The Roles of Orphan Nuclear Receptors in the Endocrine Pancreas

The hormone insulin plays a critical role in carbohydrate metabolism of animals. The production and secretion of insulin by beta-cells of the pancreatic islet need to be tightly regulated to maintain proper blood glucose levels in the circulation. Dysfunction of this important endocrine system is responsible for diabetic mellitus. Over the last several years, research has suggested that the function and integrity of beta-cells can be dramatically affected by exposure to and accumulation of lipids. Several Orphan Nuclear Receptors (ONRs) have been identified and characterized in other cell types as "lipid sensors" that respond to elevated cellular lipid levels to regulate gene expression. Therefore the goal of my thesis research is to evaluate the expression and role of these transcription factors on beta-cell function and glucose metabolism. First, the complement of nuclear hormone receptors in mouse islets, and representative alpha- and beta- cell lines was determined by quantitative real-time PCR. Many nuclear receptors are expressed in the cells of the islet and several show differential expression levels under varying glucose conditions which suggests these nuclear receptors may be important for normal islet cell function. Of particular interest to our group LXRbeta, and to a lesser extent LXRalpha, are present in the beta cell of islets, and respond to synthetic LXR agonists to upregulate previously identified target genes. Exposing isolated mouse islets to the synthetic LXR agonist T1317 results in increased glucose-stimulated insulin secretion (GSIS). Incubation of islets from Lxr-null mice with this ligand has no effect on GSIS thus suggesting the T-compound effect is mediated by LXR. In addition, oral administration of T1317 to wild type, but not Lxr-null mice, altered islet GSIS in vivo and promoted efficient glucose clearance. These results suggest that activation of LXR in islet cells can modify islet function and help to control serum glucose levels. We also identified ChREBP as a novel target gene of LXR in the beta cells of the islet and characterized the importance of the LXR-ChREBP axis in insulin secretion from pancreatic islets. In addition to LXR, HNF4gamma is also an ONR of interest in beta cells. Realtime PCR results suggested that HNF4gamma and HNF4alpha are highly expressed in the pancreatic beta cells. Losing the function of HNF4alpha in beta cells has been shown to cause a rare form of diabetes called MODY1 (maturity-onset diabetes of the young).