Beneficial insulin-sensitizing and vascular effects of s15261 in the insulin-resistant JCR : LA-cp rat

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 defi ne the insulin-sensitizing effects of S15261, the cleavage products, and tr oglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesi ty/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 weigh ts, whereas Y415 had no effect. Troglitazone caused a small increase in foo d 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 improve ment. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carbo xylase and acyl-CoA synthase. S15261 also reduced the expression of carniti ne palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesen teric resistance vessels to norepinephrine, and increased the maximal nitri c oxide-mediated relaxation. S15261, through S15511, increased insulin sens itivity, decreased insulin levels, and reduced the vasculopathy of the JCR: LA-cp rat. S15261 may thus offer effective treatment for the insulin resis tance syndrome and its associated vascular complications.