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A Kir6.2 Mutation Causing Neonatal Diabetes Impairs Electrical Activity and Insulin Secretion From INS-1 ß-Cells

¹ University Laboratory of Physiology, Oxford University, Oxford, U.K
² Institute of Biomedical and Clinical Science, Peninsula Medical School, Plymouth, U.K
³ Institute of Cell Biology, University of Essen, Essen, Germany

Address correspondence and reprint requests to Prof. F.M. Ashcroft, University Laboratory of Physiology, Parks Road, Oxford, OX1 3PT, U.K. E-mail: frances.ashcroft{at}physiol.ox.ac.uk

Abbreviations: K_ATP channel, ATP-sensitive K⁺ channel

ATP-sensitive K⁺ channels (K_ATP channels) couple ß-cell metabolism to electrical activity and thereby play an essential role in the control of insulin secretion. Gain-of-function mutations in Kir6.2 (KCNJ11), the pore-forming subunit of this channel, cause neonatal diabetes. We investigated the effect of the most common neonatal diabetes mutation (R201H) on ß-cell electrical activity and insulin secretion by stable transfection in the INS-1 cell line. Expression was regulated by placing the gene under the control of a tetracycline promoter. Transfection with wild-type Kir6.2 had no effect on the ATP sensitivity of the K_ATP channel, whole-cell K_ATP current magnitude, or insulin secretion. However, induction of Kir6.2-R201H expression strongly reduced K_ATP channel ATP sensitivity (the half-maximal inhibitory concentration increased from 20 µmol/l to 2 mmol/l), and the metabolic substrate methyl succinate failed to close K_ATP channels or stimulate electrical activity and insulin secretion. Thus, these results directly demonstrate that Kir6.2 mutations prevent electrical activity and insulin release from INS-1 cells by increasing the K_ATP current and hyperpolarizing the ß-cell membrane. This is consistent with the ability of the R201H mutation to cause neonatal diabetes in patients. The relationship between K_ATP current and the membrane potential reveals that very small changes in current amplitude are sufficient to prevent hormone secretion.

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