Hyperinsulinism of infancy : The regulated release of insulin by KATP channel-independent pathways

Hyperinsulinism of infancy (HI) is a congenital defect in the regulated release of insulin from pancreatic beta-cells. Here we describe stimulus-secretion coupling mechanisms in beta-cells and intact islets of Langerhans isolated from three patients with a novel SUR1 gene defect. 2154+3 A to G SUR1...

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Published in:	Diabetes (New York, N.Y.) Vol. 50; no. 2; pp. 329 - 339
Main Authors:	STRAUB, Susanne G, COSGROVE, Karen E, LINDLEY, Keith J, SHARP, Geoffrey W. G, AYNSLEY-GREEN, Albert, DUNNE, Mark J, ÄMMÄLÄ, Carina, SHEPHERD, Ruth M, O'BRIEN, Rachel E, BARNES, Philippa D, KUCHINSKI, Na'Ama, CHAPMAN, Joanna C, SCHAEPPI, Michela, GLASER, Benjamin
Format:	Journal Article
Language:	English
Published:	Alexandria, VA American Diabetes Association 01-02-2001
Subjects:	Adenosine Diphosphate - physiology Adenosine Triphosphate - physiology ATP-Binding Cassette Transporters Biological and medical sciences Calcium - physiology Calcium Signaling Cytosol - physiology Diabetes. Impaired glucose tolerance Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Exocytosis - physiology Genotype Humans Hyperinsulinism - congenital Hyperinsulinism - genetics Hyperinsulinism - metabolism Hyperinsulinism - physiopathology In Vitro Techniques Infant, Newborn Insulin - metabolism Insulin Secretion Islets of Langerhans - metabolism Islets of Langerhans - physiopathology Medical sciences Molecular Sequence Data Mutation - physiology Patch-Clamp Techniques Potassium Channels - genetics Potassium Channels - metabolism Potassium Channels - physiology Potassium Channels, Inwardly Rectifying Receptors, Drug - genetics Receptors, Drug - metabolism Sulfonylurea Receptors Endocrinopathy Human Hyperinsulinemia Pancreatic hormone Family study Langerhans islet Infant Ionic channel Insulin Endocrine secretion Regulation(control) B-Cell Genetics Caucasoid Potassium Endocrine pancreas
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Summary:	Hyperinsulinism of infancy (HI) is a congenital defect in the regulated release of insulin from pancreatic beta-cells. Here we describe stimulus-secretion coupling mechanisms in beta-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 (KATP channels) in beta-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 beta-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 beta-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 KATP channel-independent pathways of regulated insulin secretion in diseased human beta-cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0012-1797 1939-327X
DOI:	10.2337/diabetes.50.2.329