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Intermediary
metabolism in humans. Diabetes is a major health
care problem in the United States. Over ninety percent of diabetics fall into
the category of type 2 and while the primary factors causing this disease are
unknown it is clear that insulin resistance has a primary role in its development.
The primary objective of my lab is to elucidate the molecular mechanism(s) behind
the insulin resistance which occurs in patients with type 2 diabetes in the hope
that this will enable the rational development of new therapeutic agents to reverse
this pathologic condition as well assist with identification of candidate genes
which make individuals prone to this disease. Since liver and muscle are the two
key insulin responsive organs which account for most of the glucose metabolized
in humans we are currently focusing our attention on these tissues in normal and
diabetic subjects as well as genetically altered mouse models of type 2 diabetes
using nuclear magnetic resonance spectroscopy (NMR). This approach has major advantages
over existing techniques currently being used for clinical investigation in that
it is noninvasive, it involves no ionizing radiation and repeated measurements
of biochemical metabolites (both isotopically labeled and unlabeled) in plasma
and tissue can be performed which then yield localized metabolic flux rates and
information regarding rate controlling steps of glucose metabolism. Recent
publications: Kim
JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret
P, Shoelson SE, Shulman GI. Prevention
of fat-induced insulin resistance by salicylate. J Clin Invest. 2001 Aug 1;108(3):437-446.
Fernandez AM, Kim JK, Yakar S, Dupont J, Hernandez-Sanchez C, Castle AL,
Filmore J, Shulman GI, Le Roith D. Functional
inactivation of the IGF-I and insulin receptors in skeletal muscle causes type
2 diabetes. Genes Dev. 2001 Aug 1;15(15):1926-34.
Zhang CY, Baffy
G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig AJ, Boss O, Kim
YB, Zheng XX, Wheeler MB, Shulman GI, Chan CB, Lowell BB. OMIM
Uncoupling protein-2 negatively regulates insulin secretion and is a major link
between obesity, beta cell dysfunction, and type 2 diabetes. Cell. 2001 Jun
15;105(6):745-55.
Kim JK, Zisman A, Fillmore JJ, Peroni OD, Kotani K,
Perret P, Zong H, Dong J, Kahn CR, Kahn BB, Shulman GI. Related
Articles Glucose toxicity and the development of diabetes in mice with muscle-specific
inactivation of GLUT4. J Clin Invest. 2001 Jul;108(1):153-60.
gerald.shulman@yale.edu | |