The ultimate purpose of this research proposal is to determine the role of feedback inhibition of Insulin Receptor Substrate (IRS-1) in insulin resistance. Differentiated 3T3-L1 adipocytes, treated with the phosphatase inhibitor okadate acid (OKA), have been shown to exhibit insulin resistance, accompanied by decreased insulin stimulated tyrosine phosphorylation of IRS-1 and an increase serine/threonine kinase activity capable of phosphorylating IRS-1. We are attempting to identify the serine threonine kinase activity, first by examining the role of two likely candidate proteins, MAP kinase and Protein Kinase C, and by attempting to purify a novel kinase. We will attempt to establish the biological relevance of this kinase activity by examining the effect of expressing IRS-1 mutants, lacking one or more of the potential ser/thr phosphorylation sites, on the OKA induced insulin resistance. We hope to establish a direct correlation between ser/thr phosphorylation of IRS-1 and a decrease in its tyrosine phosphorylation by insulin stimulated IR, decreased PI-3 kinase binding and decreased glucose uptake.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK009310-01
Application #
2136390
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Hyde, James F
Project Start
1996-01-15
Project End
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305