Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic beta-cell adenosine triphosphate-sensitive potassium channels.
BACKGROUND
Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is clinically and genetically heterogeneous. Hyperinsulinemic hypoglycemia occurs in about 50% of children with BWS and, in the majority of infants, it resolves spontaneously. However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear.


METHODS
Using patch-clamp techniques on pancreatic tissue obtained at the time of surgery, we investigated the electrophysiological properties of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells in a patient with BWS and severe medically-unresponsive hyperinsulinemic hypoglycemia.


RESULTS
Persistent hyperinsulinism was found to be caused by abnormalities in K(ATP) channels of the pancreatic beta-cell. Immunofluorescence studies using a SUR1 antibody revealed perinuclear pattern of staining in the BWS cells, suggesting a trafficking defect of the SUR1 protein. No mutations were found in the genes ABCC8 and KCNJ11 encoding for the two subunits, SUR1 and KIR6.2, respectively, of the K(ATP) channel. Genetic analysis of this patients BWS showed evidence of mosaic paternal isodisomy.


CONCLUSIONS
In this novel case of BWS with mosaic paternal uniparental disomy for 11p15, persistent hyperinsulinism was due to abnormalities in K(ATP) channels of the pancreatic beta-cell. The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K(ATP) channel remains to be elucidated.
Hussain
K
K
London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom. k.hussain@ich.ucl.ac.uk
Cosgrove
K E
KE
Shepherd
R M
RM
Luharia
A
A
Smith
V V
VV
Kassem
S
S
Gregory
J W
JW
Sivaprasadarao
A
A
Christesen
H T
HT
Jacobsen
B B
BB
Brusgaard
K
K
Glaser
B
B
Maher
E A
EA
Lindley
K J
KJ
Hindmarsh
P
P
Dattani
M
M
Dunne
M J
MJ
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002880:Chromosomes, Human, Pair 11; D006801:Humans; D006946:Hyperinsulinism / Q000209:etiology*; D007003:Hypoglycemia / Q000209:etiology*; D007223:Infant; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000502:physiology; D024182:Uniparental Disomy; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel; C435500:ABCC11 protein, human