Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats.
CS-045 is a new oral antidiabetic agent that was effective in insulin-resistant diabetic animal models, including the KK mouse, the ob/ob mouse, and the Zucker fatty rat. CS-045 was not effective in the streptozocin-treated mouse, an insulin-deficient diabetic animal model. In fed KK mice, CS-045 lowered the plasma glucose levels in a dose-dependent manner after a single oral administration, and the hypoglycemic effect lasted for at least 18 h. In normal rats, however, plasma glucose levels were not changed after administration of CS-045. CS-045 when given chronically (2 wk) to diabetic KK and ob/ob mice as a 0.2% food admixture dramatically improved hyperglycemia, hyperinsulinemia, and hypertriglyceridemia to near-normal values and decreased plasma lactate, free fatty acid, and ketone body levels without reducing food intake or body weight. In the obese Zucker fatty rat, oral administration of CS-045 had a similar effect in lowering plasma glucose, insulin, triglyceride, free fatty acid, lactate, and ketone body levels. The CS-045-treated Zucker fatty rats showed increased glucose tolerance and decreased insulin secretion in response to oral glucose. After 9 days of treatment, insulin binding to adipocyte plasma membranes from both CS-045-treated Zucker fatty rats and KK mice was increased. Furthermore, 2-deoxyglucose uptake in CS-045-treated adipocytes was increased and the insulin dose-response curve was shifted to the left. These findings suggest that CS-045 increases not only insulin sensitivity but also insulin responsiveness. Based on its pharmacological profile, CS-045 is a new orally effective antidiabetic agent that may reduce abnormalities of glucose and lipid metabolism in obese and non-insulin-dependent diabetes mellitus patients with insulin resistance.
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001578:Benzopyrans / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D002839:Chromans / Q000627:therapeutic use*; D003847:Deoxyglucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007657:Ketone Bodies / Q000097:blood; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D011924:Rats, Zucker; D011972:Receptor, Insulin / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones; D014280:Triglycerides / Q000097:blood; D000077288:Troglitazone
D001578:Benzopyrans; D001786:Blood Glucose; D002839:Chromans; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D007657:Ketone Bodies; D007773:Lactates; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; D019344:Lactic Acid; D003847:Deoxyglucose; D011972:Receptor, Insulin; D000077288:Troglitazone