#140 - Gerald Shulman, MD, PhD: Insulin resistance—molecular mechanisms and clinical implications

The location where Dr. Shulman moved to adapt nuclear magnetic resonance spectroscopy for human studies.

Where George Radda pioneered phosphorus NMR techniques.

A medical journal where papers by Tainter and others described the beneficial effects of dinitrophenol for weight loss.

A newly created regulatory body in 1937 that famously pulled dinitrophenol (DNP) from the counters due to its toxicity.

A research center where Dr. Shulman serves as co-director, focusing on metabolism and diabetes research.

A prestigious scientific journal that featured a study on the Mexican cave fish, linking its insulin receptor mutation to hepatic insulin resistance and survival during starvation.

A major liver center facing challenges with living liver donors due to the prevalence of fatty liver, which reduces eligible donors.

Where Dr. Shulman visited as a medical student in the 70s and became interested in in vivo metabolism studies with tracers.

Where Dr. Shulman completed his fellowship in endocrinology.

Where Dr. Shulman completed his residency in medicine.

Where Philip Randle conducted his pioneering studies on fatty acids and insulin resistance in the 1960s.

A colleague who trained with Dr. Shulman and has shown that short-term hypocaloric feeding can reverse type 2 diabetes by reducing ectopic lipid.

A PhD student with Dr. Shulman who showed that PKC epsilon in the liver binds to and directly inhibits the insulin receptor kinase itself.

Host of the Drive podcast, interested in translating longevity science and deeply fascinated by insulin resistance.

Pioneered phosphorus NMR at Oxford University, providing a method to study high-energy phosphates in living tissues.

Worked with Dr. Shulman at Yale to develop methods for measuring glucose 6-phosphate and intracellular glucose non-invasively in human muscle using phosphorus NMR.

A biochemist who, in the 1960s, first postulated that fatty acids might cause insulin resistance by altering oxidation and inhibiting phosphofructokinase.

A fellow who worked with Dr. Shulman and published a study in the New England Journal demonstrating the acute effects of exercise on muscle insulin resistance and liver fat reduction.

A clinical fellow with Dr. Shulman who showed a single bout of exercise could significantly reduce de novo lipogenesis and liver triglycerides.

Scientist who, in his 1988 Banting Lecture, first highlighted insulin resistance as a driver of various conditions beyond diabetes, including atherosclerosis, hypertension, and polycystic ovarian disease.

A collaborator of Dr. Shulman and a mass spectrometry expert who identified the threonine phosphorylation event on the insulin receptor by PKC epsilon using untargeted phosphoproteomics.

Professor of Medicine and Cellular and Molecular Physiology at Yale, co-director of the Yale Diabetes Research Center, and recipient of the 2018 Banting Medal for Scientific Achievement. He pioneered magnetic resonance spectroscopy (MRS) techniques to study glucose and fat metabolism, especially in understanding insulin resistance.

Researchers who published conflicting papers over decades regarding the direct and indirect effects of insulin, a controversy that Dr. Shulman's model unifies.

A researcher who worked in Dr. Shulman's group and demonstrated in preclinical animal models that insulin pumps accelerate tumor growth and insulin sensitizing agents slow it down.

Dr. Shulman's wife and a researcher who authored a 2007 PNAS paper demonstrating the impact of muscle insulin resistance on liver fat synthesis and dyslipidemia in young, euglycemic individuals.

An MD-PhD student with Dr. Shulman who conducted studies making mice with a mutated threonine in the insulin receptor, showing protection from hepatic insulin resistance despite high-fat feeding.

A condition closely linked to insulin resistance, where fat accumulates in the liver. Dr. Attia later refers to it as 'metabolic associated fatty liver disease' (MAFLD).

A common drug for type 2 diabetes, discussed for its mechanisms of action, particularly its effect on gluconeogenesis and mitochondrial redox state, not complex I inhibition at clinical doses.

A drug that was famously pulled by the FDA, being the second major act after DNP, but is now back in clinical use for specific indications.

A class of drugs that are gaining popularity for their effect on energy intake, leading to weight loss and some reversal of fatty liver disease.

Used in low doses to activate lipoprotein lipase during intralipid infusions, leading to increased fatty acid delivery to cells.

A class of drugs that cause glucose loss in the urine, leading to calorie loss and some weight reduction, as well as mild reductions in liver fat.

An uncoupling agent originally used in munitions factories and later as a weight loss drug in the 1930s. It promoted heat generation and caused dangerous hyperthermia, leading to its withdrawal by the FDA.

A condition mentioned by Dr. Shulman as being associated with insulin resistance, as highlighted by Jerry Reaven.

A crucial enzyme in the insulin signaling pathway, activated downstream of IRS1, which is required for Glut4 translocation.

An enzyme activated by heparin, which breaks down triglycerides to raise free fatty acids, facilitating their delivery into cells.

A protein activated by exercise, which causes a 'short-circuiting' of the insulin signaling pathway by inducing GLUT4 translocation independently of PI3-kinase.

An inflammatory cytokine mentioned as being released by macrophages (crown-like structures) in fat cells, promoting increased lipolysis and contributing to fasting hyperglycemia.

A hormone involved in appetite and metabolism, mentioned in the context of lipodystrophy where it may not be working effectively.

An inflammatory cytokine, like TNF-alpha, released from fat cells due to inflammation, which promotes lipolysis and exacerbates insulin resistance and hyperglycemia.

A technique used in conjunction with MRS to non-invasively examine cellular glucose and fat metabolism.

An enzyme involved in glucose phosphorylation in the liver, and its translocation is considered important for glucose rate control into hepatocytes.

A pathological condition characterized by insulin resistance, hyperinsulinemia, and impaired glucose disposal, leading to widespread chronic diseases.

A bioactive lipid metabolite identified as a key mediator of lipid-induced insulin resistance in muscle and liver, activating novel protein kinase Cs.

Novel isoforms, specifically theta and epsilon, are activated by diacylglycerols (DAGs) and block insulin signaling by interfering with receptor tyrosine phosphorylation.

A key intermediate in the insulin signaling pathway specific to the liver, undergoing tyrosine phosphorylation to activate PI3-kinase.

A protein kinase activated in the insulin signaling cascade in the liver, leading to phosphorylation of FOXO and down-regulation of gluconeogenesis.

An enzyme involved in gluconeogenesis that is allosterically regulated by acetyl-CoA, playing a critical role in controlling glucose production.

A glucose transporter protein that facilitates glucose uptake into muscle and fat cells. In insulin resistance, its translocation to the cell membrane is impaired.

An enzyme responsible for synthesizing glycogen from glucose, a key pathway for glucose storage, which is impaired in insulin resistance.

An enzyme in the mitochondria that Metformin is proposed to indirectly inhibit, leading to changes in NADH and NAD+ levels and substrate-dependent inhibition of gluconeogenesis.

Considered the most prestigious award in the field of diabetes research, received by Dr. Shulman in 2018.

An enzyme involved in the first step of glucose metabolism inside the cell, phosphorylating glucose to glucose-6-phosphate. Its activity can be affected by metabolic conditions.

An intracellular protein that is phosphorylated after insulin binds to its receptor, initiating downstream signaling events for glucose uptake.

Elevated insulin levels in the blood, often occurring as the body tries to compensate for insulin resistance, which can precede and drive various chronic diseases.

A condition characterized by a lack of fat cells, leading to patients having no subcutaneous or visceral fat but massive hepatic fat accumulation and severe diabetes.

A term preferred by Dr. Shulman over NAFLD, indicating its link to metabolic dysfunction and position as the most common cause of liver disease, inflammation, and cancer.

An end product of fatty acid beta-oxidation that allosterically regulates pyruvate carboxylase, crucial for gluconeogenesis. Its concentration in the liver tracks perfectly with rates of gluconeogenesis.

A scientific journal where a recent paper by Dr. Shulman's group about diacylglycerol stereoisomers and PKC epsilon activation in insulin resistance was published.

Proceedings of the National Academy of Sciences, where Kit Petersen's 2007 paper on the link between muscle insulin resistance and liver fat accumulation was published.

A triglyceride emulsion given intravenously, often used for hyperalimentation, which, when combined with heparin, can acutely raise plasma fatty acids and induce insulin resistance in healthy individuals.

Affiliated with Mass General, where Dr. Shulman did his fellowship.

Research cited by Peter Attia indicating that even after 40 days of starvation, a significant portion of CNS energy in humans still comes from glucose.

A prestigious medical journal where a study by Dr. Shulman's group on exercise reversing muscle insulin resistance in offspring of type 2 diabetics was published.

A traditional method used to track tumor growth by observing glucose uptake, but Dr. Shulman prefers non-radioactive methods for research volunteers.

A non-invasive technique pioneered by Dr. Shulman to examine cellular glucose and fat metabolism in vivo, providing 'video-like' insight into metabolic flux rather than static snapshots.