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 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.
- AMP-Activated Protein Kinases Aminoimidazole Carboxamide/administration & dosage/analogs & derivatives/pharmacology Animals Blood Glucose/metabolism Diabetes Mellitus, Type 1/drug therapy/metabolism/pathology Enzyme Activation/drug effects Glucose/administration & dosage/metabolism/pharmacology Hormones/metabolism/*physiology Hypoglycemia/drug therapy/metabolism/pathology Hypothalamus, Middle/drug effects/*enzymology/metabolism Male Multienzyme Complexes/genetics/*metabolism Protein-Serine-Threonine Kinases/genetics/*metabolism Rats Rats, Sprague-Dawley Reverse Transcriptase Polymerase Chain Reaction Ribonucleosides/administration & dosage/pharmacology Sodium Chloride/administration & dosage/pharmacology