Role of miR-483 in Pancreatic Alpha and Beta Cells

Michigan Technological University, Houghton MI

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Abstract

? DESCRIPTION (provided by applicant): Insulin and glucagon work in an opposing manner to regulate and maintain normal blood glucose concentration. Beta cell loss is associated with significant ?-cell expansion during the development of type 2 diabetes. Recent discoveries concerning microRNAs (miRNAs) demonstrated that these novel non-coding RNAs regulate gene expression in different aspects of cell differentiation, proliferation and survival. In order o identify key miRNAs that differentiate beta cells from alpha cells, we performed miRNA screenings in pancreatic beta cells and alpha cells, respectively. One novel miRNA, miR-483 has been identified for its high expression in beta cells, but much less so in alpha cells. Interestingly, overexpression of miR-483 induces insulin secretion and ?-cell proliferation while inhibiting glucagon secretion through activation of insulin signaling. Moreover, increased miR-483 is shown in the islets of prediabetic db/db mice, which is correlated with compensatory ?-cell mass expansion during the early stage of diabetes. Based on our preliminary data, we hypothesize that miR-483 will enhance ?-cell proliferation, insulin secretion, and the susceptibility to diet-induced diabetes. The objective of this research project will focus on 1) Determining the physiological functions of miR-483 using conditional knockout mice; 2) Define the molecular mechanisms by which miR-483 regulates alpha and beta cell functions; 3) Determine the interactions between miR-483 and its host gene Igf2. The results obtained from this project will help understanding of the molecular mechanisms of beta cell loss in diabetes and guide the development of therapies for the disease. This project will also provide research opportunities for both undergraduate and graduate students.