title: Activation of AMP-activated protein kinase within the ventromedial hypothalamus amplifies counterregulatory hormone responses in rats with defective counterregulation.
abstract: Defective counterregulatory responses (CRRs) to hypoglycemia are associated with a marked increase in the risk of severe hypoglycemia. The mechanisms leading to the development of defective CRRs remain largely unknown, although they are associated with antecedent hypoglycemia. Activation of AMP-activated protein kinase (AMPK) in the ventromedial hypothalamus (VMH) amplifies the counterregulatory increase in glucose production during acute hypoglycemia. To examine whether activation of AMPK in the VMH restores defective CRR, controlled hypoglycemia ( approximately 2.8 mmol/l) was induced in a group of 24 Sprague-Dawley rats, all of which had undergone a 3-day model of recurrent hypoglycemia before the clamp study. Before the acute study, rats were microinjected to the VMH with either 5-aminoimidazole-4-carboxamide (AICAR; n=12), to activate AMPK, or saline (n=12). In a subset of rats, an infusion of H(3)-glucose was additionally started to calculate glucose turnover. Stimulation of AMPK within the VMH was found to amplify hormonal CRR and increase endogenous glucose production. In addition, analysis of tissue from both whole hypothalamus and VMH showed that recurrent hypoglycemia induces an increase in the gene expression of AMPK alpha(1) and alpha(2). These findings suggest that the development of novel drugs designed to selectively activate AMPK in the VMH offer a future therapeutic potential for individuals with type 1 diabetes who have defective CRRs to hypoglycemia.
authors.affiliation: Department of Internal Medicine and Encocrinology, Yale University School of Medicine, P.O. Box 208020, New Haven, CT 06520-8020, USA. rory.mccrimmon@yale.edu
authors.forename: Rory J
authors.initials: RJ
authors.lastname: McCrimmon
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Fan
authors.forename: Haiying
authors.initials: H
authors.lastname: Cheng
authors.forename: Ewan
authors.initials: E
authors.lastname: McNay
authors.forename: Owen
authors.initials: O
authors.lastname: Chan
authors.forename: Margaret
authors.initials: M
authors.lastname: Shaw
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Ding
authors.forename: Wanling
authors.initials: W
authors.lastname: Zhu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sherwin
mesh_terms: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D006728:Hormones / Q000378:metabolism / Q000502:physiology*; D007003:Hypoglycemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007033:Hypothalamus, Middle / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012263:Ribonucleosides / Q000008:administration & dosage / Q000494:pharmacology; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D006728:Hormones; D009097:Multienzyme Complexes; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; D012965:Sodium Chloride; C011651:acadesine; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose