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. OBJECTIVE: The primary objective of this study is to test the hypothesis that the PC-1 gene is involved in the insulin resistance, and therefore contributes to the development of type 2 diabetes mellitus (T2DM) in Mexican Americans. If an association is observed between polymorphisms within, or near, the PC-1 gene and insulin resistance, and nearby genes can be excluded, further functional studies will be pursued. These include examination of PC-1 mRNA stability and expression levels, and direct measurement of insulin receptor tyrosine phosphorylation levels in CHO/IR cells co-expressing the insulin receptor and PC-1 variants. RESEARCH PLAN AND METHODS: State-of-the-art methods will be used to quantitate insulin receptor tyrosine phosphorylation, thereby defining the insulin resistance phenotype at the molecular level. Single nucleotide polymorphisms (SNPs) will be identified by direct DNA sequencing of the PC-1 gene in individuals with normal (N=10) and impaired (N=10) skeletal muscle insulin receptor phosphorylation. High-throughput assays will be designed to screen SNPs with allele frequencies 10%. Selected SNPs will be screened within a larger population sample of Mexican Americans (N=1137) derived from the SAFADS and GENNID studies. SNP genotypes will be statistically analyzed for association with insulin receptor tyrosine phosphorylation, insulin resistance, and other T2DM phenotypes. Linkage data will be utilized in cutting-edge combined linkage/linkage disequilibrium analyses with these SNPs to detect functional variants, which may underlie the observed linkage peak. CLINICAL

Public Health Relevance

Mexican Americans represent approximately 52% of the San Antonio population. This population has an extremely high prevalence of T2DM, and an improved understanding of the underlying genetic mechanisms of T2DM, therefore, well serves the needs of this population. In this ethnic group insulin resistance is severe and is well established before the onset of overt diabetes. Functional studies have established that mutations within the PC-1 gene lead to impaired insulin signaling. These studies provide convincing evidence of a direct mechanism for PC-1 involvement in insulin resistance. The gene is located within a chromosomal region that has been genetically linked to insulin resistance in Mexican Americans in the San Antonio Family Diabetes Study (SAFADS). The linked region, on the long arm of chromosome 6, produced a logarithm of the odds (LOD) score of 5.8 for linkage with a bivariate insulin resistance/obesity phenotype (leptin + HOMA IR). This is one of the strongest genetic signals ever recorded for a common multifactorial disease. Within this highly significant region, PC-1 is the strongest positional candidate gene and highly likely to be an important susceptibility gene for insulin resistance/T2DM in this at-risk population.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
General Clinical Research Centers Program (M01)
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University of Texas Health Science Center San Antonio
Internal Medicine/Medicine
Schools of Medicine
San Antonio
United States
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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
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
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
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

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