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 (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.
Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
S G
SG
Straub
K E
KE
Cosgrove
C
C
Ammälä
R M
RM
Shepherd
R E
RE
O'Brien
P D
PD
Barnes
N
N
Kuchinski
J C
JC
Chapman
M
M
Schaeppi
B
B
Glaser
K J
KJ
Lindley
G W
GW
Sharp
A
A
Aynsley-Green
M J
MJ
Dunne
D018528:ATP-Binding Cassette Transporters; D000244:Adenosine Diphosphate / Q000502:physiology; D000255:Adenosine Triphosphate / Q000502:physiology*; D002118:Calcium / Q000502:physiology; D020013:Calcium Signaling; D003600:Cytosol / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D005838:Genotype; D006801:Humans; D006946:Hyperinsulinism / Q000151:congenital* / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism* / Q000503:physiopathology; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism; D064233:Sulfonylurea Receptors
C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D002118:Calcium