An ascochlorin derivative, AS-6, reduces insulin resistance in the genetically obese diabetic mouse, db/db.
An ascochlorin derivative, AS-6, is a new hypoglycemic agent orally active in both obese hyperinsulinemic and insulin-deficient diabetic animal models. AS-6, when given as a 0.025-0.2% admixture in the diet, dose-dependently ameliorated polydipsia, polyuria, and glycosuria in the genetically obese diabetic mouse, C57BL/KsJ db/db, while neither insulin nor tolbutamide showed any beneficial effects. The amelioration by AS-6 was associated with a marked decrease in serum glucose and triglyceride. The effects persisted at least 10 wk, accompanied by a steady decrease in drinking water consumption. The chronic treatment prevented pancreatic islet degeneration, e.g., degranulation of the beta-cells, basophilic appearance of the exocrine border around the islets, and small round cell infiltration. The isolated islets from AS-6-treated mice released much more insulin in response to glucose than those from untreated controls. A significant correlation between serum immunoreactive insulin and glucose/triglyceride from both treated and untreated mice suggests that AS-6 restores sensitivity and responsiveness to insulin to the mice. In fact, the combined treatment with insulin synergistically decreased serum glucose by 50% below AS-6 treatment alone. Furthermore, the epididymal fat pad slices from AS-6-treated db/db mice increased CO2 generation and lipogenesis over the untreated controls, and the glucose metabolic rate (CO2 generation plus lipogenesis from U-[14C]-glucose) in the slices and the serum glucose level inversely correlated at r = 0.8799.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004357:Drug Synergism; D004435:Eating / Q000187:drug effects; D006016:Glycolates / Q000494:pharmacology* / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D051379:Mice; D008820:Mice, Obese; D051381:Rats; D014044:Tolbutamide / Q000627:therapeutic use
D001786:Blood Glucose; D006016:Glycolates; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D014044:Tolbutamide; C043832:4-O-carboxymethylascochlorin