Gerald I Shulman MD, PhD
George R. Cowgill Professor of Medicine (Endocrinology) and Professor of Cellular and Molecular Physiology; Investigator, Howard Hughes Medical Institute
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.
- 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.
- Petersen K, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman D, DiPietro L,
Cline G, Shulman GI. Mitochondrial dysfunction in the elderly: Possible role in
insulin resistance. Science, 16(5622):1140-2, 2003.
- Petersen K, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired
mitochondrial activity in the insulin resistant offspring of patients with type 2
diabetes. N Eng J Med, 350:664-71, 2004.
- Gillum M, Zhang D, Zhang X, Erion D, Jamison R, Choi C, Dong J,
Shanabrough M, Duenas H, Frederick D, Hsiao J, Horvath T, Lo C, Tso P, Cline
G, Shulman GI. N-acylphosphatidylethanolamine, a gut-derived circulating factor
induced by fat ingestion, inhibits food intake. Cell, 135:813-24, 2008.
- Morino K, Petersen K, Dufour S, Befroy D, Frattini J, Shatzkes N, Neschen S,
White M, Bilz S, Sono S, Pypaert M, Shulman GI. Reduced mitochondrial
density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest, 115:3587-93, 2005.
- Petersen KF, Dufour S, Savage D, Bilz S, Solomon G, Yonemitsu S, Cline G,
Befroy D, Zemany L, Kahn B, Papademetris X, Rothman D, Shulman GI. The
role of skeletal muscle insulin resistance in the pathogenesis of the metabolic
syndrome. Proc Natl Acad Sci USA, 104:12587-94, 2007.