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


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 mug) to acutely inhibit GK activity, 3) high-dose alloxan (24 microg), 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.
Levin
Barry E
BE
Neurology Service, Department of Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018-1095, USA. levin@umdnj.edu
Becker
Thomas C
TC
Eiki
Jun-ichi
J
Zhang
Bei B
BB
Dunn-Meynell
Ambrose A
AA
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology; D004789:Enzyme Activation; D005941:Glucokinase / Q000378:metabolism*; D006706:Homeostasis; D007003:Hypoglycemia / Q000139:chemically induced / Q000201:enzymology*; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014697:Ventromedial Hypothalamic Nucleus / Q000201:enzymology*
D007328:Insulin; D005941:Glucokinase