The objectives of this research project are to provide a better understanding of the mechanism by which insulin resistance develops in various animal models of obesity, hyperinsulinemia and impaired glucose tolerance and to determine the mechanism by which exercise and physical training improve tissue sensitivity and/or responsiveness to insulin. In addition to studies in normal rats, the effects of exercise and physical training on the insulin resistance which develops in obese Zucker (fa/fa) rats, normal Sprague-Dawley rats as they become older and more obese, chronically hyperinsulinemic rats and rats made mildly to moderately diabetic with streptozotocin will be examined. Parallel studies will be done in skeletal muscle, liver and adipose cells, the 3 major target tissues of insulin action. Insulin action in muscle will be characterized by measuring 125I-labeled insulin binding, 2-deoxy-d-glucose transport, and incorporation of D-[3H-5]-glucose into glycogen and 3H2O in soleus and epitrochlearis muscles incubated in vitro. The number of glucose transport units and their distribution between muscle plasma membranes and the intracellular pool will be determined to test the hypotheses that exercise increases glucose transport activity in muscle by producing a translocation of glucose transport units from the intracellular pool into plasma membranes and that physical training results in an increase in total glucose transport unit number. It is proposed that, decreased glucose transport unit number, altered cellular distribution or failure of exercise and/or insulin to produce normal translocation into plasma membranes may play a major role in the development of insulin resistance in muscle, in a manner similar to that which occurs in adipose cells. Studies in incubated muscles and adipose cells will be correlated with measurements of insulin sensitivity and responsiveness in vivo using the hyperinsulinemic-euglycemic clamp technique; with plasma concentrations of glucose, insulin, FFA and triglycerides and with muscle and liver contents of glycogen and triglyceride. In addition, the hyperinsulinemic-euglycemic clamp technique will be used to measure hepatic glucose production and its sensitivity to suppression by insulin in sedentary, exercised and physically trained animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK026317-06
Application #
3227827
Study Section
Metabolism Study Section (MET)
Project Start
1980-09-01
Project End
1989-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Napoli, R; Cittadini, A; Chow, J C et al. (1996) Chronic growth hormone treatment in normal rats reduces post-prandial skeletal muscle plasma membrane GLUT1 content, but not glucose transport or GLUT4 expression and localization. Biochem J 315 ( Pt 3):959-63
Napoli, R; Davalli, A M; Hirshman, M F et al. (1996) Islet transplantation under the kidney capsule fully corrects the impaired skeletal muscle glucose transport system of streptozocin diabetic rats. J Clin Invest 97:1389-97
Hirshman, M F; Fagnant, P M; Horton, E D et al. (1995) Pioglitazone treatment for 7 days failed to correct the defect in glucose transport and glucose transporter translocation in obese Zucker rat (fa/fa) skeletal muscle plasma membranes. Biochem Biophys Res Commun 208:835-45
Napoli, R; Hirshman, M F; Horton, E S (1995) Mechanisms of increased skeletal muscle glucose transport activity after an oral glucose load in rats. Diabetes 44:1362-8
Napoli, R; Hirshman, M F; Horton, E S (1995) Mechanisms and time course of impaired skeletal muscle glucose transport activity in streptozocin diabetic rats. J Clin Invest 96:427-37
Rosholt, M N; King, P A; Horton, E S (1994) High-fat diet reduces glucose transporter responses to both insulin and exercise. Am J Physiol 266:R95-101
King, P A (1994) Effects of insulin and exercise on amino acid transport in rat skeletal muscle. Am J Physiol 266:C524-30
King, P A; Betts, J J; Horton, E D et al. (1993) Exercise, unlike insulin, promotes glucose transporter translocation in obese Zucker rat muscle. Am J Physiol 265:R447-52
Hirshman, M F; Goodyear, L J; Horton, E D et al. (1993) Exercise training increases GLUT-4 protein in rat adipose cells. Am J Physiol 264:E882-9
King, P A; Horton, E D; Hirshman, M F et al. (1992) Insulin resistance in obese Zucker rat (fa/fa) skeletal muscle is associated with a failure of glucose transporter translocation. J Clin Invest 90:1568-75

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