Ventromedial Hypothalamic Glucokinase Is an Important Mediator of the Counterregulatory Response to Insulin-Induced Hypoglycemia
Barry E. Levin 1 2 ,
Thomas C. Becker 3 ,
Jun-ichi Eiki 4 ,
Bei B. Zhang 5 and
Ambrose A. Dunn-Meynell 1 2
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
Abstract
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.
ARC, arcuate hypothalamic nucleus
AUC, area under the curve
GK, glucokinase
shRNA, short hairpin RNA
VMH, ventromedial hypothalamus
VMN, ventromedial hypothalamic nucleus
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 21 February 2008. DOI: 10.2337/db07-1755.
B.E.L., J.E., and B.B.Z. hold stock in Merck.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted Febru...

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

10.2337/db07-1755