126-OR: MIR192-5p Is a Novel Regulator of GLP-1R and Insulin Secretion That May Contribute to Risk of Statin-Induced Diabetes

Statins are a commonly prescribed cardiovascular disease drug class that can increase risk of type 2 diabetes (T2D). To investigate molecular mechanisms underlying this effect, we created induced pluripotent stem cells (iPSCs) from normoglycemic patients identified from electronic health records of Kaiser Permanente of Northern California who developed T2D after statin initiation or controls who maintained normal fasting glucose on statin treatment (24 per group). RNAseq analysis of iPSCs incubated with 250nM atorvastatin, 500nM simvastatin or mock buffer for 24h identified MIR194-2HG as one of the transcripts exhibiting the greatest differential change between cases vs. controls. Both statins increased MIR194-2HG in the controls but decreased levels in cases. This long non-coding RNA encompasses two microRNAs: MIR-192 and MIR-194. MIR192-5p is predicted to bind the 3’ UTR of the glucagon like peptide 1 receptor gene (GLP1R), and we found that transfection of a rat insulinoma cell line (INS-1) with a MIR192-5p mimic caused increased Glp1r transcript (1.4-fold) and protein (2.1-fold) levels compared to a scrambled control. Using a luciferase reporter containing human GLP1R 3’ UTR, we observed similar increases in signal; however, this elevation remained even after disruption of the predicted MIR192-5p binding site demonstrating that MIR192-5p upregulates GLP1R through an indirect mechanism. GLP1R augments glucose-stimulated insulin secretion, and we found that the MIR192-5p mimic increased insulin levels in media of glucose-stimulated INS-1 cells (1.4-fold). Reduction in media insulin in INS-1 cells treated with 1 μM simvastatin was rescued by MIR192-5p overexpression, while a MIR192-5p antisense inhibitor abolished this effect. These findings implicate MIR192-5p in statin-induced impairment of glucose stimulated insulin secretion through the regulation of GLP1R, an effect that may contribute to the increased risk of T2D in statin users.