THE GLUCOSE TRANSPORT SYSTEM AND MECHANISMS OF HUMAN INSULIN RESISTANCE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Insulin Resistance Syndrome provides the "common soil" for the development of Type 2 Diabetes Mellitus and Cardiovascular Disease. It is responsible for extensive morbidity and mortality in our society. The long-term objective is the necessity of finding the environmental and genetic determinants together with the biochemical or molecular basis of this insulin resistance. The knowledge will present new targets for drug development and will create rational approaches for preventive strategies. In NIDDM, insulin resistance is largely due to impaired stimulation of the glucose transport system in skeletal muscle; however, the molecular mechanisms have not been elucidated. Insulin stimulates glucose transport via translocation of intracellular GLUT4 glucose transporters to the cell surface. Insulin resistance in NIDDM is caused by profound depletion of GLUT4 in fat, while in muscle GLUT4 expression is normal, suggesting that GLUT4 translocation to the plasma membrane may be defective. The specific aim is to test the hypothesis that insulin resistance is due to defects in GLUT4 trafficking which impair insulin-mediated GLUT4 translocation in skeletal muscle. In order to accomplish this, it will be important to include healthy individuals along the insulin sensitive-resistant continuum as well as type 2 diabetics. Consented subjects will be admitted to the inpatient GCRC where a thorough medical history, physical examination, EKG, pre/post activity blood pressure measurements, and laboratory blood/urine testing will be performed. Individuals meeting entry criteria will then undergo a one-time series of metabolic studies that will characterize body composition, energy expenditure, glucose tolerance, in-vivo insulin sensitivity, in-vivo glucose metabolism, insulin secretion, and lipid metabolism. Admission should not exceed 5 to 7 days. These studies include an oral glucose tolerance test, 24 hour urine, V02Max study, indirect calorimetry, room calorimetry, DEXA scan, NMR spectroscopy of the leg, percutaneous biopsies of thigh muscle, lower abdominal wall fat biopsies, intravenous glucose tolerance test or hyperinsulinemic euglycemic insulin clamp study.