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.
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.
|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|
|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|
|Coletta, D K; Sriwijitkamol, A; Wajcberg, E et al. (2009) Pioglitazone stimulates AMP-activated protein kinase signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: a randomised trial. Diabetologia 52:723-32|
|Coletta, Dawn K; Schneider, Jennifer; Hu, Shirley L et al. (2009) Genome-wide linkage scan for genes influencing plasma triglyceride levels in the Veterans Administration Genetic Epidemiology Study. Diabetes 58:279-84|
|Abdul-Ghani, Muhammad A; Molina-Carrion, Marjorie; Jani, Rucha et al. (2008) Adipocytes in subjects with impaired fasting glucose and impaired glucose tolerance are resistant to the anti-lipolytic effect of insulin. Acta Diabetol 45:147-50|
|Arar, Nedal H; Freedman, Barry I; Adler, Sharon G et al. (2008) Heritability of the severity of diabetic retinopathy: the FIND-Eye study. Invest Ophthalmol Vis Sci 49:3839-45|
|Habib, Samy L; Danial, Elaine; Nath, Subrata et al. (2008) Genetic polymorphisms in OGG1 and their association with angiomyolipoma, a benign kidney tumor in patients with tuberous sclerosis. Cancer Biol Ther 7:23-7|
|Samudrala, Narahari; Farook, Vidya S; Dodd, Gerald D et al. (2008) Autosomal genome-wide linkage analysis to identify loci for gallbladder wall thickness in Mexican Americans. Hum Biol 80:11-28|
Showing the most recent 10 out of 20 publications