Insulin resistance is defined as the decreased ability of insulin to perform its biological function in fat, liver and muscle. The insulin resistance observed in skeletal muscle is particularly important as this tissue, under normal physiological conditions, is the main site of insulin-stimulated glucose disposal. Both genetic and environmental factors contribute to the pathogenesis of insulin resistance, which is an underlying feature of a number of diseases including obesity and type 2 diabetes. However, the role of epigenetic factors in the pathogenesis of insulin resistance is less understood. Epigenetic modifications encompass both DNA methylation and histone modifications, and can be described as heritable changes in gene function that occur without a change in nucleotide sequence. DNA methylation (and histone modifications) of the genome may provide a potential link between the genetic and environmental factors observed in insulin resistance. While epigenetics refers to the study of single genes or sets of genes, epigenomics, which simply means 'above the genome', refers to more global analyses of epigenetic changes across the entire genome. The overall goal of the experiments included in this proposal is to determine global patterns of changes in DNA methylation in metabolically well-characterized insulin sensitive and resistant volunteers and to determine whether these changes can explain alterations in gene expression and protein abundance in the insulin resistance associated with obesity and type 2 diabetes. Specifically, we will use these findings to determine whether changes in DNA methylation could explain a reduced response to muscle contraction in insulin resistant individuals. These findings will allow us to determine whether changes in protein abundance we have observed in insulin resistance occur in conjunction with changes in methylation of the promoters of the genes coding for these proteins. This study brings a transdisciplinary team of investigators together to address critical gaps in our understanding of global epigenetic markers, specifically DNA methylation, in understanding the pathophysiology of insulin resistance in both skeletal muscle and whole blood tissues.

Public Health Relevance

Insulin resistance is an underlying feature of obesity and type 2 diabetes, which are critical public health issues that have created major societal, medical, economic and research challenges. This study will examine how global DNA methylation contributes to the pathophysiology of insulin resistance in both human skeletal muscle and whole blood tissues.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Blondel, Olivier
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Arizona State University-Tempe Campus
Other Basic Sciences
Schools of Arts and Sciences
United States
Zip Code
Day, Samantha E; Garcia, Luis A; Coletta, Richard L et al. (2017) Alterations of sorbin and SH3 domain containing 3 (SORBS3) in human skeletal muscle following Roux-en-Y gastric bypass surgery. Clin Epigenetics 9:96
Day, Samantha E; Coletta, Richard L; Kim, Joon Young et al. (2017) Potential epigenetic biomarkers of obesity-related insulin resistance in human whole-blood. Epigenetics 12:254-263
Campbell, Latoya E; Langlais, Paul R; Day, Samantha E et al. (2016) Identification of Novel Changes in Human Skeletal Muscle Proteome After Roux-en-Y Gastric Bypass Surgery. Diabetes 65:2724-31
Day, Samantha E; Coletta, Richard L; Kim, Joon Young et al. (2016) Next-generation sequencing methylation profiling of subjects with obesity identifies novel gene changes. Clin Epigenetics 8:77
Kim, Joon Young; Coletta, Dawn K; Mandarino, Lawrence J et al. (2012) Glucose response curve and type 2 diabetes risk in Latino adolescents. Diabetes Care 35:1925-30