Ventromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemia

Abstract

Objective: The counterregulatory response (CRR) to insulin-induced hypoglycemia (IIH) is mediated by the ventromedial hypothalamus (VMH) which contains specialized glucosensing neurons, many of which utilize glucokinase (GK) as the rate-limiting step in glucose's regulation of neuronal activity. Since conditions associated with increased VMH GK expression are associated with a blunted CRR, we tested the hypothesis that increasing VMH GK activity would similarly attenuate, while decreasing GK activity would enhance the CRR to IIH.

Research Design And Methods: The CRR to IIH was evaluated in Sprague-Dawley rats following bilateral VMH injections of: 1) a GK activator drug (Compound A) to increase VMH GK activity; 2) low dose alloxan (4 μg) to acutely inhibit GK activity; 3) high dose alloxan (24 μg) or 4) an adenovirus expressing GK shRNA to chronically reduce GK expression and activity.

Results: Compound A increased VMH GK activity 6-fold in vitro and reduced the epinephrine, norepinephrine and glucagon responses to IIH by 40-62% when injected into the VMH in vivo. On the other hand, acute and chronic reductions of VMH GK mRNA or activity had a lesser and more selective effect on increasing primarily the epinephrine response to IIH by 23-50%.

Conclusions: These studies suggest that VMH GK activity is an important regulator of the CRR to IIH and that a drug which specifically inhibited the rise in hypothalamic GK activity following IIH might improve the dampened CRR seen in tightly controlled diabetic subjects.