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

Neurology Service, Department of Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018-1095, USA.
Diabetes (Impact Factor: 8.47). 06/2008; 57(5):1371-9. DOI: 10.2337/db07-1755
Source: PubMed

ABSTRACT 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.
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.
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%.
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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    • "Similar to its role in pancreatic beta-cells, glucokinase appears to act as a critical glucose sensor in a substantial proportion of these VMN neurons (Kang et al. 2006). Glucose-sensing neurons play a critical role in regulating release of counter-regulatory hormones, such as glucagon, in response to hypoglycemia (Borg et al. 1995, 1997; Levin et al. 2008). In situations such as diet-induced obesity, where there is defective central counter-regulatory response to hypoglycemia, VMN glucokinase mRNA expression is increased (Dunn-Meynell et al. 2002). "
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    • "The robust feeding response seen in our rats with VMH 5TG injections further supports a role for VMH glucosensing in glucoprivic feeding. Taken together with previous studies demonstrating the importance of the VMH (Borg et al., 1994; Borg et al., 1995; Borg et al., 1997), and particularly VMH GK activity and glucosensing in producing the counterregulatory neuroendocrine responses to glucopenia and hypoglycemia (Tkacs et al., 2000; Dunn-Meynell et al., 2002; Kang et al., 2008; Levin et al., 2008), the current studies support VMH glucosensing as a mediator of both the behavioral and neuroendocrine responses to systemic glucoprivation. Among the VMH glucosensing neurons, the orexigenic ARC neuropeptide Y neurons are a likely candidate as an effector of this feeding since they, express GK mRNA (Dunn-Meynell et al., 2002), are activated by hypoglycemia (Muroya et al., 1999; Fioramonti et al., 2007) and NPY-deficient mice have defective glucoprivic feeding.(Sindelar "
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