Low level expression of overactive KATP channels in mouse pancreatic β-cells induces a late-onset insulin-secretory defect

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University of Sheffield (2001) J Physiol 535P, S057

Communications: Low level expression of overactive KATP channels in mouse pancreatic β-cells induces a late-onset insulin-secretory defect

J.C. Koster*, B.A. Marshall†, N. Ensor†, J.A. Corbett‡ and C.G. Nichols*

* Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO 63110, †Department of Pediatrics, St Louis Childrens Hospital, St Louis, MO 63110 and ‡The Edward A. Doisy Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, St Louis, MO 63104, USA

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ATP-sensitive K+ (KATP) channels couple cell metabolism to electrical activity. To probe the role of KATP in glucose-induced insulin secretion, we have generated transgenic mice expressing an N-terminal truncated form of the KATP channel subunit Kir6.2 under control of the insulin promoter (Kir6.2 [▓Dgr│N-2-30], tagged with GFP). In exogenous expression, Kir6.2 [▓Dgr│N-2-30] + SUR1 mutant channels exhibit a 10-fold reduction in ATP sensitivity (Koster et al. 1999) and thus are predicted to attenuate glucose-induced insulin release in vivo. Previously, we demonstrated that four out of five Kir6.2 [▓Dgr│N-2-30] transgenic mice lines (A, B, C and E) develop profound hyperglycaemia, hypoinsulinaemia and ketoacidosis as neonates, and generally die prematurely (Koster et al. 2000). In contrast, in the fifth transgenic line (line D), all mice were euglycaemic, developed normally, and were fertile. Expression of the Kir6.2 [▓Dgr│N-2-30] transgene in line D was confirmed in adult transgenic mice by the appearance of pancreatic KATP channels with reduced ATP sensitivity and β-cell-specific green fluorescence of the GFP-tagged channel. Qualitatively, however, the number of β-cells fluorescing green was significantly reduced when compared with lines A, B, C and E. Although the D-line mice were euglycaemic, a defect in glucose-induced insulin secretion was evident in fat-fed, transgenic adult mice (approximately 1 year of age; n = 8) as both a reduced rate of glucose disposal in a glucose tolerance test and a decrease in glucose-induced insulin release in insulin release assays. These defects were not observed in young, lean transgenic mice (approximately 3 months of age; n = 4) nor in control fat-fed mice. At the end of the experiments, animals were humanely killed under Metofane anaesthesia. Taken together, these results indicate that modest expression of pancreatic KATP channels with reduced ATP sensitivity can exacerbate the diabetic phenotype resulting from fat feeding. A further implication of these results is that even very minimally overactive KATP channels might predispose humans to diabetes.

All animal procedures complied with the ethical standards for the care and use of animal subjects as stated in the Guide for the Care and Use of Laboratory Animals (NIH publication no. 85-23, revised 1996).

    Koster, J.C., Marshall, B.A., Ensor, N., Corbett, J.A. & Nichols, C.G. (2000). Cell 100, 645-654.

    Koster, J.C., Sha, Q., Shyng, S.L. & Nichols, C.G. (1999). J. Physiol. 515, 19-30. abstract

Where applicable, experiments conform with Society ethical requirements.

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