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.


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.

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