Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia

Abstract

Glucokinase is a key regulatory enzyme in the pancreatic beta-cell. It plays a crucial role in the regulation of insulin secretion and has been termed the glucose sensor in pancreatic beta-cells. Given its central role in the regulation of insulin release it is understandable that mutations in the gene encoding glucokinase (GCK) can cause both hyper- and hypoglycemia. Heterozygous inactivating mutations in GCK cause maturity-onset diabetes of the young (MODY) subtype glucokinase (GCK), characterized by mild fasting hyperglycemia, which is present at birth but often only detected later in life during screening for other purposes. Homozygous inactivating GCK mutations result in a more severe phenotype presenting at birth as permanent neonatal diabetes mellitus (PNDM). A growing number of heterozygous activating GCK mutations that cause hypoglycemia have also been reported. A total of 620 mutations in the GCK gene have been described in a total of 1,441 families. There are no common mutations, and the mutations are distributed throughout the gene. The majority of activating mutations cluster in a discrete region of the protein termed the allosteric activator site. The identification of a GCK mutation in patients with both hyper- and hypoglycemia has implications for the clinical course and clinical management of their disorder.

Recognition and Management of Individuals With Hyperglycemia Because of a Heterozygous Glucokinase Mutation

“…More than 600 different mutations have been identified throughout the 10 pancreatic b-cell exons of the GCK gene in .1,400 families (60). Almost all cases of GCK-MODY are due to missense (65%), nonsense, frameshift, or splice site mutations (61).…”

Berberine ameliorates hyperglycemia in alloxan-induced diabetic C57BL/6 mice through activation of Akt signaling pathway

“…Impaired glucokinase activity was found in diabetic individuals [29,30]. Inactivation or the activation mutation of glucokinase gene have been linked to the development of maturity-onset diabetes of the young (MODY), Type 2 (MODY2) and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) [31][32][33]. Patrick B et al have demonstrated that the activation of Akt signal pathway increases glucokinase gene expression [7].…”

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

“…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].…”