Vol. 295, Issue 2, 753-760, November 2000

Beneficial Insulin-Sensitizing and Vascular Effects of S15261 in the Insulin-Resistant JCR:LA-cp Rat¹

James C. Russell, Denis Ravel, Jean-Paul Pégorier, Pascal Delrat, Roeline Jochemsen, Sheila F. O'Brien² , Sandra E. Kelly, Sandra T. Davidge and David N. Brindley

Departments of Surgery (J.C.R., S.F.O., S.E.G.), Biochemistry (Signal Transduction Laboratories) (D.N.B.), and Physiology and Obstetrics and Gynaecology (S.T.D.), University of Alberta, Edmonton, Alberta, Canada; the Metabolism Division (D.R., R.J.), Institut de Recherches Internationales Servier, Courbevoie, France; Servier Research and Development (P.D.), Fulmer, Slough, England; and Service d'Endocrinologie, Métabolisme et Développement, Centre National de la Recherche Scientifique (J.P.P.), Meudon, France

S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P < .05). Treatment with S15261 or S15511 decreased plasma insulin levels in fed rats and prevented the postprandial peak in insulin levels in a meal tolerance test. Y415 had no effect on insulin levels. Troglitazone halved the insulin response to the test meal, but metformin gave no improvement. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carboxylase and acyl-CoA synthase. S15261 also reduced the expression of carnitine palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesenteric resistance vessels to norepinephrine, and increased the maximal nitric oxide-mediated relaxation. S15261, through S15511, increased insulin sensitivity, decreased insulin levels, and reduced the vasculopathy of the JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.