In vitro insulin secretion by pancreatic tissue from infants with diazoxide-resistant congenital hyperinsulinism deviates from model predictions.

Details

Serval ID
serval:BIB_AF2F13CB211C
Type
Article: article from journal or magazin.
Collection
Publications
Title
In vitro insulin secretion by pancreatic tissue from infants with diazoxide-resistant congenital hyperinsulinism deviates from model predictions.
Journal
Journal of Clinical Investigation
Author(s)
Henquin J.C., Nenquin M., Sempoux C., Guiot Y., Bellanné-Chantelot C., Otonkoski T., de Lonlay P., Nihoul-Fékété C., Rahier J.
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Publication state
Published
Issued date
2011
Peer-reviewed
Oui
Volume
121
Number
10
Pages
3932-3942
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
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.
Keywords
ATP-Binding Cassette Transporters/genetics, Congenital Hyperinsulinism/drug therapy, Congenital Hyperinsulinism/genetics, Cyclin-Dependent Kinase Inhibitor p57/genetics, Cyclin-Dependent Kinase Inhibitor p57/metabolism, Diazoxide/pharmacology, Drug Resistance, Humans, In Vitro Techniques, Infant, Insulin/secretion, Islets of Langerhans/secretion, Models, Biological, Mutation, Potassium Channels, Inwardly Rectifying/agonists, Potassium Channels, Inwardly Rectifying/antagonists & inhibitors, Receptors, Drug/genetics, Sulfonylurea Receptors, Tolbutamide/pharmacology
Pubmed
Web of science
Open Access
Yes
Create date
29/01/2015 13:06
Last modification date
20/08/2019 15:18
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