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

The polygenic New Zealand obese (NZO) mouse model displays the characteristics of early type 2 diabetes: fasting hyperglycemia, hyperinsulinemia, and insulin resistance. The expression of the ATP-sensitive potassium (KATP) channels in the β cells was reported to be reduced.

To define at the cellular level the role of the KATP channel function for the altered insulin secretion of NZO mice.

We measured the plasma membrane potential, KATP channel currents, cytosolic Ca²⁺ concentration ([Ca²⁺]_i), and insulin secretion of NZO mouse islets and β cells in comparison with those of metabolically healthy NMRI mice.

The potassium current of NZO β cells had half the extent of that of NMRI β 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 β cells was less polarized, and consequently, [Ca²⁺]_i was higher in NZO β cells than in NMRI β cells. The depolarization and [Ca²⁺]_i increase by tolbutamide were not different. Insulin secretion of the NZO islets was higher than that of NMRI islets at low glucose and in the presence of diazoxide, but was lower than that of NMRI islets in the presence of tolbutamide and of high glucose.

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.