327-LB: Transgenic Overexpression of MicroRNA-30d Impairs Glucose Homeostasis by Regulating Beta-Cell Proliferation and Dedifferentiation

MicroRNAs (miRNAs) are small non-coding RNAs that bind to target mRNAs and inhibit the translation in mammals. Abnormal miRNA functions are closely associated with pancreatic beta-cell loss and dysfunction in type 2 diabetes. Downregulation of miR-30d has been observed in the islets of diabetic mice. To investigate the in vivo function of miR-30d in pancreatic beta cells, we generated the transgenic mice that overexpressed miR-30d specifically in the pancreatic beta cells. Compared to wild type mice, the transgenic mice that overexpressed miR-30d resulted in hyperglycemia and glucose intolerance with reduced beta-cell mass and insulin production following high fat diet treatment. Strikingly, loss of beta-cell mass was partially due to beta-cell dedifferentiation to glucagon-producing alpha-cells, resulted in increased plasma glucagon level. The transcriptomic analysis combined with bioinformatic analysis of islets isolated from transgenic verses control mice identified connective tissue growth factor (CTGF) and Cyclin E2 as miR-30d potential targets. Moreover, several β-cell disallowed genes (e.g., MCT4/SLC16A3, LDHA) were observed upregulated in transgenic mice, which have been reported as positive markers of dedifferentiated human β-cells from type 2 diabetic patients. Taken together, miR-30d plays an essential role in maintaining mature beta-cell identity. Disclosure X. Tang: None. Funding National Institutes of Health