Increased circulating levels of the nutrients glucose and free fatty acids (FFA) contribute to the development of insulin resistance, with its important sequelae of hyperlipidemia, accelerated atherosclerosis and type 2 diabetes mellitus (DM2). The present proposal is designed to study the role of the hexosamine biosynthetic pathway in the inductions of nutrient- induced insulin resistance in humans. We hypothesize that carbon flux through the GlcN pathway induces peripheral insulin resistance by affecting the glycosylation status of key intracellular proteins, including such transcription factors as sp-1. Increased availability of these nutrients in animal models enhances flux into the GlcN pathway, followed by a more gradual onset of insulin resistance and increased expression of genes associated with the insulin resistance syndrome. While the rate- limiting enzyme for entry into the GlcN pathway is upregulated in humans with DM2, a casual link between the GlcN pathway and nutrient-induced insulin resistance in humans has not yet been established. We will compare the effects of increased nutrient availability and oral glucosamine administration on peripheral insulin action (using insulin clamp techniques), accumulation of products of the GlcN pathway, and gene expression (by microarray technique) in DM2 and nondiabetic subjects. We will thereby determine whether increased flux into the GlcN pathway mediates nutrient-induced insulin resistance and whether alterations in gene expression might underlie the metabolic pertubations of the insulin resistance syndrome.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Education Projects (R25)
Project #
1R25RR015407-01
Application #
6231493
Study Section
Special Emphasis Panel (ZRR1-CR-9 (01))
Program Officer
Wilde, David B
Project Start
2000-09-01
Project End
2001-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$36,476
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461