Identifying miRNA-Mediated Mechanisms Driving the Protective Effects of Metformin on Beta-Cell Function

Loss of pancreatic β-cell function is the core defect in the development and progression of type 2 diabetes (T2D); therefore, understanding mechanisms of interventions such as metformin that may preserve β-cell function is critical to prevent complications and treatment failure. Epigenetic regulation of gene expression by short non-coding RNAs such as microRNAs (miRNAs) including miR-375 and miR-7 is critical to β-cell proliferation and survival and may play a role in β-cell treatment response to metformin. The objective of this proposal is to determine whether islet cell miRNAs such as miR-375, miR-7, and others mediate the effect of metformin on the β-cell. To achieve this goal, we propose an in vitro study using next-generation miRNA sequencing following by functional experiments with miRNA inhibitors or mimics in primary mouse islets with replication of key outcomes in isolated human β-cells. Successful completion of the aims outlined in this project is expected to contribute new knowledge toward preventing complications and treatment failure in type 2 diabetes.