Key role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia

TY - JOUR

T1 - Key role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia

AU - McCrimmon, Rory J.

AU - Shaw, Margaret

AU - Fan, Xiaoning

AU - Cheng, Haiying

AU - Ding, Yuyan

AU - Vella, Monica C.

AU - Zhou, Ligang

AU - Mcnay, Ewan C.

AU - Sherwin, Robert S.

PY - 2008/2

Y1 - 2008/2

N2 - OBJECTIVE-To examine in vivo in a rodent model the potential role of AMP-activated protein kinase (AMPK) within the ventromedial hypothalamus (VMH) in glucose sensing during hypoglycemia.RESEARCH DESIGN AND METHODS-Using gene silencing technology to selectively downregulate AMPK in the 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 that had been microinjected bilaterally to the VMH with an adeno-associated viral (AAV) vector expressing a short hairpin RNA for AMPK alpha.RESULTS-In comparison with control studies, VMH AMPK downregulation resulted in suppressed glucagon (similar to 60%) and epinephrine (similar to 40%) responses to acute hypoglycemia. Rats with VMH AMPK downregulation 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.

AB - OBJECTIVE-To examine in vivo in a rodent model the potential role of AMP-activated protein kinase (AMPK) within the ventromedial hypothalamus (VMH) in glucose sensing during hypoglycemia.RESEARCH DESIGN AND METHODS-Using gene silencing technology to selectively downregulate AMPK in the 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 that had been microinjected bilaterally to the VMH with an adeno-associated viral (AAV) vector expressing a short hairpin RNA for AMPK alpha.RESULTS-In comparison with control studies, VMH AMPK downregulation resulted in suppressed glucagon (similar to 60%) and epinephrine (similar to 40%) responses to acute hypoglycemia. Rats with VMH AMPK downregulation 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.

KW - DIFFERING INSULIN LEVELS

KW - CENTRAL-NERVOUS-SYSTEM

KW - SENSITIVE K+ CHANNELS

KW - FOOD-INTAKE

KW - EQUIVALENT HYPOGLYCEMIA

KW - PORTAL-VEIN

KW - SYMPATHOADRENAL RESPONSE

KW - PROJECTION NEURONS

KW - ACCUMBENS NUCLEUS

KW - AUTONOMIC FAILURE

UR - https://www.scopus.com/pages/publications/40749132626

U2 - 10.2337/db07-0837

DO - 10.2337/db07-0837

M3 - Article

SN - 0012-1797

VL - 57

SP - 444

EP - 450

JO - Diabetes

JF - Diabetes

IS - 2

ER -