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


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 AMPKalpha.


RESULTS
In comparison with control studies, VMH AMPK downregulation resulted in suppressed glucagon ( approximately 60%) and epinephrine (approximately 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.
McCrimmon
Rory J
RJ
FRCP, Yale University School of Medicine, P.O. Box 208020, New Haven, CT 06520-8020, USA. rory.mccrimmon@yale.edu
Shaw
Margaret
M
Fan
Xiaoning
X
Cheng
Haiying
H
Ding
Yuyan
Y
Vella
Monica C
MC
Zhou
Ligang
L
McNay
Ewan C
EC
Sherwin
Robert S
RS
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D020868:Gene Silencing; D005822:Genetic Vectors; D015309:Glucose Clamp Technique; D006706:Homeostasis; D007003:Hypoglycemia / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008845:Microinjections; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013698:Templates, Genetic; D014697:Ventromedial Hypothalamic Nucleus / Q000201:enzymology*
D017931:DNA Primers; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases