120-OR: MicroRNA-7a-5p Overexpression in the VMH Restores the Sympathoadrenal Response to Hypoglycemia in Recurrently Hypoglycemic Rats

Abstract

We tested the hypothesis that the impaired sympathoadrenal response induced by recurrent hypoglycemia (RH) is mediated by changes in key microRNA expression in the ventromedial hypothalamus (VMH). MicroRNA-sequencing data from the VMH of RH rats indicated a 67% downregulation of microRNA-7a-5p and a 2.3-fold upregulation of microRNA-665. Rescue experiments were conducted consisting of lentiviral-mediated overexpression of microRNA-7a-5p or downregulation of microRNA-665 targeted to the VMH. Rats were randomized to, 1) recurrent saline (RS), 2) RH (25-50 mg/dl x 3 days), 3) RH + Lenti-scrambled microRNA, or 4) RH + Lenti-targeted microRNA. All rats were subsequently subjected to hyperinsulinemic-hypoglycemic (40-50 mg/dl) clamps. As expected, RH induced a blunted sympathoadrenal hormone response to hypoglycemia. Targeted VMH overexpression (∼3.5 fold) of microRNA-7a-5p in RH rats normalized the epinephrine response to hypoglycemia coinciding with a 30% decreased glucose infusion rate. Targeted VMH downregulation of microRNA-665, however, did not improve counterreguatory responses. These findings indicate that microRNA-7a-5p is a potential mediator of impaired VMH glucose sensing/counterregulation and may be an effective therapeutic target to restore impaired sympathoadrenal responses to hypoglycemia. Disclosure R. Agrawal: None. M.G. Montgomery: None. D. Verma: None. G.T. Durupt: None. A. Vieira de Abreu: None. S. Swaminathan: None. S. Fisher: None.