Severe Persistent Hyperinsulinemic Hypoglycemia due to a De Novo Glucokinase Mutation

Diabetes - Tập 53 Số 8 - Trang 2164-2168 - 2004
Antonio L. Cuesta‐Muñoz1, Hanna Huopio2, Timo Otonkoski3, Juan Miguel Gómez‐Zumaquero1, Kirsti Näntö‐Salonen4, Jacques Rahier5, Soledad López1, María Adelaida García-Gimeno6, Pascual Sanz6, Federico C. Soriguer1, Edward G. Lakatta7
1Hospital Carlos Haya Foundation and Department of Endocrinology, Diabetes, and Nutrition of Carlos Haya University Hospital, Málaga, Spain
2Department of Paediatrics, University of Kuopio, Kuopio, Finland
3Hospital for Children and Adolescents, Program of Developmental and Reproductive Biology, Biomedicum, University of Helsinki, Helsinki, Finland
4Department of Paediatrics, University of Turku, Turku, Finland
5Department d'Anatomie Pathologique, Cliniques Universitaires Sain Luc, Brussels, Belgium
6Institute of Biomedicine of Valencia (CSIC), Valencia, Spain
7Department of Medicine, University of Kuopio, Kuopio, Finland

Tóm tắt

Glucokinase (GK) is a glycolytic key enzyme that functions as a glucose sensor in the pancreatic β-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 kcat. 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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Tài liệu tham khảo

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Diabetes

Tập 53 Số 8

2164-2168

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