Recent estimates indicate that -two-thirds of adults in the US are overweight or obese. Insulin resistance, acommon feature associated with obesity, increases the risk of type 2 diabetes. The cellular mechanismsresponsible for the development of diet-induced insulin resistance are complex and not fully understood.However, a key observation has been the reduced signaling through the IRS1 PI 3-kinase pathway anddiminished glucose uptake and utilization in skeletal muscle. Two complementary mechanisms haveemerged as potential mediators of the reduced IRS1 PI 3-kinase signaling: enhanced basal IRS-1 serinephosphorylation and altered expression of the PI 3-kinase p85 regulatory subunits. Recently, we observedthat 3d of overfeeding in humans enhanced p85a expression and correlated with the reduced insulinsensitivity. We hypothesize that increased p85or in skeletal muscle is an early defect in the development ofdietary-induced insulin resistance and accompanies the key changes in IRS-1 serine phosphorylation. Ourstudies will focus on identifying the mechanisms for diet-induced dysregulation of p85cr and the relationshipbetween p85or and IRS-1 serine phosphorylation as mediators of skeletal muscle insulin resistance.

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 #
5F32DK075252-03
Application #
7391143
Study Section
Special Emphasis Panel (ZRG1-F06-E (20))
Program Officer
Hyde, James F
Project Start
2006-04-01
Project End
2008-06-30
Budget Start
2008-04-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2008
Total Cost
$14,357
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Moriarty, M W; McCurdy, C E; Janssen, R C et al. (2009) In vivo knockdown of p85alpha with an antisense oligonucleotide improves insulin sensitivity in Lep(ob/ob) and diet-induced obese mice. Horm Metab Res 41:757-61
Barbour, Linda A; McCurdy, Carrie E; Hernandez, Teri L et al. (2007) Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care 30 Suppl 2:S112-9