Transcriptional regulation of the beta cell in health and disease

The beta cells of the pancreatic islets of Langherhans are the only cells capable of producing and secreting physiologically relevant amounts of insulin in response to increased extracellular blood glucose. Defects in beta cell function lead to profound disorders of glucose metabolism, and underlie all forms of diabetes mellitus. Worldwide, the prevalence of diabetes is increasing in epidemic proportions, and the development of new treatment strategies for this disease requires an understanding of the metabolic pathways that impact pancreatic islet function. The work presented here is an exploration of the transcriptional regulation of the pancreatic beta cell under normal conditions and in states of disease. We originally hypothesized that glucose acutely regulates opening of the DNA-chromatin complex within the islet enabling rapid changes in insulin gene transcription. Our results show that acetylation of histone H4 in human islets increases acutely in response to high glucose and measurement of insulin pre-mRNA can be used to estimate rapid changes in insulin gene transcription. We further hypothesized that chronic exposure to high glucose and lipids, conditions typical of Type 2 diabetes, would have detrimental effects on islet function and euchromatin structure. Our results show that progressive hyperglycemia and hyperlipidemia lead to decreased levels of H3-dimethyl Lys4 at the promoters of key beta cell genes. These changes are partially reversed by pioglitazone, an agonist of the nuclear receptor PPAR-gamma, which functions to decrease activation of endoplasmic reticulum stress pathways and maintain gene expression and chromatin competence within the islet. Finally, we hypothesized that Liver X receptor (LXR) agonists modulate islet function independent of their effects on lipid synthetic pathways. Results of these studies show that LXR activation increases insulin gene transcription and insulin secretion in the absence of islet triglyceride accumulation. Taken together, the work presented here characterizes several aspects of normal islet physiology and examines the molecular mechanisms underlying islet dysfunction in the setting of Type 2 diabetes.