Extremes of Clinical and Enzymatic Phenotypes in Children With Hyperinsulinism Caused by Glucokinase Activating Mutations
Samir Sayed 1 ,
David R. Langdon 2 ,
Stella Odili 3 ,
Pan Chen 2 ,
Carol Buettger 3 ,
Alisa B. Schiffman 2 ,
Mariko Suchi 4 , 5 ,
Rebecca Taub 6 ,
Joseph Grimsby 6 ,
Franz M. Matschinsky 3 , 7 and
Charles A. Stanley 1 , 2
1 Clinical Translational Research Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;
2 Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;
3 Diabetes and Endocrinology Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania;
4 Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin;
5 Department of Pathology, Children's Hospital of Wisconsin, Milwaukee, Wisconsin;
6 Department of Metabolic Diseases, Roche, Nutley, New Jersey;
7 Department of Biochemistry and Biophysics, the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
Corresponding author: Charles A. Stanley, stanleyc{at}email.chop.edu .
Abstract
OBJECTIVE Heterozygous activating mutations of glucokinase have been reported to cause hypoglycemia attributable to hyperinsulinism
in a limited number of families. We report three children with de novo glucokinase hyperinsulinism mutations who displayed
a spectrum of clinical phenotypes corresponding to marked differences in enzyme kinetics.
RESEARCH DESIGN AND METHODS Mutations were directly sequenced, and mutants were expressed as glutathionyl S-transferase–glucokinase fusion proteins.
Kinetic analysis of the enzymes included determinations of stability, activity index, the response to glucokinase activator
drug, and the effect of glucokinase regulatory protein.
RESULTS Child 1 had an ins454A mutation, child 2 a W99L mutation, and child 3 an M197I mutation. Diazoxide treatment was effective
in child 3 but ineffective in child 1 and only partially effective in child 2. Expression of the mutant glucokinase ins454A,
W99L, and M197I enzymes revealed a continuum of high relative activity indexes in the three children (26, 8.9, and 3.1, respectively;
wild type = 1.0). Allosteric responses to inhibition by glucokinase regulatory protein and activation by the drug RO0281675
were impaired by the ins454A but unaffected by the M197I mutation. Estimated thresholds for glucose-stimulated insulin release
were more severely reduced by the ins454A than the M197I mutation and intermediate in the W99L mutation (1.1, 3.5, and 2.2
mmol/l, respectively; wild type = 5.0 mmol/l).
CONCLUSIONS These results confirm the potency of glucokinase as the pancreatic β-cell glucose sensor, and they demonstrate that responsiveness
to diazoxide varies with genotype in glucokinase hyperinsulinism resulting in hypoglycemia, which can be more difficult to
control than previously believed.
Footnotes
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Received December 26, 2008.
Accepted March 7, 2009.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
© 2009 by the American Diabetes Association....

Extremes of Clinical and Enzymatic Phenotypes in Children With Hyperinsulinism Caused by Glucokinase Activating Mutations

10.2337/db08-1792