Key Role for AMP-Activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia
- Rory J. McCrimmon,
- Margaret Shaw,
- Xiaoning Fan,
- Haiying Cheng,
- Yuyan Ding,
- Monica C. Vella,
- Ligang Zhou,
- Ewan C. McNay and
- Robert S. Sherwin
- Yale University School of Medicine, Department of Internal Medicine and Endocrinology, New Haven, Connecticut
- Address correspondence and reprint requests to Rory J. McCrimmon, MD, FRCP, Yale University School of Medicine, P.O. Box 208020, New Haven, CT 06520-8020. E-mail: rory.mccrimmon{at}yale.edu
Abstract
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 AMPKα.
RESULTS—In comparison with control studies, VMH AMPK downregulation resulted in suppressed glucagon (∼60%) and epinephrine (∼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.
- ACTH, adrenocorticotrophin hormone
- AAV vector, adeno-associated viral vector
- AICAR, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside
- AMPK, AMP-activated protein kinase
- Arc, Arcuate nucleus
- CAG, chicken β-actin promoter
- CRH, corticotrophin-releasing hormone
- CRR, counterregulatory response
- DMH, dorsomedial hypothalamus
- GFP, green fluorescent protein
- GIR, glucose infusion rate
- NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases
- PBT, 0.04% Triton X-100 in PBS
- PVN, paraventricular nucleus
- Ra, rate of endogenous glucose production
- Rd, rate of whole-body glucose uptake
- VMH, ventromedial hypothalamus
- VMN, ventromedial nucleus
- WPRE, woodchuck posttranscriptional regulatory element
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 31 October 2007. DOI: 10.2337/db07-0837.
R.J.M. and M.S. contributed equally to this article.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted October 26, 2007.
- Received June 20, 2007.
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