Fellowship for Xiaoqing Tang: Role of MicroRNAs in Insulin Production and Secretion in Pancreatic Beta-Cells

Diabetes is a major cause of cardiovascular diseases. Recent studies indicate that a novel population of small cellular RNAs, termed microRNAs (miRNAs), may play an important role in the development of type 2 diabetes. The expression of these miRNAs may be highly regulated under various environmental and physiological conditions; dysregulation of these small RNAs may lead to the development of type 2 diabetes. For example, miR-375 has been discovered to be specifically expressed in pancreatic beta cells and to be important in insulin secretion. The functions of most miRNAs in beta cells await to be investigated. The hypothesis of this project is that miRNAs are not functioning alone, but rather, multiple miRNAs act in cohort to regulate beta cell development and insulin production and secretion in response to glucose. The specific aims of this project are: (1) To compare the miRNA expression profiles in isolated islets between ob/ob mice and control mice, in order to identify type 2 diabetes-associated miRNAs using a recently developed miRNA microarray technology; (2) To compare miRNA expression profiles in isolated islets treated with low or high glucose and to identify glucose-regulated miRNAs; (3) To analyze the function of the identified glucoseregulated and diabetes-associated miRNAs in the insulinoma cell line MIN6 and in isolated rat islets by overexpressing synthetic miRNAs or by knocking down their expression using 2'-Q-methyl RNA oligonucleotides. The effects of overexpression or knockdown of miRNAs on insulin production and secretion and beta-cell function will be analyzed. The results obtained from the proposed project will likely provide new insights into function of miRNAs in glucose-regulated insulin production and secretion in pancreatic beta cells and may lead to the discovery of novel type 2 diabetic biomarkers and potential therapeutic approaches to treat or prevent type 2 diabetes and its associated complications such as cardiovascular disease.