(Scanned from the applicant's description) Type 2 diabetes mellitus has major clinical and social impact, but its underlying pathophysiology is poorly understood. Since the disease is diagnosed as a disorder of carbohydrate metabolism, i.e., hyperglycemia, the possible contribution of abnormal lipid metabolism to its etiology has been largely overlooked. The predominant, obesity-related form of diabetes is characterized by hyperinsulinemia, resistance to insulin-mediated glucose disposal in skeletal muscle, and elevated plasma free fatty acid and triglyceride levels. It has been suggested that a derangement of lipid metabolism is an early event contributing to the development of both hyperinsulinemia and insulin resistance. Our laboratory has demonstrated the essential role that plasma fatty acids play in sustaining normal glucose-stimulated insulin secretion in fasted subjects, and has also utilized novel 1-H NMR spectroscopic techniques to illustrate the strong correlation between intramyocellular lipid (IMCL) content and skeletal muscle insulin resistance. In the current proposal, we seek to expand on this theme by investigating the effects of high-fat feeding, pharmacologic inhibition of lipid oxidation, and leptin administration on insulin secretion and insulin sensitivity in rats and determining how these changes might be linked to alterations in muscle and islet triglyceride content. Because deficiencies of leptin and/or leptin signaling can precipitate the development of obesity/diabetes mellitus, it is conceivable that the primary function of leptin is to control lipid oxidation and lipolysis in a manner that prevents tissue lipid accumulation, thus maintaining normal glucose metabolism. We will administer leptin intracerebroventricularly to rats consuming a high fat diet and determine if this reverses the development of hyperinsulinemia and insulin resistance. Parallel measurements of IMCL, muscle P13-kinase activation and islet triglyceride levels will seek to establish a direct link between fat dissipation and improved function in these tissues. Future studies will explore the biochemical pathways through which leptin regulates lipid metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057558-03
Application #
6635242
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
2001-06-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2003
Total Cost
$234,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Szczepaniak, Lidia S; Nurenberg, Pamela; Leonard, David et al. (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288:E462-8
Dobbins, Robert L; Szczepaniak, Lidia S; Zhang, Weiguo et al. (2003) Chemical sympathectomy alters regulation of body weight during prolonged ICV leptin infusion. Am J Physiol Endocrinol Metab 284:E778-87
Dobbins, Robert L; Szczepaniak, Lidia S; Myhill, Jeff et al. (2002) The composition of dietary fat directly influences glucose-stimulated insulin secretion in rats. Diabetes 51:1825-33