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Effects of S 15511, a therapeutic metabolite of the insulin‐sensitizing agent S 15261, in the Zucker Diabetic Fatty rat
Author(s) -
Pickavance L. C.,
Wilding J. P. H.
Publication year - 2007
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2006.00586.x
Subject(s) - medicine , insulin , endocrinology , secretagogue , metabolite , diabetes mellitus , insulin resistance , glucose homeostasis , homeostasis , type 2 diabetes , glucose tolerance test
Aim: 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. Methods: 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. Results: 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‐β; 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. Conclusion: 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 β‐cell response preservation up to day 21. Thus, previously reported insulin secretagogue effects are likely to be attributable to the parent compound.