A masterclass on insulin resistance—mechanisms and implications | Gerald Shulman, M.D., Ph.D. (#140 rebroadcast)
Gerald Shulman, Professor of Medicine at Yale, clarifies insulin resistance in muscle and liver, its evolutionary purpose, and mechanisms leading to and resolving it. He discusses the roles of diet, exercise, and pharmacology, including Metformin's action and suitability as a longevity agent.
Deep Dive Analysis
13 Topic Outline
Gerald Shulman's Background and Interest in Metabolism
Insulin Resistance as a Root Cause of Chronic Disease
Understanding Metabolism with Nuclear Magnetic Resonance (NMR) Spectroscopy
Defining and Diagnosing Insulin Resistance in Muscle
The Role of Lipids and Diacylglycerols in Muscle Insulin Resistance
Exercise's Impact on Muscle Insulin Resistance and Glucose Disposal
How Muscle Insulin Resistance Drives Fatty Liver Disease
Molecular Basis of Liver Insulin Resistance: DAGs and PKC Epsilon
Evolutionary Explanation for Insulin Resistance: Survival During Starvation
Revisiting Gluconeogenesis Regulation by Insulin and Acetyl-CoA
Inflammation and Fat Cell Dysfunction in Driving Hyperglycemia
Therapeutic Approaches for Fatty Liver and Insulin Resistance
Metformin's Mechanism of Action and Longevity Implications
7 Key Concepts
Insulin Resistance
A condition where the same amount of insulin does not produce its normal effects, requiring more insulin to cause muscle to take up glucose, the liver to turn off glucose production, or fat cells to regulate fat breakdown. It's a common phenomenon, affecting about half the population, often asymptomatically before blood sugar levels rise.
NMR Spectroscopy
A non-invasive technique that uses the spin properties of atomic nuclei in a strong magnetic field to measure the amount and location of metabolites within living cells. It allows scientists to track the metabolism of labeled molecules (like C13 glucose) and measure intracellular pathway flux, providing biochemical information without ionizing radiation.
Diacylglycerol (DAG)
A lipid intermediate, specifically the SN1-2 isoform in the plasma membrane, that accumulates when fatty acid uptake into a cell exceeds its oxidation or storage as triglyceride. DAGs are bioactive metabolites that activate novel protein kinase C (PKC) isoforms, leading to the inhibition of insulin signaling and thus insulin resistance.
Novel Protein Kinase C (nPKC)
A family of enzymes, specifically PKC theta in muscle and PKC epsilon in liver, that are activated by increased levels of diacylglycerols. When activated, these PKCs interfere with the insulin signaling cascade, blocking the phosphorylation of key proteins like IRS-1 and the insulin receptor itself, ultimately impairing glucose transport into cells.
De Novo Lipogenesis (DNL)
The process by which glucose is converted into fat, primarily in the liver. In insulin-resistant individuals, especially those with muscle insulin resistance and compensatory hyperinsulinemia, DNL is significantly upregulated, contributing to increased liver fat synthesis and the development of metabolic associated fatty liver disease (MAFLD).
Gluconeogenesis
The metabolic pathway that generates glucose from non-carbohydrate precursors like amino acids and lactate, primarily in the liver. It is a critical process for maintaining blood glucose levels during fasting and starvation, but its acceleration in type 2 diabetes, driven by increased hepatic acetyl-CoA and peripheral lipolysis, contributes to fasting hyperglycemia.
Mitochondrial Uncoupling
A process where the efficiency of mitochondrial oxidative phosphorylation is reduced, causing mitochondria to burn more fat to generate the same amount of ATP, with the excess energy dissipated as heat. Targeted uncoupling in the liver is being explored as a therapeutic strategy to reduce liver fat, reverse insulin resistance, and improve lipid profiles in conditions like NAFLD and NASH.
10 Questions Answered
In a healthy person, ingested carbohydrates are primarily stored as liver and muscle glycogen (80-90%). In a person with type 2 diabetes, there's a block in glucose uptake by muscle and the liver produces twice the normal amount of glucose through gluconeogenesis, leading to elevated blood sugar.
The primary biochemical block in muscle insulin resistance is at the glucose transport step, meaning glucose has difficulty entering the muscle cell. This is evidenced by reduced levels of both glucose 6-phosphate and intracellular glucose in muscle cells of insulin-resistant individuals.
Increased intracellular diacylglycerols (DAGs) in muscle cells activate novel protein kinase C (PKC) isoforms (theta and epsilon). These activated PKCs then interfere with insulin signaling, specifically by reducing insulin tyrosine phosphorylation of IRS-1 and subsequent PI3 kinase activation, which is required for GLUT4 glucose transporter translocation to the cell membrane.
When muscle is insulin resistant, ingested glucose cannot be efficiently stored as muscle glycogen and is instead diverted to the liver. The compensatory hyperinsulinemia in the portal vein then stimulates de novo lipogenesis (DNL) in the liver, leading to increased liver fat synthesis, elevated plasma triglycerides, and reduced HDL cholesterol.
Exercise can bypass the block in insulin-stimulated glucose transport by activating AMPK (AMP-activated protein kinase), which causes GLUT4 translocation to the cell membrane independently of the PI3 kinase pathway. Chronic exercise can also reduce intracellular lipids and DAGs, improving overall insulin signaling.
Similar to muscle, diacylglycerols (DAGs), specifically the SN1-2 isoform, accumulate in the liver and activate PKC epsilon. PKC epsilon directly binds to and inhibits the insulin receptor kinase itself, preventing proper insulin signaling and leading to reduced glucose uptake and glycogen synthesis in the liver.
Insulin resistance likely evolved as a protective mechanism to aid survival during starvation. By promoting insulin resistance in muscle and liver, glucose is preserved in circulation for critical organs like the central nervous system, which relies heavily on glucose for energy.
Insulin primarily regulates gluconeogenesis indirectly by putting the brakes on peripheral lipolysis, which reduces fatty acid delivery to the liver. Less fatty acid delivery leads to less generation of acetyl-CoA in the liver, which in turn reduces pyruvate carboxylase activity, a key enzyme in gluconeogenesis.
Fasting hyperglycemia in type 2 diabetes is primarily driven by increased gluconeogenesis in the liver. This is exacerbated by inflammation in fat cells, which promotes increased lipolysis, leading to more fatty acid delivery to the liver, elevated hepatic acetyl-CoA, and a twofold increase in gluconeogenesis.
At clinically relevant concentrations (50-100 micromolar), Metformin is believed to inhibit mitochondrial glycerol 3-phosphate dehydrogenase. This inhibition leads to an increase in cytosolic NADH and a decrease in NAD, altering the redox state and specifically inhibiting gluconeogenesis from lactate and glycerol, but not from other substrates like alanine.
12 Actionable Insights
1. Prioritize Metabolic Health for Longevity
Focus on fixing your metabolism to delay the onset of chronic diseases like atherosclerosis, cancer, and dementia, as these conditions are significantly amplified by metabolic dysfunction.
2. Implement Diet and Exercise for Weight Loss
Actively pursue diet and exercise as the primary means for weight loss, as this is described as the best way to reverse type 2 diabetes and address underlying metabolic issues.
3. Find a Sustainable Weight Loss Strategy
Choose a weight loss approach that you can adhere to long-term, as consistent adherence is more crucial for preventing weight regain than short-term success.
4. Engage in Regular Aerobic Exercise
Perform regular exercise, such as three 15-minute bouts on a StairMaster at approximately 65% MVO2 max for six weeks, to normalize insulin-stimulated muscle glycogen synthesis and reverse insulin resistance.
5. Utilize Acute Exercise for Glucose Disposal
Incorporate a single 45-minute bout of exercise to immediately improve glucose uptake into muscle, reduce de novo lipogenesis, and lower liver triglycerides.
6. Combine Carbohydrate Restriction with Exercise
Pair reduced carbohydrate consumption with exercise to activate AMPK and enhance insulin-independent glucose uptake, effectively managing glucose even with minimal insulin.
7. Consider Carbohydrate Restriction or Fasting
Explore carbohydrate restriction or periodic fasting as effective strategies for weight loss, especially if insulin resistant, as these methods can be easier to adhere to than general caloric restriction.
8. Re-evaluate Personal Health Norms
Shift your understanding of ’normal’ health parameters by comparing your metrics to those of truly insulin-sensitive individuals, rather than relying on population averages.
9. Consult on GLP-1 Agonists for Weight Loss
Discuss with a doctor the use of GLP-1 agonists, which can aid weight loss by reducing food intake through central mechanisms that decrease appetite.
10. Consult on SGLT-2 Inhibitors for Glucose/Weight
Talk to a doctor about SGLT-2 inhibitors, which promote glucose loss in urine (around 400 calories/day) and can lead to mild weight and liver fat reductions.
11. Metformin: Consider Personal Metabolic State
If insulin resistant, metformin can be a beneficial agent, but if you are lean, insulin-sensitive, and vigorously exercising, it may not provide benefit; always consult a doctor.
12. Listen to AMA #20 for Insulin Resistance
Access AMA #20, ‘Simplifying the Complexities of Insulin Resistance,’ with Bob Kaplan for a more detailed explanation of complicated areas of this topic.
7 Key Quotes
Insulin resistance is the foundation upon which the major three chronic diseases sit. So you described some ways in which patients with type 2 diabetes die, specifically through amputations or complications of amputation, such as infections, and obviously through end-stage renal disease. But I would argue that the majority of the mortality through diabetes comes not so much through diabetes, but through its amplification of atherosclerotic disease, cancer, and dementia, all of which are force multiplied in spades by type 2 diabetes.
Peter Attia
Insulin resistance is driving a lot of disease, and you're also spot on in that that's what's killing our patients with type 2 diabetes. It is heart disease.
Gerald Shulman
Insulin resistance, which is very common, it's probably one quarter of our population and one half of our population has it perfectly asymptomatic. You don't know you have it.
Gerald Shulman
If something's important, it usually hangs around. That's a long time.
Gerald Shulman
In my view, insulin resistance was a protective mechanism throughout evolution that allowed us to survive all species during starvation, which was probably the predominant environmental exposure we've had for the last many, many millennia. And it's only in recent years, recent decades, that now we're in this toxic environment of overnutrition.
Gerald Shulman
If I had to pick two molecules that are driving metabolic disease, it's acetyl-CoA driving pervert carboxylase. And again, the diacyl-glycerol is activating epsilon.
Gerald Shulman
Whatever works to everyone is so different, different likes, different dislikes. I say, look at the scale, whatever works for you to lose weight, because I know if you lose the weight, your diabetes is going to get better.
Gerald Shulman
1 Protocols
Exercise Regimen to Reverse Muscle Insulin Resistance
Gerald Shulman- Engage in StairMaster exercise.
- Perform three 15-minute bouts.
- Maintain an intensity of approximately 65% MVO2 max.
- Continue for six weeks.