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Expression of ATP-Insensitive K_ATP Channels in Pancreatic ß-Cells Underlies a Spectrum of Diabetic Phenotypes

From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri

Address correspondence and reprint requests to C.G. Nichols, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110. E-mail: cnichols{at}cellbiology.wustl.edu

Abbreviations: GFP, green fluorescence protein; GSIS, glucose-stimulated insulin secretion; GTT, glucose tolerance test; HFD, high-fat diet; K_ATP channel, ATP-sensitive K⁺ channel; NDM, neonatal diabetes mellitus; RIP I, rat insulin promoter I

Glucose metabolism in pancreatic ß-cells elevates cytoplasmic [ATP]/[ADP], causing closure of ATP-sensitive K⁺ channels (K_ATP channels), Ca²⁺ entry through voltage-dependent Ca²⁺ 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 ß-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 ß-cell K_ATP channels and provide models for the corollary neonatal diabetes in humans.

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