s-15261 and Weight-Gain

S 15261 is a novel oral antihyperglycaemic drug with both insulin secretagogue and insulin-sensitizing effects. The study was designed to determine the biological activity of its two major metabolites, S 15511 and Y 415, and whether or not they have an additive effect.. Zucker Diabetic Fatty rats were treated for 28 days with S 15511 (10 mg/kg), Y 415 (10 mg/kg), or a combination at the same doses for a period of 4 weeks starting at 6-7 weeks of age. An additional group was pair-fed to the level of S 15511-treated animals to determine if possible effects were due to reduced food intake.. S 15511 alone and combined with Y 415 reduced energy intake and weight gain (-13% vs. controls; both p < 0.01). Baseline fasting plasma glucose levels were maintained by S 15511, S 15511 + Y 415 and pair-feeding (p < 0.01) for the entire treatment period (p < 0.01). Baseline insulin was maintained by pair-feeding only, whereas all other treated groups became hyperinsulinaemic (+110-276%; p < 0.05). Deterioration in insulin sensitivity [homeostasis model assessment (HOMA)-IR: + 239%; p < 0.01] was attenuated by S 15511, S 15511 + Y 415 and pair-feeding (p < 0.01) and was compensated for by improved insulin secretion (HOMA-beta; p < 0.01). Oral glucose tolerance tests, performed on days 0, 14 and 28, showed that all groups had an impaired insulin response, but by day 28, S 15511, S 15511 + Y 415 and pair-feeding had improved glucose disposal compared to the progressive deterioration in untreated controls (-44% to -48% vs. controls; p < 0.01), associated with progression to frank diabetes in these animals.. Treatment with these agents in a genetic model of type 2 diabetes reveals that they all have a transient effect compared to the progressive worsening of vehicle-treated controls. The improvements in glucose metabolism observed with S 15511 are significant, however, suggesting it has more therapeutic activity than the Y 415 metabolite of S 15261. It is associated with less frequent progression to diabetes; i.e. Y 415 exerts a non-significant effect alone and no significant additive effect when combined with S 15511. The mechanism of action of S 15511 may be via increased insulin sensitivity and beta-cell response preservation up to day 21. Thus, previously reported insulin secretagogue effects are likely to be attributable to the parent compound.

Topics: Animals; Blood Glucose; Body Fat Distribution; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Eating; Fluorenes; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Rats; Rats, Zucker; Weight Gain