Cellular and Molecular Biology of Diabetes and Obesity
Type-2 diabetes mellitus is characterized by insulin resistance in target tissues such as adipose, muscle and the liver and is often accompanied by obesity. We are interested in the role of adipose tissue as an endocrine organ and its endocrine and paracrine effects on liver and muscle, as well as autocrine effects on adipose tissue itself. Of particular interest is the aberrant regulation of adipokines, such as omentin and adiponectin, or inflammatory cytokines such as TNF-alpha in pathophysiological states such as diabetes, obesity and cardiovascular disease. We utilize “state of the art” gene expression, immunofluorescence and proteonomics approaches to address these topics in cell culture, organ culture and animal-model systems.
Functional genomics studies of diabetes and obesity examine global gene expression by microarray analysis and validation by quantitative RT-PCR. Changes in gene expression are analyzed in human muscle and adipose tissue in various pathophysiological states with interventions such as exercise and insulin sensitizing drugs. We also use rodent models to evaluate changes in gene expression in many tissues after diabetes drugs and/or dietary manipulation such as high fat feeding.
Diabetes, obesity and cardiovascular disease are polygenic diseases that have a significant environmental contribution. A number of candidate gene polymorphisms that may predict onset of diabetes and obesity have been identified by the EDN Genetics Group. We functionally characterize some of these mutations to determine their relative impact on diabetes and obesity phenotypes. Modern molecular and cellular techniques are used to evaluate these polymorphisms including but not limited to transcription analysis, protein overexpression and analysis of signal transduction pathways.
Shuldiner, A.R., McLenithan, J.C. (2004) Genes and pathophysiology of type 2 diabetes: more than just the Randle cycle all over again. J Clin Invest. 114(10):1414-7.
Pollin, T., Tanner, K., O'Connell, J., Ott, S., Damcott, C., Shuldiner, A., McLenithan, J., Mitchell, B. (2005) Linkage of Plasma Adiponectin Levels to 3q27 Explained by Association With Variation in the APM1 Gene. Diabetes. 54(1):268-74
Batista, C.M.S., Pollin, T., Yang, R., Gong, D., Shuldiner, A., McLenithan, J. (2005) The Effects of Obesity on Plasma Levels of Omentin, a Depot-Specific Adipokine, in the Old Order Amish. Diabetes 54 (Suppl 2)
Prior, S.J., Hagberg, J.M., Paton C.M., Douglass, L.W., Brown, M.D., McLenithan, J.C., Roth S.M. (2005 Dec 9; [Epub ahead of print]). DNA sequence variation in the promoter region of the VEGF gene impacts VEGF gene expression and maximal oxygen consumption. Am J Physiol Heart Circ Physiol.
Yang, R.Z., Lee, M.J., Hu, H., Pray, J.E., Wu, H.B., Hansen, B.C., Fried, S.K., Shuldiner, A.R., McLenithan, J.C., Gong, D.W. Identification of Omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action. Am J Physiol Endocrinol Metab. 2006 Jun;290(6):E1253-61. Epub 2006 Mar 10.