Expression of ATP-insensitive KATP channels in pancreatic beta-cells underlies a spectrum of diabetic phenotypes

Abstract

Glucose metabolism in pancreatic beta-cells elevates cytoplasmic [ATP]/[ADP], causing closure of ATP-sensitive K(+) channels (K(ATP) channels), Ca(2+) entry through voltage-dependent Ca(2+) channels, and insulin release. Decreased responsiveness of K(ATP) channels to the [ATP]/[ADP] ratio should lead to decreased insulin secretion and diabetes. We generated mice expressing K(ATP) channels with reduced ATP sensitivity in their beta-cells. Previously, we described a severe diabetes, with nearly complete neonatal lethality, in four lines (A-C and E) of these mice. We have now analyzed an additional three lines (D, F, and G) in which the transgene is expressed at relatively low levels. These animals survive past weaning but are glucose intolerant and can develop severe diabetes. Despite normal islet morphology and insulin content, islets from glucose-intolerant animals exhibit reduced glucose-stimulated insulin secretion. The data demonstrate that a range of phenotypes can be expected for a reduction in ATP sensitivity of beta-cell K(ATP) channels and provide models for the corollary neonatal diabetes in humans.