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). STUDY DESIGN: 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.
OBJECTIVE: To evaluate the clinical response to sulphonylurea treatment in a child with a homozygous T168AGCK (glucokinase) mutation, causing permanent neonatal diabetes mellitus (PNDM). STUDY DESIGN: 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.
Authors: David Carmody; Charles D Bell; Jessica L Hwang; Jazzmyne T Dickens; Daniela I Sima; Dania L Felipe; Carrie A Zimmer; Ajuah O Davis; Kateryna Kotlyarevska; Rochelle N Naylor; Louis H Philipson; Siri Atma W Greeley Journal: J Clin Endocrinol Metab Date: 2014-12 Impact factor: 5.958
Authors: Nicola L Beer; Martijn van de Bunt; Kevin Colclough; Christine Lukacs; Paul Arundel; Constance L Chik; Joseph Grimsby; Sian Ellard; Anna L Gloyn Journal: J Biol Chem Date: 2011-03-29 Impact factor: 5.157
Authors: JaeAnn M Dwulet; Nurin W F Ludin; Robert A Piscopio; Wolfgang E Schleicher; Ong Moua; Matthew J Westacott; Richard K P Benninger Journal: Biophys J Date: 2019-11-05 Impact factor: 4.033