(-)-BM-13.0913 - A NEW ORAL ANTIDIABETIC AGENT THAT IMPROVES INSULIN SENSITIVITY IN ANIMAL-MODELS OF TYPE-II (NON-INSULIN-DEPENDENT) DIABETES-MELLITUS

Insulin resistance is one of the key features of non-insulin-dependent diabetes mellitus (NIDDM). Therefore, a drug that causes an improvement in insulin sensitivity would be of great interest for the treatment of NIDDM. In addition to the insulin-sensitizing thiazolidinediones, we have found another class of insulin-sensitizing agents: the alpha-activated carbonic acids. (-)-BM 13.0913, a member of this class, was effective in improving insulin resistance in hyperinsulinemic and hypoinsulinemic insulin-resistant animal models of NIDDM. The 50% effective dose (ED(50)) for the glucose-lowering action was 4, 2.4, and 8 mg/kg in ob/ob, yellow KK, and db/db mice, respectively. The ED(50) for the insulin-lowering action was 14.5, 5, and 26 mg/kg. This rightward shift of the dose-response curve for insulin indicates that improving glucose homeostasis is the primary effect of the drug, followed by an insulin-decreasing action. This effect on glucose homeostasis may be brought about by sensitizing peripheral target tissues to the effects of insulin. An increase in deoxyglucose uptake and glucose oxidation measured in adipocytes from rats that had been treated for 14 days with (-)-BM 13.0983 supports this conclusion. Glucose uptake and oxidation was increased at all insulin concentrations tested, suggesting an improved responsiveness. Insulin sensitivity in adipocytes was not influenced by the drug. Studies in the moderately hypoinsulinemic, low-dose streptozotocin (STZ) diabetic rat with a residual insulin concentration showed a decrease in blood glucose concentrations, as well as a decrease in urinary glucose. Data obtained with STZ-diabetic rats with no residual insulin concentration and (-) BM 13.0913 showed no effect on blood and urinary glucose, further supporting the insulin-sensitizing action of the drug. Additionally, no clinical signs of hypoglycemia were detected in any of the animal models tested. Furthermore, a decrease in serum nonesterified fatty acids (NEFA) and triglycerides was seen with an ED(50) Of 6 mg/kg. The (+) enantiomer of BM 13.0913 showed no effect on glucose and insulin concentrations in any of the mice models tested. An enantioselective action was thus demonstrated. From these results, it is concluded that the (-) enantiomer of BM 13.0913 may prove to be an active drug in treating insulin resistance as seen in NIDDM. Copyright (C) 1995 by W.B. Saunders Company