Severe Persistent Hyperinsulinemic Hypoglycemia due to a De Novo Glucokinase Mutation

Abstract

Glucokinase (GK) is a glycolytic key enzyme that functions as a glucose sensor in the pancreatic ␤-cell, where it governs glucose-stimulated insulin secretion (GSIS). Heterozygous inactivating mutations in the glucokinase gene (GCK) cause a mild form of diabetes (maturityonset 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 Stransferase 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. Diabetes

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat

“…Similarly, it has been shown that glucokinase plays a critical role in restoring beta cell mass following acute beta cell loss triggered by transgenic manipulation [27]. Clinically, it has been observed that a gain-of-function glucokinase mutation results in enlarged islets [7,10]. These findings support a hypothesis that chronic treatment with a GKA may help to preserve beta cell mass in patients with type 2 diabetes, and thereby provide a more durable form of antihyperglycaemic action.…”

“…There is considerable interest in the development of GKAs as potential therapies for type 2 diabetes because glucokinase activity plays an essential role in glucose-sensing by beta cells and glucose metabolism by hepatocytes [2][3][4][5]. The importance of this enzyme in glucose homeostasis was first widely recognised with the discovery of clinical syndromes resulting from loss-of-function and gain-of-function glucokinase gene mutations [6][7][8][9][10]. The gain-of-function mutations produce dominant/recessive clinical phenotypes of hyperinsulinaemic hypoglycaemia and are of particular pharmacological interest because they alter glucokinase function in a manner closely related to GKA action [11].…”

Upregulation of β-cell genes and improved function in rodent islets following chronic glucokinase activation

“…Loss of both GK alleles results in permanent neonatal diabetes, whereas heterozygous inactivating mutations of GK lead to maturity-onset diabetes of the young (MODY2; Hattersley et al 1992). Conversely, rare activating mutations of GK result in hyperinsulinaemic hypoglycaemia (Glaser et al 1998, Christesen et al 2002, Gloyn et al 2003, Cuesta-Munoz et al 2004.…”

Hipoglicemia hiperinsulinêmica da infância

“…A ativação dessa enzima aumenta a oxidação de glutamato e aumenta a relação ATP/ADP na célula B. As mutações ativadoras de GCK (7p15-p13) reduzem o limite da secreção de insulina estimulada pela glicose (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41).…”