title: Differential impairment of glucagon responses to hypoglycemia, neuroglycopenia, arginine, and carbachol in alloxan-diabetic mice.
abstract: To gain insight into the mechanisms responsible for the loss of the glucagon response to insulin-induced hypoglycemia in type 1 diabetes, glucagon responses to 4 different stimuli were examined over 3 months of diabetes in alloxan-treated mice. At 1, 6, and 12 weeks after alloxan (60 mg/kg), phloridzin (0.1 g/kg) was administered to overnight fasted diabetic mice to match the glucose levels of those in nondiabetic control mice before administration of the acute stimuli. Despite the elevation of baseline glucagon levels produced by the phloridzin treatment, the glucagon responses to insulin (2 U/kg intraperitoneally [IP])-induced hypoglycemia was not impaired at 1 week. However, the response was reduced by greater than 60% after 6 and 12 weeks of diabetes (P <.05). In contrast, the glucagon response to arginine (0.25 g/kg intravenously [IV]) was not reduced after 1, 6, or 12 weeks of diabetes, ruling out a generalized impairment of the A-cell responses. The glucagon response to the neuroglucopenic agent, 2-deoxyglucose (2-DG; 500 mg/kg IV) was impaired, like that to insulin-induced hypoglycemia, after 6 and 12 weeks of diabetes (P <.05), suggesting that supersensitivity to the potential inhibitory effects of exogenous insulin is not the mechanism responsible for the impairment. Finally, the glucagon response to the cholinergic agonist, carbachol (0.53 micromol/kg IV), was not impaired in the diabetic animals, arguing against a defect in the A-cell's responsiveness to autonomic stimulation. The data suggest that the impairment of the glucagon response to insulin-induced hypoglycemia in alloxan diabetic mice is not due to a generalized impairment of A-cell responsiveness, to desensitization by a suppressive action of insulin, or to impairment of the A-cell response to autonomic stimuli. The remaining mechanisms which are likely to explain the late loss of the glucagon response to insulin-induced hypoglycemia include (1) a defect in the A-cell recognition of glucopenic stimuli, or (2) a defect in the autonomic inputs to the A cell that are known to be activated by glucopenic stimuli.
authors.affiliation: Department of Medicine, Lund University, Lund, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Taborsky
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Havel
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology*; D003847:Deoxyglucose / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000097:blood*; D005260:Female; D005934:Glucagon / Q000097:blood*; D005947:Glucose / Q000172:deficiency*; D007003:Hypoglycemia / Q000097:blood* / Q000139:chemically induced; D007004:Hypoglycemic Agents; D007328:Insulin; D051379:Mice; D008815:Mice, Inbred Strains
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D002217:Carbachol; D005934:Glucagon; D001120:Arginine; D003847:Deoxyglucose; D005947:Glucose