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- Title
Hyperinsulinism of Infancy.
- Authors
Straub, Susanne G.; Cosgrove, Karen E.; Ämiuälä, Carina; Shepherd, Ruth M.; O'Brien, Rachel E.; Barnes, Philippa D.; Kuchinski, Na'ama; Chapman, Joanna C.; Schaeppi, Michela; Glaser, Benjamin; Lindley, Keith J.; W. G. Sharp, Geoffrey; Aynsley-Green, Albert; Dunne, Mark J.
- Abstract
Hyperinsulinism of infancy (HI) is a congenital defect in the regulated release of insulin from pancreatic β-cells. Here we describe stimulus-secretion coupling mechanisms in β-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[sub ATP] channels) in β-cells and impaired ADP-dependent regulation. There were no apparent defects in the regulation of Ca[sup 2+]- and voltage-gated K+ channels or delayed rectifier K+ channels. Intact HI β-cells were spontaneously electrically active and generating Ca[sup 2+] 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 ([Ca[sup 2+]]i) over basal values. Capacitance measurements used to monitor exocytosis in control and HI β-cells revealed that there were no defects in Ca[sup 2+]-dependent exocytotic events. Finally, insulin release studies documented that whereas tolbutamide failed to cause insulin secretion as a consequence of impaired [Ca[sup 2+]]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 Ca[sup 2+]. These findings document the relationship between SUR1 gene defects and insulin secretion in vivo and in vitro and describe for the first time K[sub ATP] channel-independent pathways of regulated insulin secretion in diseased human β-cells. Diabetes 50:329-339, 2001
- Publication
Diabetes, 2001, Vol 50, Issue 2, p329
- ISSN
0012-1797
- Publication type
Academic Journal