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Previous Volume 355:456-466 August 3, 2006 Number 5 Next

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ABSTRACT

Background The ATP-sensitive potassium (K_ATP) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P_O, which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes.

Methods We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type K_ATP channels.

Results We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P_O than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia.

Conclusions Dominant mutations in ABCC8 accounted for 12 percent of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide–dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved.

Source Information

From the Departments of Molecular and Cellular Biology (A.P.B., J.B.) and Medicine (L.A.-B.), Baylor College of Medicine, Houston; the Faculty of Medicine, René Descartes University, INSERM Unité 0363, Hôpital Necker Enfants Malades, Paris (M.P., K.B., R.S.); the Departments of Genetic Biochemistry (H.C.) and Pediatric Endocrinology (P.C.), Hôpital Robert Debré, Paris; Centre National de la Recherche Scientifique Unité 8090, the Pasteur Institute, Lille, France (M.V., P.F.); and the Department of Genomic Medicine, Imperial College London, Hammersmith Hospital, London (P.F.).

Drs. Babenko and Polak contributed equally to this article.

Address reprint requests to Dr. Polak at the Faculty of Medicine, René Descartes, Pediatric Endocrinology, INSERM Unité 0363, Hôpital Necker Enfants Malades, Paris, France, or at michel.polak{at}nck.aphp.fr.

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