RT Journal Article
SR Electronic
T1 Activation of AMP-Activated Protein Kinase Within the Ventromedial Hypothalamus Amplifies Counterregulatory Hormone Responses in Rats With Defective Counterregulation
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 1755
OP 1760
DO 10.2337/db05-1359
VO 55
IS 6
A1 McCrimmon, Rory J.
A1 Fan, Xiaoning
A1 Cheng, Haiying
A1 McNay, Ewan
A1 Chan, Owen
A1 Shaw, Margaret
A1 Ding, Yuyan
A1 Zhu, Wanling
A1 Sherwin, Robert S.
YR 2006
UL http://diabetes.diabetesjournals.org/content/55/6/1755.abstract
AB 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 (∼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 H3-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 α1 and α2. 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.