Endocrine Abstracts (2006) 11 P356

Noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) caused by an activating glucokinase mutation

HBT Christesen1, K Brusgaard2, H Beck-Nielsen3, J Malec1 & B Brock Jacobsen1


1Odense University Hospital, Dept. of Paediatrics, Odense, Denmark; 2Odense University Hospital, Dept of Clinical Genetics, Odense, Denmark; 3Odense University Hospital, Dept. of Endocrinology, Odense, Denmark.


NIPHS is a rare cause of adult onset hyperinsulinaemic hypoglycaemia with islet hypertrophy/nesidioblastosis, but without mutations in the ABBC8 and KCNJ11 genes coding for the beta cell KATP-channel subunits SUR1 and Kir6.2. NIPHS patients with GCK mutations have never been described.

We report of a 42-y-old woman with asymptomatic hypoglycaemia down to 2.9 mmol/l with simultaneous p-insulin 208 pmol/l (12–77 pmol/l), p-C-peptide 1574 pmol/l (130–760 pmol/l), p-proinsulin 88 pmol/l (2–23 pmol/l), (normal ranges at euglycaemia in brackets by Delphia method).

Her son had congential hyperinsulinism with remission at the age of 8 months, but relaps at age 14 y treated with diazoxide, thiazide and octreotide up to the actual age of 20.

No insulinoma was detected. ABBC8 and KCNJ11 genetic analysis was normal. In the glucokinase gene, however, a novel activating mutation, A456V, was found in the mother and child. Functional mutation analysis showed a left shift of the glucose dependency curve (in contrast to MODY 2). After 5 years of asymptomatic hyperinsuliniaemic hypoglycaemia without treatment, the mother had an attack of convulsions and unconsciousness during a slimming diet. Blood glucose was 3.2 mmol/l on admission. Treatment with diazoxide and thiazide was commenced.

During a slimming diet, the 24 y-old daughter of the mother’s brother had an accident and was found hypoglycaemic, 2.7 mmol/l, with a simultaneous increased p-insulin of 88 pmol/l and p-C-peptide, 1014 pmol/l. After a) 6 h fasting; and b) 3½ h after an OGTT, she had hypoglycaemic symptoms and a blood glucose of a) 1.6 mmol/l; and b) 1.9 mmol/l. She also had the GCK mutation A456V and responded to octreotide treatment.

Conclusion: NIPHS due to an activating GCK mutation was demonstrated in 3 family members with an onset ranging from the neonatal period to 47 years of age. NIPHS-GCK has so far been medical responsive.

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