Cilnidipine Improves Insulin Sensitivity in the Otsuka Long-Evans Tokushima Fatty Rat, a Model of Spontaneous NIDDM

Summary. Among the antihypertensive drugs, fast-acting Ca²⁺ antagonists have been reported to worsen insulin sensitivity. This effect may be attributable to reflex increases in sympathetic activity. On the other hand, however, it has been reported that long-acting, dihydropiridine Ca²⁺ antagonists improve insulin-resistance. The purpose of this study was to investigate whether cilnidipine, another long-acting dihydropidine Ca²⁺ antagonist, improves insulin sensitivity in Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of spontaneous NIDDM. 25 weeks OLETF rats were divided into the following groups; normal-diet group, cilnidipine-supplemented group (cilnidipine 3mg/kg/day) and angiotensin II receptor antagonist CS-866-supplemented group (CS-866 1mg/kg/day). As a non-diabetic control, we used Long-Evans-Tokushima-Otsuka rats (non-diabetic rats). Glucose infusion rate (GIR), an index of insulin resistance, as measured by the hyperinsulinemic euglycemic clamp technique was significantly decreased in OLETF rats. Cilnidipine-treatment partially but significantly improved insulin sensitivity in addition to systolic blood pressure in OLETF rats at 30 weeks of age, although it did not decrease accumulation of abdominal fat or serum levels of glucose or insulin. CS-866, an angiotensin 2 receptor antagonist, which lowers blood pressure through a different mechanism, did not improve insulin resistant states in OLETF rats. These results suggest that cilnidipine has a beneficial effect on insulin-resistance together with the antihypertensive effect.