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Ventromedial Hypothalamic Glucokinase Is an Important Mediator of the Counterregulatory Response to Insulin-Induced Hypoglycemia

¹ Neurology Service, Department of Veterans Affairs New Jersey Health Care System, East Orange, New Jersey
² Department of Neurology and Neurosciences, New Jersey Medical School, University of Medicine and Dentistry New Jersey, Newark, New Jersey
³ Department of Internal Medicine, The Sarah W. Stedman Nutrition and Metabolism Center, and Division of Endocrinology, Metabolism and Nutrition, Duke University Medical Center, Durham, North Carolina
⁴ Tsukuba Research Institute, Banyu Pharmaceutical, Tsukuba, Ibaraki, Japan
⁵ Merck Research Laboratories, Rahway, New Jersey

Corresponding author: Barry E. Levin, MD, Neurology Service (127C), VA Medical Center, E. Orange, NJ 07018-1095. E-mail: levin{at}umdnj.edu

Abbreviations: ARC, arcuate hypothalamic nucleus; AUC, area under the curve; GK, glucokinase; shRNA, short hairpin RNA; VMH, ventromedial hypothalamus; VMN, ventromedial hypothalamic nucleus

OBJECTIVE—The counterregulatory response to insulin-induced hypoglycemia is mediated by the ventromedial hypothalamus (VMH), which contains specialized glucosensing neurons, many of which use 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 counterregulatory response, we tested the hypothesis that increasing VMH GK activity would similarly attenuate, while decreasing GK activity would enhance the counterregulatory response to insulin-induced hypoglycemia.

RESEARCH DESIGN AND METHODS—The counterregulatory response to insulin-induced hypoglycemia was evaluated in Sprague-Dawley rats after 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 short hairpin RNA (shRNA) to chronically reduce GK expression and activity.

RESULTS—Compound A increased VMH GK activity sixfold in vitro and reduced the epinephrine, norepinephrine, and glucagon responses to insulin-induced hypoglycemia 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 insulin-induced hypoglycemia by 23–50%.

CONCLUSIONS—These studies suggest that VMH GK activity is an important regulator of the counterregulatory response to insulin-induced hypoglycemia and that a drug that specifically inhibited the rise in hypothalamic GK activity after insulin-induced hypoglycemia might improve the dampened counterregulatory response seen in tightly controlled diabetic subjects.

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