Format

Send to

Choose Destination
Diabetes. 2009 Jun;58(6):1419-27. doi: 10.2337/db08-1792. Epub 2009 Mar 31.

Extremes of clinical and enzymatic phenotypes in children with hyperinsulinism caused by glucokinase activating mutations.

Author information

1
Clinical Translational Research Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

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 beta-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.

PMID:
19336674
PMCID:
PMC2682682
DOI:
10.2337/db08-1792
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center