Insulin resistant individuals become diabetic when beta-cells lose their normal ability to respond to glucose and to compensate for the pre- existing insulin resistance. To identify the beta-cell defect that results in NIDDM, we plan to characterize in rats the molecular, metabolic and physiologic components of the normal beta-cell compensatory response induced 1) by hyperglycemic clamping, 2) by dexamethasone treatment, and 3) by obesity and compare these with beta-cells of various rat models that cannot compensate these same factors (eg ZDF-drt rats, GK rats, Zucker fa/fa rats and rats after subdiabetic streptozotocin treatment). Functional measurement include 1) insulin responses to 5, 10, 20 mM glucose, glyceraldehyde and monomethyl succinate to localize a block, 2) measurements of glucose transport metabolism, utilization, oxidation and glucokinase activity further to localize such a block, 3) quantitation of beta-cell proinsulin, GLUT-2, glucokinase and G protein alpha mRNA to determine if expression of key proteins is impaired, 4) morphometric analysis of percent GLUT-2 and glucokinase containing beta- cell mass by immunocytochemistry, 5) beta-cell volume to determine if expansion of the beta-cell mass impaired and 6) morphometric assessment of mitochondrial integrity by electronmicroscopy. Longitudinal measurements will be made a weekly intervals from six weeks before and until six weeks after the onset of diabetes. The hope is to find a consistent difference in various diabetic rat models of seemingly crucial component of the normal compensatory response that might point to the pathogenic locus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK002700-39
Application #
2608343
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
1977-12-01
Project End
1998-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
39
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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