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

Authors: Levin, BE  Becker, TC  Eiki, J  Zhang, BB  Dunn-Meynell, AA 
Citation: Levin BE, etal., Diabetes. 2008 May;57(5):1371-9. Epub 2008 Feb 21.
Pubmed: (View Article at PubMed) PMID:18292346
DOI: Full-text: DOI:10.2337/db07-1755

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 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.

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CRRD Object Information
CRRD ID: 2301900
Created: 2008-11-07
Species: All species
Last Modified: 2008-11-07
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.