Gerald I Shulman MD, PhD, FACP, FACE
George R. Cowgill Professor of Medicine (Endocrinology) and Professor of Cellular and Molecular Physiology; Investigator, Howard Hughes Medical Institute; Co-Director, Yale Diabetes Research Center; Director, Yale Mouse Metabolic Phenotyping Center
Cellular and molecular mechanisms responsible for insulin resistance.
Despite much work the cellular mechanisms responsible for insulin resistance in type 2 diabetes and the metabolic syndrome remain unknown. In this regard recent studies measuring muscle triglyceride content by biopsy or intramyocellular lipid content by 1H magnetic resonance spectroscopy have shown a strong relationship between intramuscular lipid content and insulin resistance in skeletal muscle. Recent studies have also demonstrated increases in intramyocellular lipid content in insulin resistant offspring of parents with type 2 diabetes suggesting that dysregulation of fatty acid metabolism may be responsible for mediating the insulin resistance in these individuals. Increases in the intramyocellular concentration of fatty acid metabolites in turn have been postulated to activate a serine kinase cascade leading to decreased insulin stimulated insulin receptor substrate-1 associated phosphatidylinositol 3-kinase activity resulting in reduced glucose transport activity and glycogen synthesis. This presentation will focus on recent studies using noninvasive 13C, 31P and 1H magnetic resonance spectroscopy techniques in humans that elucidate the pathogenesis of insulin resistance that occurs in obesity, type 2 diabetes, lipodystrophy and the metabolic syndrome.
- Perry RJ, Kim T, Zhang XM, Lee HY, Pesta D, Popov VB, Zhang, D, Rahimi Y, Jurczak MJ, Cline GW, Spiegel DA, Shulman GI. Reversal of hypertriglyceridemia, fatty liver disease and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metabolism. 2013;(18):740-48. PMID: 24206666. PMCID: 4104686.
- Befroy DE, Perry RJ, Jain N, Dufour S, Cline GW, Trimmer J, Brosnan J, Rothman DL, Petersen KF, Shulman GI. Direct assessment of hepatic mitochondrial oxidation and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy. Nature Medicine 2013;1:(20):98-102. PMID: 24317120. PMCID: 3947269.
- Perry RJ, Samuel VT, Petersen, KF, Shulman GI. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature. 2014;510(7503):84-91. PMID: 24899308.
- Perry RJ, Zhang XM, Zhang D, Kumashiro N, Camporez JP, Cline GW, Rothman DL, Shulman GI. Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis. Nature Medicine. 2014;20(7):759-63. PMID: 24929951.
- Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak, M, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510:542-46. PMID:24847880.
- Shulman, GI. Role of ectopic fat in insulin resistance, dyslipidemia and cardiometabolic disease. N Engl J Med. 2014;371(12)1131-1141. PMID: 25229917.
- Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG. Direct
quantitation of muscle glycogen synthesis in normal man and noninsulin-dependent diabetics by 13C Nuclear Magnetic Resonance Spectroscopy. N Eng J Med, 322:223-8, 1990.
- Rothman DL, Magnusson I, Katz LD, Shulman RG, Shulman GI. Quantitation
of Hepatic Glycogenolysis and Gluconeogenesis in Humans with 13C NMR. Science, 254:573-6, 1991.
- Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW,
Slezak LA, Andersen DK, Hundal RS, Rothman DL, Petersen KF, Shulman
GI. Effect of free fatty acids on IRS-1 associated phosphatidyl inositol 3-kinase
activity. J Clin Invest, 103:253-9, 1999.
- Cline G, Petersen KR, Krssak M, Shen J, Hundal RS, Trajanoski Z,
Inzucchi S, Dresner A, Rothman DL, Shulman GI. Impaired glucose transport as a cause of decreased insulin stimulated muscle glycogen synthesis in type 2 diabetes. N Eng J Med, 341:240-6, 1999.