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

¹Neurology Service, Department of Veterans Affairs New Jersey Health Care System, 385 Tremont Ave, East Orange, New Jersey 07018; E-mail: levin{at}umdnj.edu, Telephone: 973-676-1000 ext 1412, Fax: 973-395-7233
²Department of Neurology and Neurosciences, New Jersey Medical School, University of Medicine and Dentistry New Jersey, Newark, New Jersey 07101
³Department of Internal Medicine, The Sarah W. Stedman Nutrition and Metabolism Center, and Division of Endocrinology, Metabolism and Nutrition, Duke University Medical Center, Durham, NC
⁴Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
⁵Merck Research Laboratories, Rahway, New Jersey

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.

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