#140 - Gerald Shulman, M.D., Ph.D.: A masterclass on insulin resistance—molecular mechanisms and clinical implications

Drive with Dr. Peter Attia

Podcast Notes Key Takeaways “If we are going to be serious about the business of delaying onset of death, we have to be serious about the business of delaying the onset of chronic disease.” – Peter AttiaInsulin resistance is the root cause of diabetes and downstream chronic diseaseDiabetes amplifies atherosclerotic disease, Alzheimer’s disease, and cancerAbout 50% of people with insulin resistance are asymptomaticYoung, lean adults are presenting with profound insulin resistance in muscle with no problems in the liverUnderstanding insulin resistance will be critical for preventing and treating disease Nuclear Magnetic Resonance (NMR) allows us to get biochemical information of metabolites (i.e., glucose) and key intermediates inside cells

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Gerald Shulman is a Professor of Medicine, Cellular & Molecular Physiology, and the Director of the Diabetes Research Center at Yale. His pioneering work on the use of advanced technologies to analyze metabolic flux within cells has greatly contributed to the understanding of insulin resistance and type 2 diabetes. In this episode, Gerald clarifies what insulin resistance means as it relates to the muscle and the liver, and the evolutionary reason for its existence. He goes into depth on mechanisms that lead to and resolve insulin resistance, like the role of diet, exercise, and pharmacological agents. As a bonus, Gerald concludes with insights into Metformin’s mechanism of action and its suitability as a longevity agent.

We discuss:

Gerald’s background and interest in metabolism and insulin resistance (4:30); Insulin resistance as a root cause of chronic disease (8:30); How Gerald uses NMR to see inside cells (12:00); Defining and diagnosing insulin resistance and type 2 diabetes (19:15); The role of lipids in insulin resistance (31:15); Confirmation of glucose transport as the root problem in lipid-induced insulin resistance (40:15); The role of exercise in protecting against insulin resistance and fatty liver (50:00); Insulin resistance in the liver (1:07:00); The evolutionary explanation for insulin resistance—an important tool for surviving starvation (1:17:15); The critical role of gluconeogenesis, and how it’s regulated by insulin (1:22:30); Inflammation and body fat as contributing factors to insulin resistance (1:32:15); Treatment approaches for fatty liver and insulin resistance, and an exciting new pharmacological approach (1:41:15); Metformin’s mechanism of action and its suitability as a longevity agent (1:58:15); More.

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