title: In vitro insulin secretion by pancreatic tissue from infants with diazoxide-resistant congenital hyperinsulinism deviates from model predictions.
abstract: Congenital hyperinsulinism (CHI) is the major cause of persistent neonatal hypoglycemia. CHI most often occurs due to mutations in the ABCC8 (which encodes sulfonylurea receptor 1) or KCNJ11 (which encodes the potassium channel Kir6.2) gene, which result in a lack of functional KATP channels in pancreatic β cells. Diffuse forms of CHI (DiCHI), in which all β cells are abnormal, often require subtotal pancreatectomy, whereas focal forms (FoCHI), which are characterized by localized hyperplasia of abnormal β cells, can be cured by resection of the lesion. Here, we characterized the in vitro kinetics of insulin secretion by pancreatic fragments from 6 DiCHI patients and by focal lesion and normal adjacent pancreas from 18 FoCHI patients. Responses of normal pancreas were similar to those reported for islets from adult organ donors. Compared with normal pancreas, basal insulin secretion was elevated in both FoCHI and DiCHI tissue. Affected tissues were heterogeneous in their secretory responses, with increased glucose levels often producing a rapid increase in insulin secretion that could be followed by a paradoxical decrease below prestimulatory levels. The KATP channel blocker tolbutamide was consistently ineffective in stimulating insulin secretion; conversely, the KATP channel activator diazoxide often caused an unanticipated increase in insulin secretion. These observed alterations in secretory behavior were similar in focal lesion and DiCHI tissue, and independent of the specific mutation in ABCC8 or KCNJ11. They cannot be explained by classic models of β cell function. Our results provide insight into the excessive and sometimes paradoxical changes in insulin secretion observed in CHI patients with inactivating mutations of KATP channels.
authors.affiliation: Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain, Brussels, Belgium. jean-claude.henquin@uclouvain.be
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Henquin
authors.forename: Myriam
authors.initials: M
authors.lastname: Nenquin
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.forename: Yves
authors.initials: Y
authors.lastname: Guiot
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: Timo
authors.initials: T
authors.lastname: Otonkoski
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Claire
authors.initials: C
authors.lastname: Nihoul-Fékété
authors.forename: Jacques
authors.initials: J
authors.lastname: Rahier
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D044903:Congenital Hyperinsulinism / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics; D064233:Sulfonylurea Receptors; D014044:Tolbutamide / Q000494:pharmacology; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D050761:Cyclin-Dependent Kinase Inhibitor p57; D003981:Diazoxide; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014044:Tolbutamide; D000099161:Kcnj11 Channel; C493964:CDKN1C protein, human