NN414, a SUR1/Kir6.2-selective potassium channel opener, reduces blood glucose and improves glucose tolerance in the VDF Zucker rat

A novel potassium channel opener compound, NN414, selective for the SUR1/Kir6.2 subtype of the ATP-sensitive potassium channel, was used to examine the effect of reducing beta-cell workload in the male Vancouver diabetic fatty (VDF) Zucker rat model of mild type 2 diabetes. Two chronic dosing protocols of NN414 of 3 weeks' duration were compared with appropriate vehicle-treated controls. In the first group, rats received NN414 (continued group; 1.5 mg/kg p.o. twice daily), during which an oral glucose tolerance test (OGTT) (on day 19 of dosing) was performed and insulin secretion from an in situ perfused pancreas preparation (on day 21) was measured. The second group received NN414 (discontinued group; same dose), but active treatment was replaced by vehicle treatment 2 days before the OGTT and for a further 2 days before the perfused pancreas study. Basal glucose was significantly reduced by NN414, with the fall averaging 0.64 mmol/l after 3 weeks of treatment (P < 0.0001). The glucose excursion and hyperinsulinemia during the OGTT were significantly different between the continued, discontinued, and vehicle groups (glucose area under the curve [AUC]: 640 +/- 29, 740 +/- 27, and 954 82 mmol (.) l(-1) (.) min(-1), respectively, P < 0.0001; insulin AUC: 38.9 +/- 4.2, 44.2 +/- 4.2, and 55.1 +/- 2.6 nmol (.) l(-1) (.) min(-1), respectively, P < 0.0001). Hyperinsulinemia during the pancreas perfusion with 4.4 mmol/l glucose was significantly reduced in both treatment groups versus vehicle (P < 0.0005). Insulin secretory responsiveness to a step increase in glucose from 4.4 to 16.6 mmol/l, calculated relative to basal, was significantly improved in the continued group versus vehicle (P < 0.01). In conclusion, administration of NN414 for 3 weeks in VDF rats reduces basal hyperglycemia, improves glucose tolerance, and reduces hyperinsulinemia during an OGTT and improves insulin secretory responsiveness ex vivo. NN414 may therefore represent a novel approach to the prevention and treatment of impaired glucose tolerance and type 2 diabetes.