Attenuation of hyperinsulinemia by NN414, a SUR1/Kir6.2 selective K+-adenosine triphosphate channel opener, improves glucose tolerance and lipid profile in obese Zucker rats

Chronic attenuation of hyperinsulinemia by diazoxide (DZ), a K-adenosine triphosphate (ATP) channel opener and an inhibitor of glucose-mediated insulin secretion, improved glucose tolerance and lipid profile and decreased the rate of weight gain in obese Zucker rats. To determine whether suppression of hyperinsulinemia alters daily food consumption, rate of weight gain, glucose tolerance, and lipid profile, we compared the effects of NN414, a potent and SUR1/Kir6.2 selective K-ATP channel opener, with DZ in obese and lean Zucker rats. DZ (150 mg/kg/d), low-dose (LDNN414: 10 mg/kg/d), high-dose (HDNN414: 30 mg/kg/d), and vehicle (C) were administered to 7-week-old obese and lean female Zucker rats for a period of 6 weeks. Each animal underwent an intraperitoneal glucose tolerance test (IPGTT) at the end of study period. While NN414 treatment did not affect food intake and rate of weight gain in any of the strains, DZ treatment reduced food intake (P < .001) and rate of weight gain (P < .001) in obese rats. The fasting plasma insulin levels and area under the curve (AUC) insulin response to IPGTT were significantly attenuated in LDNN414 (P < .05), HDNN414 (P < .01), and DZ (P < .01) obese and lean rats compared with their controls. This was accompanied by a significant reduction in AUC glucose only in LDNN414 (P < .05), HDNN414 (P < .01), and DZ (P < .01) obese rats compared with controls. While hemoglobin A(1c) (HbA(1c)) was not affected in LDNN414 obese rats, it was higher in HDNN414 obese animals (P < .001), LD-, HDNN414 (P < .001), and DZ (P < .005) lean rats compared with their respective controls. DZ obese rats showed lower HbA(1c) levels than C obese rats (P < .02). The plasma free fatty acid (FFA) levels were only decreased in HDNN414 (P < .05) and DZ (P < .002) obese rats, whereas plasma triglyceride (TG) levels were decreased in LDNN414 (P < .05), HDNN414 (P < .001), and DZ (P < .001) obese rats compared with controls. Finally, plasma leptin level was only decreased in DZ obese rats compared with controls (P < .001). The new SUR1/Kir6.2 selective K-ATP channel opener, NN414, reduced hyperinsulinemia in a dose-dependent manner without a significant effect on food consumption and rate of weight gain. NN414-induced beta-cell rest in obese rats was associated with a significant improvement in glucose responsiveness, suggesting an increase in insulin sensitivity after its withdrawal. There was an overall deterioration in glycemic control at the high dose as measured by HbA(1c). There was a dose-dependent improvement in lipid profiles of obese Zucker rats. These results suggest that pharmacologic attenuation of hyperinsulinemic state by low-dose NN414 may be therapeutically beneficial in insulin-resistant states without any deterioration in overall glycemic control. (C) 2004 Elsevier Inc. All rights reserved.