This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OVERVIEW: 'Molecular Regulation of Muscle Glucose Metabolism in Man': The presence of insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes attests to its hereditary nature. The insulin receptor signaling system is a likely focus of insulin resistance. In type 2 diabetes, there are defects in insulin receptor signaling that include decreased insulin stimulation of insulin receptor and IRS-1 tyrosine phosphorylation and the association of PI 3-kinase with IRS-1. In diabetics one bout of exercise improves insulin receptor tyrosine phosphorylation but does not increase the association of IRS-1 with PI 3-kinase, suggesting that the latter abnormality may be intrinsic or hereditary. In normal glucose tolerant subjects with a family history of type 2 diabetes, insulin resistance is associated with a defect in insulin stimulated IRS-1 tyrosine phosphorylation and association of PI 3-kinase activity with IRS-1. In contrast, insulin-stimulated tyrosine phosphorylation of the insulin receptor is normal. Taking these findings together, we hypothesize that a defect in IRS-1 function in skeletal muscle plays a key role in insulin resistance and type 2 diabetes. Specifically, we propose: 1) To identify sites of serine/threonine phosphorylation of endogenous IRS-1 in human skeletal muscle in vivo. We will use recombinant IRS-1 proteins and synthetic peptides to identify candidate serine/threonine phosphorylation sites phosphorylated by known kinases or human skeletal muscle lysates and subcellular fractions. Sites will be identified by consensus sequence analysis, two-dimensional phosphopeptide mapping, MALDI-TOF and HPLC-ESI/MS/MS analysis. Based on these results, we will target the serine/threonine phosphorylation sites that are held in common by recombinant known kinases and human muscle lysates and fractions. Then we will identify endogenous IRS-1 phosphorylation sites by HPLC-ESI/MS/MS and MALDI-TOF analysis of immunoprecipitated IRS-1 from muscle biopsies taken from subjects basally and during insulin infusion (euglycemic hyperinsulinemic clamp). 2) To determine the role of serine/threonine phosphorylation of IRS-1 in insulin resistance. 3) To determine if common mutations in IRS-1 are associated with defects in IRS-1 function in nondiabetic Mexican American individuals who have a strong family history of type 2 diabetes and decreased insulin-stimulated association of IRS-1 with PI 3-kinase. 4) To use DNA microarray technology to search for genes that are abnormally expressed in normal glucose-tolerant subjects with a strong family history of type 2 diabetes. We will test the hypothesis that these subjects respond differently to experimental conditions that provoke insulin resistance. This protocol is one of seven experiments contained in the grant, 'Molecular Regulation of Muscle Glucose Metabolism in Man,' which has an overall hypothesis that 'a defect in IRS-1 function in skeletal muscle plays a key role in insulin resistance and T2DM and may be involved in a hereditary abnormality in the regulation of insulin signaling.' The goal of this study is to investigate the nature of biochemical and molecular abnormalities present in skeletal muscles of type 2 diabetics. Specifically, study 2a will investigate whether insulin resistance is associated with increased serine phosphorylation of IRS-1.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
General Clinical Research Centers Program (M01)
Project #
Application #
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center San Antonio
Internal Medicine/Medicine
Schools of Medicine
San Antonio
United States
Zip Code
Kawaguchi-Suzuki, Marina; Cusi, Kenneth; Bril, Fernando et al. (2018) A Genetic Score Associates With Pioglitazone Response in Patients With Non-alcoholic Steatohepatitis. Front Pharmacol 9:752
Hayden, Kathleen M; Baker, Laura D; Bray, George et al. (2018) Long-term impact of intensive lifestyle intervention on cognitive function assessed with the National Institutes of Health Toolbox: The Look AHEAD study. Alzheimers Dement (Amst) 10:41-48
Unick, Jessica L; Gaussoin, Sarah A; Hill, James O et al. (2017) Objectively Assessed Physical Activity and Weight Loss Maintenance among Individuals Enrolled in a Lifestyle Intervention. Obesity (Silver Spring) 25:1903-1909
Kawaguchi-Suzuki, M; Bril, F; Kalavalapalli, S et al. (2017) Concentration-dependent response to pioglitazone in nonalcoholic steatohepatitis. Aliment Pharmacol Ther 46:56-61
Johnson, Karen C; Bray, George A; Cheskin, Lawrence J et al. (2017) The Effect of Intentional Weight Loss on Fracture Risk in Persons With Diabetes: Results From the Look AHEAD Randomized Clinical Trial. J Bone Miner Res 32:2278-2287
Lorenzo, Carlos; Festa, Andreas; Hanley, Anthony J et al. (2017) Novel Protein Glycan-Derived Markers of Systemic Inflammation and C-Reactive Protein in Relation to Glycemia, Insulin Resistance, and Insulin Secretion. Diabetes Care 40:375-382
Beavers, Kristen M; Leng, Iris; Rapp, Stephen R et al. (2017) Effects of Longitudinal Glucose Exposure on Cognitive and Physical Function: Results from the Action for Health in Diabetes Movement and Memory Study. J Am Geriatr Soc 65:137-145
Chao, Ariana M; Wadden, Thomas A; Gorin, Amy A et al. (2017) Binge Eating and Weight Loss Outcomes in Individuals with Type 2 Diabetes: 4-Year Results from the Look AHEAD Study. Obesity (Silver Spring) 25:1830-1837
Marquez, Becky; Anderson, Andrea; Wing, Rena R et al. (2016) The relationship of social support with treatment adherence and weight loss in Latinos with type 2 diabetes. Obesity (Silver Spring) 24:568-75
Williams, Robert C; Elston, Robert C; Kumar, Pankaj et al. (2016) Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND). BMC Genomics 17:325

Showing the most recent 10 out of 600 publications