Permanent neonatal diabetes mellitus caused by a novel homozygous (T168A) glucokinase (GCK) mutation: initial response to oral sulphonylurea therapy.
OBJECTIVE
To evaluate the clinical response to sulphonylurea treatment in a child with a homozygous T168A GCK (glucokinase) mutation, causing permanent neonatal diabetes mellitus (PNDM).


METHODS
Oral glibenclamide was given for 3 months. Pancreatic beta cell function was assessed by a glucagon stimulation test. Mutant and wild-type (WT) GCK were characterized.


RESULTS
Sulphonylurea treatment resulted in a 12-fold increase in basal and stimulated C-peptide levels. HbA1c levels were reduced from 9.4% to 8.1% on a reduced insulin dose (0.85 to 0.60 U/kg/day). Mutant T168A-GST-GCK showed reduced kinetic activity (0.02 fold) compared to WT.


CONCLUSIONS
Sulphonylureas can close the adenosine triphosphate (ATP)-sensitive potassium channel and elicit insulin secretion, but the ATP generated from metabolism is insufficient to fully restore insulin secretory capacity. Nonetheless, sulphonylurea treatment should be tried in patients with GCK-PNDM, particularly those with mutations resulting in less severe kinetic defects, in whom improved glycemic control may be obtained with lower doses of insulin.
From the Department of Pediatric Endocrinology, Akdeniz University Hospital, Antalya, Turkey.
Doga
D
Turkkahraman
Iffet
I
Bircan
Nicholas D
ND
Tribble
Sema
S
Akçurin
Sian
S
Ellard
Anna L
AL
Gloyn
D000284:Administration, Oral; D003920:Diabetes Mellitus / Q000235:genetics*; D005192:Family Health; D005941:Glucokinase / Q000737:chemistry / Q000235:genetics*; D005905:Glyburide / Q000627:therapeutic use; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D011487:Protein Conformation; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D007328:Insulin; D013453:Sulfonylurea Compounds; D005941:Glucokinase; D005905:Glyburide