Summary
The Drive podcast episode features an interview with Dr. Gerald Shulman, a professor of medicine and cellular and molecular physiology at Yale, about insulin resistance and its effects on the body. Insulin resistance is a leading cause of type 2 diabetes, atherosclerosis, high uric acid, polycystic ovarian disease, metabolic-associated fatty liver disease, heart disease, and cancer. Dr. Shulman's work involves using magnetic resonance spectroscopy combined with mass spec to non-invasively examine cellular glucose and fat metabolism. The interview delves into technical details, but the show notes provide valuable figures to help understand the concepts. The interview also discusses the use of metformin as a longevity agent.
The podcast discusses how insulin resistance is a common phenomenon affecting a large portion of the population, with many people being asymptomatic. Measuring flux, or production versus uptake, of metabolites is more important than just measuring concentration. Traditional methods involve putting a label on a molecule and tracking its turnover through blood sampling. However, newer methods such as nuclear magnetic resonance spectroscopy allow for non-invasive measurement of metabolites and flux within cells. The speaker also discusses the difference between the fate of glucose in a healthy individual versus someone with type 2 diabetes, where the liver makes too much glucose and there is a block in glucose uptake by the muscle. Insulin resistance is a major factor in type 2 diabetes, and reversing it through hypocaloric feeding can lead to improvements in glucose metabolism.
The podcast also discusses the use of proton NMR to measure fat inside cells, specifically inside muscle cells. The researchers found that fat inside muscle cells was the best predictor of insulin resistance in all volunteers, regardless of age or activity level. They used intralipid infusions to raise plasma fatty acids and found that after three to four hours, they could make healthy individuals as insulin resistant as those with type 2 diabetes. They discovered that this was due to a block in glycogen synthesis caused by a lipid intermediate called diacylglycerol (DAG), which interferes with insulin activation of transport.
The podcast discusses how pkcs in muscle theta and epsilon theta blocks insulin action, leading to reduced insulin tyrosine phosphorylation and less food for translocation. The real culprit behind insulin resistance is the activation of both npkcs in muscle. Exercise can reverse muscle and insulin resistance and prevent fatty liver and liver insulin resistance. The podcast also talks about the significance of de novo lipogenesis and how it contributes to metabolic fatty liver disease.
The podcast episode discusses the relationship between insulin resistance, exercise, and fatty liver disease. The speaker explains that insulin resistance in muscle is caused by a block in transport, leading to decreased glucose uptake and increased fat accumulation in the liver. However, exercise can bypass this abnormality and improve insulin signaling. The molecular explanation for this is the activation of a protein called AMPK, which causes glucose transporters to move to the membrane and glucose to enter the cell.
The context discusses a study on the role of insulin resistance in protecting the body during starvation. The study focused on the liver and found that a specific amino acid, threonine, plays an important role in mediating lipid-induced insulin resistance. The study also found that hepatic insulin resistance promotes glucose in circulation, which is important for the CNS to operate during starvation.
The podcast episode discusses the relationship between insulin resistance and chronic diseases such as atherosclerosis, cancer, and Alzheimer's disease. The speaker explains that uncoupling the liver can be a safe and effective treatment for metabolic diseases like NAFL and NASH. The concept of uncoupling was first discovered in the early 1900s when workers in munition factories were exposed to dinitrophenol (DNP), which caused weight loss. DNP was later introduced as a weight loss drug but was pulled from the market due to its toxic effects on the whole body. The speaker proposes targeting the liver specifically for uncoupling to avoid toxicity. The podcast also touches on the use of metformin for diabetes and the mechanism behind its effect on gluconeogenesis. The speaker suggests that metformin's major effect is on gluconeogenesis through a mechanism other than complex one inhibition. The podcast concludes with a discussion on the effectiveness of different dietary approaches for weight loss and the importance of finding a sustainable approach for long-term success.
