Defining new molecular determinants of cardiometabolic disease

Wednesday, March 15, 2023

Statins, or HMG-CoA reductase inhibitors, are the most commonly prescribed class of drugs used to treat and prevent cardiovascular disease. While their efficacy in reducing major adverse cardiovascular events is well-established, there is extensive evidence that statin use increases the risk of developing new-onset diabetes (NOD). While statins have been shown to impair insulin secretion, the underlying mechanism remains undefined. To understand why some individuals are susceptible to the dysglycemic effects of statin, we recruited a cohort of statin users who developed NOD (cases) or maintained normal fasting glucose levels after statin initiation (controls). We then created a repository of induced pluripotent stem cells (iPSCs) from these individuals which we profiled using RNAseq after in vitro incubation with statin or mock buffer. From this analysis we identified the MIR194-2 host gene (HG) as one of the most differentially expressed genes as statin treatment decreased MIR194-2HG in iPSCs from NOD cases but increased levels in controls. MIR194-2HG is a non-coding RNA that encodes miR192, which has previously implicated as a Type 1 and Type 2 Diabetes biomarker. Glucagon-like protein 1 (GLP-1) is an incretin hormone that promotes glucose stimulated insulin secretion (GSIS) upon receptor binding in the pancreatic beta-cell, and miR192 is predicted to bind the GLP-1 receptor (GLP-1R). We found evidence that miR192 increases GLP-1 potentiated GSIS in insulinoma cell lines and primary murine islets, effects that were attributed to increased levels of GLP-1R. In addition, administration of miR192 rescued statin-induced impairment of insulin secretion. Together these findings implicate miR192 as a novel molecular mediator of the NOD in statin users.