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

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Dec 7, 2020

Gerald Shulman, a Professor at Yale and expert in insulin resistance, shares fascinating insights into the molecular mechanisms behind this condition and its role in chronic diseases like type 2 diabetes. He discusses how diet and exercise influence insulin sensitivity and explains the evolutionary purpose of insulin resistance in survival. The implications of his research on gluconeogenesis and lipid metabolism shed light on metabolic health, while his analysis of Metformin reveals its potential as a longevity agent. A masterclass in understanding metabolism!

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INSIGHT

NMR Spectroscopy

NMR spectroscopy allows non-invasive study of cellular metabolism.
By tracking labeled molecules, researchers measure metabolic flux within cells.

INSIGHT

Glucose Metabolism

In healthy individuals, ingested glucose is primarily stored as glycogen.
In diabetics, the liver produces too much glucose, and muscle uptake is impaired.

INSIGHT

Muscle Insulin Resistance

Insulin resistance often starts with impaired muscle glycogen synthesis.
A key block in this process is at the glucose transport stage.

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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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