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Severe Persistent Hyperinsulinemic Hypoglycemia due to a De Novo Glucokinase Mutation

¹ Hospital Carlos Haya Foundation and Department of Endocrinology, Diabetes, and Nutrition of Carlos Haya University Hospital, Málaga, Spain
² Department of Paediatrics, University of Kuopio, Kuopio, Finland
³ Hospital for Children and Adolescents, Program of Developmental and Reproductive Biology, Biomedicum, University of Helsinki, Helsinki, Finland
⁴ Department of Paediatrics, University of Turku, Turku, Finland
⁵ Department d’Anatomie Pathologique, Cliniques Universitaires Sain Luc, Brussels, Belgium
⁶ Institute of Biomedicine of Valencia (CSIC), Valencia, Spain
⁷ Department of Medicine, University of Kuopio, Kuopio, Finland

Glucokinase (GK) is a glycolytic key enzyme that functions as a glucose sensor in the pancreatic ß-cell, where it governs glucose-stimulated insulin secretion (GSIS). Heterozygous inactivating mutations in the glucokinase gene (GCK) cause a mild form of diabetes (maturity-onset diabetes of the young [MODY]2), and activating mutations have been associated with a mild form of familial hyperinsulinemic hypoglycemia. We describe the first case of severe persistent hyperinsulinemic hypoglycemia due to a "de novo" mutation in GCK (Y214C). A baby girl presented with hypoglycemic seizures since the first postnatal day as well as with inappropriate hyperinsulinemia. Severe hypoglycemia persisted even after treatment with diazoxide and subtotal pancreatectomy, leading to irreversible brain damage. Pancreatic histology revealed abnormally large and hyperfunctional islets. The mutation is located in the putative allosteric activator domain of the protein. Functional studies of purified recombinant glutathionyl S-transferase fusion protein of GK-Y214C showed a sixfold increase in its affinity for glucose, a lowered cooperativity, and increased k_cat. The relative activity index of GK-Y214C was 130, and the threshold for GSIS predicted by mathematical modeling was 0.8 mmol/l, compared with 5 mmol/l in the wild-type enzyme. In conclusion, we have identified a de novo GCK activating mutation that causes hyperinsulinemic hypoglycemia of exceptional severity. These findings demonstrate that the range of the clinical phenotype caused by GCK mutations varies from complete insulin deficiency to extreme hyperinsulinemia.

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