Phenotypic characterization of congenital hyperinsulinism due to novel activating glucokinase mutations

The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 cases of congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth to 24 years and severity of the phenotype was also variable. Mutant enzymes were expressed and purified for enzyme kinetics in vitro. Mutant enzymes had low glucose S_0.5 values and increased enzyme activity index compared to wild type GK. We performed functional evaluation of islets from the pancreata of 3 children with GCK-HI that required pancreatectomy. Basal insulin secretion in perifused GCK-HI islets was normal and the response to glyburide was preserved. However, the threshold for glucose-stimulated insulin secretion in perifused GCK-HI islets was decreased and glucagon secretion was greatly suppressed. Our evaluation of novel GCK disease-associated mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion, but also to a decreased counter-regulatory glucagon secretory response.