Hyperglycemia produced in mice by administration of acetazolamide and diphenylhydantoin.
Isolated mouse islets exposed to 3mM glucose released an increased amount of insulin in the presence of acetazolamide (AZM) (10 mM) and diphenylhydantoin (DPH) (0.35 or 3.5 mM), whereas insulin secretion due to 20 mM glucose was decreased in the presence of AZM (10 mM) and DPH (0.35, 0.70 or 3.5 mM). The serum insulin concentration was increased 1 h after AZM injection, but was not significantly altered 1 h after combined administration of AZM and DPH. A moderate transient hyperglycemia was found 1 and 2 h after DPH injection (100 mg/kg b.w.) in fed mice, and a slight, transient hyperglycemic response was observed 24 h after administration of AZM (1.5 g/kg b.w.) to fed mice. A steadily increasing, marked hyperglycemia was seen in both fed and starved mice when AZM was given shortly before or after DPH. All animals subjected to this kind of treatment died within 48 h after the injections. Ketones were found in urine and serum of the hyperglycemic animals, and the hyperglycemia was abolished and the survival of the animals was prolonged by insulin administration, suggesting that ketoacidosis contributed to the death. Light microscopy disclosed degeneration and necrosis of some B-cells, and occasionally insulitis after combined treatment with AZM and DPH. Pretreatment with AZM inhibited the hyperglycemic response to p-hydroxymercuribenzoate in fed mice, but did not affect the hyperglycemic response of fed mice to D-mannoheptulose. The findings indicate that AZM and DPH, when given to mice in combination and in sufficient amount, cause impaired B-cell function with an inhibited glucose-induced insulin release and a severe, fatal hyperglycemia. The B-cell changes are believed to be due to intracellular ionic alterations.
D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004347:Drug Interactions; D006902:Hydroxymercuribenzoates / Q000494:pharmacology; D006943:Hyperglycemia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D008356:Mannoheptulose / Q000494:pharmacology; D051379:Mice; D010672:Phenytoin / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism
D001786:Blood Glucose; D006902:Hydroxymercuribenzoates; D007328:Insulin; D010672:Phenytoin; D008356:Mannoheptulose; D012964:Sodium; D000086:Acetazolamide