Abstract

The long range objective of this research is to understand the molecular mechanism of insulin resistance in muscle tissue of obese individuals and diabetic patients. The most likely cause of insulin resistance in human muscle is decreased insulin receptor tyrosine kinase activity. The hypothesis is that hyperinsulinemia causes activation of PKC-beta which then serine/threonine phosphorylates and inactivates the insulin receptor to cause insulin resistance in muscles of obese individuals. It was previously demonstrated that: (1) insulin resistance can be induced by incubating insulin sensitive muscle with an activator of PKC. (2) Insulin action and insulin receptor kinase activity are restored in insulin resistant muscles that are treated with a PKC inhibitor. (3) PKC-beta is increased in muscle of obese individuals. (4) Insulin causes membrane associated PKC-beta to be increased in insulin resistant muscles. (5) Overexpression of PKC-beta decreases insulin signaling, and knockout of PKC-beta increases insulin signal transduction, in heart of transgenic mice. This proposal will continue to focus on the insulin receptor and PKC-beta to gain evidence to support the hypothesis.
Specific Aim 1 : To determine the phosphorylation pattern on the insulin receptor.
Specific Aim 2 : To investigate the role of hyperinsulinemia in activation of PKC-beta and phosphorylation of insulin receptors.
Specific Aim 3 : To study insulin action in muscle of PKC-beta knockout mice.
Specific Aim 4 : To study the serine/threonine phosphatase(s) that reactivates the insulin receptor. It will be possible to study these mechanisms because a large number of obese patients are available for study.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046121-12
Application #
6688967
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Laughlin, Maren R
Project Start
1997-01-01
Project End
2005-08-07
Budget Start
2004-01-01
Budget End
2005-08-07
Support Year
12
Fiscal Year
2004
Total Cost
$209,250
Indirect Cost

  Institution

Name
East Carolina University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858

  Publications

Gavin, Timothy P; Sloan 3rd, Ruben C; Lukosius, Eric Z et al. (2011) Duodenal-jejunal bypass surgery does not increase skeletal muscle insulin signal transduction or glucose disposal in Goto-Kakizaki type 2 diabetic rats. Obes Surg 21:231-7
Bikman, Benjamin T; Zheng, Donghai; Reed, Melissa A et al. (2010) Lipid-induced insulin resistance is prevented in lean and obese myotubes by AICAR treatment. Am J Physiol Regul Integr Comp Physiol 298:R1692-9
Thyfault, John P; Cree, Melanie G; Tapscott, Edward B et al. (2010) Metabolic profiling of muscle contraction in lean compared with obese rodents. Am J Physiol Regul Integr Comp Physiol 299:R926-34
Bikman, B T; Woodlief, T L; Noland, R C et al. (2009) High-fat diet induces Ikkbeta and reduces insulin sensitivity in rats with low running capacity. Int J Sports Med 30:631-5
Bikman, Benjamin T; Zheng, Donghai; Pories, Walter J et al. (2008) Mechanism for improved insulin sensitivity after gastric bypass surgery. J Clin Endocrinol Metab 93:4656-63
Thyfault, John P; Cree, Melanie G; Zheng, Donghai et al. (2007) Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism. Am J Physiol Cell Physiol 292:C729-39
Muoio, Deborah M; Way, James M; Tanner, Charles J et al. (2002) Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells. Diabetes 51:901-9
Jong-Yeon, Kim; Hickner, Robert C; Dohm, G Lynis et al. (2002) Long- and medium-chain fatty acid oxidation is increased in exercise-trained human skeletal muscle. Metabolism 51:460-4
Kim, Jong-Yeon; Koves, Timothy R; Yu, Geng-Sheng et al. (2002) Evidence of a malonyl-CoA-insensitive carnitine palmitoyltransferase I activity in red skeletal muscle. Am J Physiol Endocrinol Metab 282:E1014-22
Guesbeck, N R; Hickey, M S; MacDonald, K G et al. (2001) Substrate utilization during exercise in formerly morbidly obese women. J Appl Physiol 90:1007-12

Showing the most recent 10 out of 25 publications