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.
| Unger, Roger H; Scherer, Philipp E (2010) Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Trends Endocrinol Metab 21:345-52 |
| Lee, Y; Lingvay, I; Szczepaniak, L S et al. (2010) Pancreatic steatosis: harbinger of type 2 diabetes in obese rodents. Int J Obes (Lond) 34:396-400 |
| Yu, Xinxin; Park, Byung-Hyun; Wang, May-Yun et al. (2008) Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci U S A 105:14070-5 |
| Unger, Roger H (2008) Noninvasive tracking of gene expression by reporter transgene imaging. Proc Natl Acad Sci U S A 105:12641-2 |
| Lee, Y; Hirose, H; Zhou, Y T et al. (1997) Increased lipogenic capacity of the islets of obese rats: a role in the pathogenesis of NIDDM. Diabetes 46:408-13 |
| Zhou, Y T; Shimabukuro, M; Koyama, K et al. (1997) Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation. Proc Natl Acad Sci U S A 94:6386-90 |
