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Hyperinsulinism of Infancy

The Regulated Release of Insulin by K_ATP Channel—Independent Pathways

From the Institute of Molecular Physiology and Department of Biomedical Science (K.E.C., R.M.S., R.E.O., P.D.B., J.C.C., M.J.D.), University of Sheffield, Western Bank, Sheffield, and the Institute of Child Health (M.S., K.J.L., A.A.-G.), London, U.K.; the Division of Endocrinology & Metabolism (N.K., B.G.), The Hebrew University, Hadassah Medical School, Jerusalem, Israel; the Department of Molecular Medicine (S.G.S., G.W.G.S.), College of Veterinary Medicine, Cornell University, Ithaca, New York; and the Department of Molecular Endocrinology (C.Ä.), Glaxo Wellcome, Research Triangle Park, North Carolina.

Address correspondence and reprint requests to Prof. M.J. Dunne, Institute of Molecular Physiology and Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield, S10 2TN, U.K. E-mail: m.j.dunne{at}sheffield.ac.uk .

Hyperinsulinism of infancy (HI) is a congenital defect in the regulated release of insulin from pancreatic ß-cells. Here we describe stimulus-secretion coupling mechanisms in ß-cells and intact islets of Langerhans isolated from three patients with a novel SUR1 gene defect. 2154+3 A to G SUR1 (GenBank accession number L78207) is the first report of familial HI among nonconsanguineous Caucasians identified in the U.K. Using patch-clamp methodologies, we have shown that this mutation is associated with both a decrease in the number of operational ATP-sensitive K⁺ channels (K_ATP channels) in ß-cells and impaired ADP-dependent regulation. There were no apparent defects in the regulation of Ca²⁺- and voltage-gated K⁺ channels or delayed rectifier K⁺ channels. Intact HI ß-cells were spontaneously electrically active and generating Ca²⁺ action currents that were largely insensitive to diazoxide and somatostatin. As a consequence, when intact HI islets were challenged with glucose and tolbutamide, there was no rise in intracellular free calcium ion concentration ([Ca²⁺]_i) over basal values. Capacitance measurements used to monitor exocytosis in control and HI ß-cells revealed that there were no defects in Ca²⁺-dependent exocytotic events. Finally, insulin release studies documented that whereas tolbutamide failed to cause insulin secretion as a consequence of impaired [Ca²⁺]_i signaling, glucose readily promoted insulin release. Glucose was also found to augment the actions of protein kinase C— and protein kinase A—dependent agonists in the absence of extracellular Ca²⁺. These findings document the relationship between SUR1 gene defects and insulin secretion in vivo and in vitro and describe for the first time K_ATP channel—independent pathways of regulated insulin secretion in diseased human ß-cells.

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