s-15261 and Diabetes-Mellitus--Type-2

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

A histological study has been conducted on pancreata from insulin resistant sand rats treated with S15261. As previously shown, standard laboratory chow induced dietary hyperinsulinaemia, insulin resistance and hyperlipaemia in sand rats (Psammomys obesus). Degranulation, vacuolization and even necrosis of beta-cells were observed in these animals. These changes were often accompanied by fibrosis and lymphocytic infiltration. Insulin and amylin immuno-reactivity of beta-cells was markedly decreased whilst glucagon secreting cells were localized now in the centre of the islets. Chronic treatment with S15261, a compound able to restore insulin sensitivity in insulin resistant animals, promoted the regranulation of the beta-cells and maintained the usual cytoarchitecture and integrity of the islets.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Fluorenes; Gerbillinae; Insulin Resistance; Islets of Langerhans