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Key role for AMP-activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia

Yale University School of Medicine, Department of Internal Medicine and Endocrinology, New Haven, CT

Objective: To examine in vivo in a rodent model the potential role of AMP-activated protein kinase (AMPK) within the ventromedial hypothalamus in glucose-sensing during hypoglycemia.

Research Design and Methods: Using gene silencing technology to selectively down-regulate AMPK in the ventromedial hypothalamus (VMH), a key hypothalamic glucose-sensing region, we demonstrate a key role for AMPK in the detection of hypoglycemia. In vivo hyperinsulinemic hypoglycemic (50 mg dl^-1) clamp studies were performed in awake, chronically catheterized Sprague-Dawley rats who had been microinjected bilaterally to the VMH with an adeno-associated viral vector (AAV) expressing a short hairpin RNA for AMPK .

Results: In comparison to control studies, VMH AMPK down-regulation resulted in suppressed glucagon (60%) and epinephrine (40%) responses to acute hypoglycemia. Rats with VMH AMPK down-regulation also required more exogenous glucose to maintain the hypoglycemia plateau, and showed significant reductions in endogenous glucose production and whole body glucose uptake.

Conclusions: We conclude that AMPK in the VMH plays a key role in the detection of acute hypoglycemia and initiation of the glucose counterregulatory response.

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