver’s output.”

What grabbed Shulman was not the theory – it was seeing biology change in real time.

“You take away glucagon, and within five minutes the liver flips – from producing glucose to taking it up. I loved that immediacy.”

These studies showed him that metabolism is never still. It shifts from moment to moment – and you need the right tools to catch it in the act.

Opening a window into cells

During his residency at Duke University and fellowship at Massachusetts General Hospital, Shulman dug deeper into the molecular machinery behind insulin. In Joseph Avruch’s laboratory, he purified insulin receptor kinases from placentas – the same proteins textbooks used to gloss over with diagrams and question marks.

“The big question was always: how does insulin work? You would see these cartoons where insulin binds, and then somehow glucose goes in. Now we had the receptor as a kinase in a test tube.”

Just across the street, Robert Wolfe was breaking ground with stable isotope tracers – safe molecular “labels” that show how glucose moves through the body.

Then came the real breakthrough: nuclear magnetic resonance (NMR), a new kind of scan. Unlike X-rays or positron emission tomography (PET), which only show structure, NMR could capture the chemistry happening inside living cells.

For the first time, researchers could watch energy molecules at work – and follow glucose turning into stored fuel – without using radiation.

“You could see ATP, phosphocreatine, even intracellular pH. With carbon NMR, you could actually watch glucose turn into stored fuel in real time. And it was safe – no radiation. That was the dream: to look inside living cells noninvasively.”

It was a risky bet – one many thought would never work for people.

“Sometimes you have to take chances. It absolutely could have failed – but I took the chance, and it worked.”

When insulin’s door will not open

With NMR in hand, Shulman could finally ask a basic but critical question: when insulin is around, where does the glucose actually go?

“A very simple question – where does glucose go, and more importantly, where does it not go among insulin-resistant individuals with type 2 diabetes?”

For healthy people, the answer was clear: glucose moves into muscle and is stored as glycogen. But for people with diabetes, the flow nearly stopped.

“We could show in real time that glycogen synthesis – the major pathway of glucose disposal – was profoundly reduced in type 2 diabetes.”

At the time, scientists were debating whether the problem was glycogen synthase, hexokinase or transport. To find out, Shulman’s team labelled glucose with a harmless carbon tracer (¹³C) and watched it flow into glycogen, minute by minute.

They used phosphorus NMR to measure glucose-6-phosphate – ruling out glycogen synthase. Tracking glucose inside the cells ruled out hexokinase.

“It is basically like a trap door. When insulin binds, the trap door opens. In insulin resistance, the door stays shut.”

The real problem was right at the entrance: glucose was not getting into the cells. And what mattered most to Shulman was that this was not a guess – it was proven in humans.

“I would never take on a question I could not explain to my dad, who was a private practitioner. If I could not explain it to him, I would not go there. This was simple: insulin is there, glucose is outside, and it cannot get in.”

“For the first hour, two hours, nothing happened. Then around three to four hours, insulin resistance appeared. Transport was blocked.”

The results challenged an old theory – the Randle hypothesis. In the 1960s, Philip Randle had suggested that fatty acids caused insulin resistance by blocking glucose oxidation at pyruvate dehydrogenase.

“Randle was right that fatty acids cause insulin resistance. But not through pyruvate dehydrogenase. What we showed is that it blocks the insulin activation of transport.”

NMR pointed to the real culprits: tiny fat fragments called diacylglycerols that lodged in the cell membrane and flipped novel protein kinase Cs (PKCs) into action.

“It turned out to be tiny fat fragments called diacylglycerols. A specific type slips into the cell’s outer wall and flips PKCs – PKC-theta in muscle, PKC-epsilon in liver. Different switches, same effect: the insulin signal is jammed, and the door stays shut.”

Like grease in a lock, these fragments kept the insulin receptor from turning. Whether or not resistance developed came down to balance: if mitochondria could burn the fat or store it in droplets, the signal stayed clear.

Why would the body evolve a system that now seems to work against us? For Shulman, the answer is famine.

“During starvation, fatty acids flood into tissues. Diacylglycerols build up, novel PKCs are activated and you become insulin resistant. That preserves glucose for the brain, red blood cells and the renal medulla.”

The programme was written long ago – right down to a single amino acid, threonine. Shulman’s laboratory identified the exact site on the insulin receptor where PKC-epsilon shuts the door.

“Threonine has been conserved from flies to humans. It has been there for hundreds of millions of years, which tells you that this pathway was important for survival.”

That made perfect sense in a world of scarcity. But in today’s world of constant calories, the same mechanism drives disease. What once protected us in famine now pushes us toward diabetes and more.

“It made sense then. Now it is killing us.”

This evolutionary view also helped explain a puzzle: why endurance athletes, whose muscles are packed with fat, remain highly insulin sensitive.

“Everything is location, location, location. If fat is tucked safely into lipid droplets, it is inert. When it spills onto the plasma membrane, resistance appears.”

Fat in the wrong place

Rare diseases can sometimes act like nature’s experiments – and for Shulman, people with lipodystrophy made the message crystal clear.

“We studied humans with lipodystrophy – no visceral fat at all, but huge ectopic fat in the liver and muscle. They had enormous insulin resistance, full-blown diabetes.”

They looked lean on the outside but were severely ill on the inside. The missing link was leptin – the hormone that tells the brain how much fat the body has.

“When we treated them with leptin, ectopic lipid came down – and the insulin resistance was fixed.”

For Shulman, these extreme cases confirmed what he had seen again and again in scans and clamps: it is not how much fat you carry but where it ends up.

“It really showed that it is not how obese you are. It is where the fat is. Liver and muscle fat are the dangerous kinds.”

And the lesson went far beyond rare conditions. Even young, healthy adults – lean, active, and outwardly fine – sometimes showed the same early defect in muscle if both parents had diabetes.

“If you are insulin resistant and both your parents had diabetes, that is the strongest predictor that you will go on to develop it yourself.”

Defatting the liver reverses diabetes

The next big question was whether removing fat could actually reverse type 2 diabetes among real patients. Together with his wife, Kitt Petersen, Shulman designed a tightly controlled study. People with diabetes were put on a 1,200-calorie diet and tracked week by week.

“We monitored them closely. After two or three months, their fasting hyperglycaemia was gone. We fixed their diabetes.”

It did not take extreme weight loss.

“They only had to lose about 7–10% of body weight. That was enough to basically defat the liver.”

NMR scans showed what was really happening. The scale told one part of the story – but the liver told the rest.

“Every person with poorly controlled type 2 diabetes we put in the magnet had fatty liver. That was a big surprise to everyone.”

As that fat dropped, everything flipped.

“When liver fat went down, gluconeogenesis normalised, and insulin resistance disappeared.”

For Shulman, the message was simple: you could reverse type 2 diabetes without miracle drugs – just by draining fat from the liver. Roy Taylor in the United Kingdom would later prove the same thing on a larger scale, but the first proof of concept came from Yale University in New Haven, Connecticut.

Workouts unlock muscle sugar

If diet could reset the liver over months, exercise showed how rapidly things could shift.

“We even showed that a single bout of exercise opens the door for glucose uptake in muscle. You do not have to wait weeks – it happens right away.”

Regular training strengthened the effect, making muscle more insulin sensitive over time. But here was the paradox: endurance athletes have more fat inside their muscles than many people with diabetes – and yet they stay healthy.

“This is the athlete’s paradox. Marathon runners have tons of intramyocellular fat, but they are exquisitely insulin sensitive.”

The key was how the fat was stored.

“If fat is in the lipid droplet, it is safe. If it is on the plasma membrane, it blocks insulin.”

Exercise kept fat locked away in droplets and the mitochondria burning it off. Each workout helped to restore glucose flow – and kept the trap door working.

“Training restores the balance. It keeps the trap door working.”

Drugs that target fat safely

Lifestyle changes could work – but not everyone can stick to strict diets and exercise. For Shulman, drugs have to be part of the answer – but only if they target the real cause.

“We have had wonderful medicines for diabetes. But most do not treat the root cause – they just lower glucose.”

Thiazolidinediones (TZDs) were the first sign that shifting fat to the right place could make a difference.

“They really do work. They pull fat out of the liver and muscle and put it back in adipose tissue. But patients gain weight, there are bone issues and doctors do not like to prescribe them.”

The newer glucagon-like peptide-1 (GLP-1) agonists made a big impact – reducing appetite and melting away liver fat.

“You see diabetes improve even before the big weight loss. It is because liver fat comes down.”

Nevertheless, Shulman saw these drugs as only half the solution. The real goal was not just to lower glucose – it was to reverse insulin resistance itself.

Re-engineering a risky fat-burner

The missing piece of the puzzle was energy burn. Shulman found inspiration in a long-forgotten drug: dinitrophenol (DNP).

“In the 1920s, hundreds of thousands of people took DNP for weight loss. It worked – but it was dangerous.”

The issue was uncontrolled spikes in blood levels. Working with Yale University chemist David Spiegel, Shulman redesigned the drug into safer, controlled-release versions that targeted the liver.

“Only a tiny amount in the cell is enough to work, while dangerous levels are hundreds of times higher. That gave us a huge safety window.”

In rodents and primates, the compounds cleared fat from the liver, reversed insulin resistance and even reduced fibrosis. Early human trials began to show the same trend.

“We are in Phase 2 now. Insulin resistance reverses, fatty liver comes down, hyperlipidaemia improves. And it is well tolerated.”

What thrilled Shulman most was being able to separate benefit from risk.

“We can actually dissociate the toxicity – the hyperthermia – from burning fat. This is what I am most excited about now.”

To him, these compounds were the missing counterpart to GLP-1 agonists: not just less energy in – but safely burning more out.

Damage before diabetes shows

By the time most people are diagnosed with type 2 diabetes, the damage is already deep – like spotting a house fire only after the roof has collapsed. Arteries may be stiff, livers scarred, cancer quietly fuelled by metabolic changes. For Shulman, the real tragedy is how long the defect goes unnoticed.

“We have been treating the smoke, not the fire.”

Insulin resistance begins years – sometimes decades – before blood sugar ever goes up. But the medical profession still waits until glucose crosses a threshold before stepping in.

“It is driving hyperlipidaemia, cardiovascular disease, fatty liver, obesity-associated cancer – and probably Alzheimer’s disease.”

What bothers him most is how invisible it remains – not just to patients but to many doctors. To Shulman, insulin resistance is not some obscure laboratory marker. It is a slow epidemic reshaping health over a lifetime.

Catching insulin resistance early in life

Shulman’s research showed that insulin resistance can start long before any outward signs appear. Some of the young, lean volunteers in his studies – with normal weight and healthy bloodwork – carried the same muscle defects as their parents with diabetes.

“It always starts in muscle – that is the canary in the coal mine, warning long before disease appears. If we can keep muscle insulin sensitive, we can often prevent the rest from unravelling.”

At this early stage, the condition was still reversible.

“The first thing we see is muscle insulin resistance. And a single bout of exercise can open the door again.”

Shulman believes that the medical profession should treat insulin resistance as aggressively as it treats high cholesterol or blood pressure.

“If you are twenty and insulin resistant, I want to fix it – before the beta cells fail, before the heart attack.”

To him, the future is not just about better treatments – it is about catching the problem early, decades before it does damage.

Gambles that changed diabetes research

Looking back, Shulman saw his career as a series of bets – threading catheters into dogs, bringing NMR into the clinic and chasing obscure lipid fragments most others ignored.

“You have to take chances. If it does not work, you learn. If it does, you change the field.”

What guided him was always the same goal: translating science to people.

“At the end of the day, the model I care about is humans.”

At the heart of it all was balance – energy in versus out, fat stored safely versus fat gone astray, insulin’s trap door opening or staying stuck.

“Insulin resistance is the silent killer of our time. But it does not have to be. We can fix it.”

From the cabins of that childhood diabetes camp to today’s clinics, the lesson stayed the same: metabolism is not fixed. It can tip toward health – or toward disease. The trap door decides.