The NIDDK has identified the genetics of type 2 diabetes mellitus (T2D) as one of five high priority areas for research. Specifically ?Studies using quantitative statistical methods to identify diabetes genes in human populations.? and ?Development of genetic resources, patient samples and methods for studying genetic linkage for diabetes.? We propose here a novel two pronged strategy to identify genes for diabetes susceptibility (prediabetes). This powerful multilayered approach combines genome-wide gene expression with genetic linkage and association screening. In brief, the two Aims of this study are as follows.
Aim 1 : A high resolution association study of gene expression in vivo in three key tissues, adipose tissue, skeletal muscle and mononuclear cells (MNCs) in 40 matched pairs of unrelated subjects who differ by fasting specific insulin (FSI) a surrogate marker of insulin resistance (IR). Gene expression will be measured under fasted conditions in the three tissues, and in response to insulin stimulation during an insulin clamp for skeletal muscle and MNCs.
Aim 2 : A family-based linkage study of gene expression in MNCs from 1,000 subjects, who have previously been genotyped, from two large ongoing genetic studies, the Veterans Administration Genetic Epidemiology Study (VAGES) and the San Antonio Family Diabetes/Gallbladder Disease Study (SAFDGS). We will perform preliminary functional evaluation of the strongest candidate genes identified in the study. We previously reported strong evidence in those studies of linkage of IR traits with chromosome 6q23. We hypothesize that there is differential expression of genes involved in inflammation and insulin action in adipose tissue, skeletal muscle and leukocytes from subjects with differential risk for prediabetes, as manifested by IR, and that this pattern of differential gene expression contributes to T2D susceptibility.

Public Health Relevance

TO PUBLIC HEALTH: Type 2 diabetes mellitus (T2D) is the leading cause of blindness, end stage renal disease, non-traumatic amputations, and it increases the risk for other serious medical disorders such as hypertension, dyslipidemia, and atherosclerotic cardiovascular disease, and is the fifth leading cause of disease-related death in the US. Thus, T2D represents a huge public health problem that is projected to worsen in the coming decades, particularly as the mean age of the population increases. Insulin resistance (IR), usually associated with obesity, is a major risk factor for the development of T2D, however, the genes which predispose some individuals to these diseases are unknown. Identification of IR genes will greatly improve our understanding of how these diseases occur and provide new biomarkers of disease and treatment targets for future drug therapy and hope for alleviation of the accelerating diabetes/obesity epidemic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079195-05
Application #
8432037
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Mckeon, Catherine T
Project Start
2008-08-15
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$498,118
Indirect Cost
$117,582
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Winnier, Deidre A; Fourcaudot, Marcel; Norton, Luke et al. (2015) Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES). PLoS One 10:e0119941
Winner, Diedre; Norton, Luke; Kanat, Mustafa et al. (2014) Strong association between insulin-mediated glucose uptake and the 2-hour, not the fasting plasma glucose concentration, in the normal glucose tolerance range. J Clin Endocrinol Metab 99:3444-9
Kanat, Mustafa; Mari, Andrea; Norton, Luke et al. (2012) Distinct ýý-cell defects in impaired fasting glucose and impaired glucose tolerance. Diabetes 61:447-53
Farook, Vidya S; Puppala, Sobha; Schneider, Jennifer et al. (2012) Metabolic syndrome is linked to chromosome 7q21 and associated with genetic variants in CD36 and GNAT3 in Mexican Americans. Obesity (Silver Spring) 20:2083-92
Norton, L; Fourcaudot, M; Abdul-Ghani, M A et al. (2011) Chromatin occupancy of transcription factor 7-like 2 (TCF7L2) and its role in hepatic glucose metabolism. Diabetologia 54:3132-42
Kanat, Mustafa; Winnier, Diedre; Norton, Luke et al. (2011) The relationship between {beta}-cell function and glycated hemoglobin: results from the veterans administration genetic epidemiology study. Diabetes Care 34:1006-10
Puppala, Sobha; Coletta, Dawn K; Schneider, Jennifer et al. (2011) Genome-wide linkage screen for systolic blood pressure in the Veterans Administration Genetic Epidemiology Study (VAGES) of Mexican-Americans and confirmation of a major susceptibility locus on chromosome 6q14.1. Hum Hered 71:1-10
Folli, Franco; Guzzi, Valeria; Perego, Lucia et al. (2010) Proteomics reveals novel oxidative and glycolytic mechanisms in type 1 diabetic patients' skin which are normalized by kidney-pancreas transplantation. PLoS One 5:e9923
Chavez, Alberto O; Kamath, Subhash; Jani, Rucha et al. (2010) Effect of short-term free Fatty acids elevation on mitochondrial function in skeletal muscle of healthy individuals. J Clin Endocrinol Metab 95:422-9
Monroy, A; Kamath, S; Chavez, A O et al. (2009) Impaired regulation of the TNF-alpha converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: a new mechanism of insulin resistance in humans. Diabetologia 52:2169-81

Showing the most recent 10 out of 26 publications