Relevance of the KATP channel function for the basal insulin hypersecretion of islets from female NZO mice

Abstract Context The polygenic NZO mouse model displays the characteristics of early type 2 diabetes: fasting hyperglycemia, hyperinsulinaemia and insulin resistance. The expression of the KATP channels in the beta cells was reported to be reduced. Objective To define at the cellular level the role of the KATP channel function for the altered insulin secretion of NZO mice. Methods We have measured the plasma membrane potential, KATP channel currents, cytosolic Ca2+ concentration ([Ca2+]i) and insulin secretion of NZO mouse islets and beta cells in comparison with those of metabolically healthy NMRI mice. Results The potassium current of NZO beta cells had half the extent of that of NMRI beta cells and remained so in the presence of the KATP channel opener, diazoxide. The KATP channel blocker, tolbutamide, reduced the currents to the same low level. At low glucose and in the presence of diazoxide the plasma membrane potential of NZO beta cells was less polarized and in consequence ([Ca2+]i) was higher in NZO beta cells than in NMRI beta cells. The depolarization and ([Ca2+]i) increase by tolbutamide were not different. Insulin secretion of the NZO islets was higher than the one of NMRI islets at low glucose and in the presence of diazoxide, but was lower than the one of NMRI islets in the presence of tolbutamide and of high glucose. Conclusion The higher insulin secretion at basal glucose, but not the lower stimulated secretion of NZO islets is at least partly due to the reduced expression of the KATP channels.