Hyperinsulinism of Infancy: The Regulated Release of Insulin by KATP Channel—Independent Pathways
2001
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 ATP channels) in β-cells and impaired
ADP-dependent regulation. There were no apparent defects in the regulation of
Ca 2+ - and voltage-gated K + channels or delayed rectifier
K + channels. Intact HI β-cells were spontaneously electrically
active and generating Ca 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 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 2+ -dependent exocytotic events. Finally, insulin release studies
documented that whereas tolbutamide failed to cause insulin secretion as a
consequence of impaired [Ca 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 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 ATP
channel—independent pathways of regulated insulin secretion in diseased
human β-cells.
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