(-)-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 (ED50) for the glucose-lowering action was 4, 2.4, and 8 mg/kg in ob/ob, yellow KK, and db/db mice, respectively. The ED50 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 13.0913 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Freund
P
P
Department of Medical Research/Diabetes, Boehringer, Mannheim, Germany.
Wolff
H P
HP
Kühnle
H F
HF
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007700:Kinetics; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008820:Mice, Obese; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
D001786:Blood Glucose; D006538:Heptanoic Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; C093613:2-(4-methylphenoxy)-7-(4-chlorophenyl)heptanoic acid