Familial Hyperinsulinism Caused by an Activating Glucokinase Mutation

Gläser, Benjamin; Kesavan, Prabakaran; Heyman, Ma'ayan; Davis, Elizabeth A.; Cuesta, Antonio L.; Buchs, Andreas; Stanley, Charles A.; Thornton, Paul; Permutt, M. A.; Matschinsky, Franz M.; Herold, Kevan C.

doi:10.1056/nejm199801223380404

Cited by 536 publications

(416 citation statements)

References 25 publications

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“…Moreover, we demonstrate the efficacy of these compounds in stimulating glucose phosphorylation, glycolysis, and glycogen synthesis in hepatocytes. Furthermore, we show that the compounds affect the affinity for mannoheptulose but not for three other GK inhibitors, including GKRP, which suggests a similar mechanism of action of the compounds to activating mutations of the GK gene (8,9,32). The compounds cause translocation of GK from the nucleus despite the fact that they do not dissociate GK from GKRP.…”

Section: Discussionmentioning

confidence: 73%

“…However, mutations of residues distant from the catalytic site affect the affinity for glucose and mannoheptulose but not N-acetylglucosamine (31,37). Most, though not all, of the activating mutations are in the hinge region of the bipartite structure (8,9,32,38). It is assumed that they favor the closed conformation, which has a higher affinity for glucose.…”

Section: Discussionmentioning

confidence: 99%

“…Heterozygous loss-of-function mutations in the GK gene cause maturity-onset diabetes of the young, type 2 (7). Conversely, activating mutations cause hyperinsulinemia and hypoglycemia (8,9). Studies in rodents also support a critical role for GK in glucose homeostasis.…”

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confidence: 88%

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Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators

et al. 2004

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Glucokinase (GK) has a major role in the control of blood glucose homeostasis and is a strong potential target for the pharmacological treatment of type 2 diabetes. We report here the mechanism of action of two novel and potent direct activators of GK: 6-[(3-isobutoxy-5-isopropoxybenzoyl)amino]nicotinic acid (GKA1) and 5-({3-isopropoxy-5-[2-(3-thienyl)ethoxy] benzoyl}amino)-1,3,4-thiadiazole-2-carboxylic acid (GKA2), which increase the affinity of GK for glucose by 4-and 11-fold, respectively. GKA1 increased the affinity of GK for the competitive inhibitor mannoheptulose but did not affect the affinity for the inhibitors palmitoylCoA and the endogenous 68-kDa regulator (GK regulatory protein [GKRP]), which bind to allosteric sites or to N-acetylglucosamine, which binds to the catalytic site. In hepatocytes, GKA1 and GKA2 stimulated glucose phosphorylation, glycolysis, and glycogen synthesis to a similar extent as sorbitol, a precursor of fructose 1-phosphate, which indirectly activates GK through promoting its dissociation from GKRP. Consistent with their effects on isolated GK, these compounds also increased the affinity of hepatocyte metabolism for glucose. GKA1 and GKA2 caused translocation of GK from the nucleus to the cytoplasm. This effect was additive with the effect of sorbitol and is best explained by a "glucose-like" effect of the GK activators in translocating GK to the cytoplasm. In conclusion, GK activators are potential antihyperglycemic agents for the treatment of type 2 diabetes through the stimulation of hepatic glucose metabolism by a mechanism independent of GKRP. Diabetes 53:535-541, 2004

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators

et al. 2004

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“…Evidence for a link between primary insulin hypersecretion and beta cell dysfunction comes from studies in patients with persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI), who have genetic mutations causing overt insulin hypersecretion. In a family whose members had PHHI resulting from a mutation in the GCK that lowers the K m for glucose from 8.4 to 2.9 mmol/l, an older member developed diabetes requiring insulin at the age of 48 years [11]. Diabetes has also been linked to another activating mutation in GCK that causes neonatal hyperinsulinaemic hypoglycaemia [12].…”

Section: Ermentioning

confidence: 99%

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

et al. 2008

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“…13,14 These genetic mutations have only rarely been identified in adult cases. 15,16 The lack of recognized mutations in most adult cases suggests that the pathogenesis of adult nesidioblastosis may be different from infantile nesidioblastosis.…”

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confidence: 99%

Hyperinsulinemic hypoglycemia with nesidioblastosis: histologic features and growth factor expression

et al. 2009

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Hypoglycemia secondary to nesidioblastosis is rare in adults, and the pathogenesis of this condition is unknown. To determine factors leading to nesidioblastosis in adults, we analyzed 36 cases of nesidioblastosis including 27 cases of postgastric bypass nesidioblastosis and 9 cases of idiopathic nesidioblastosis in adults by immunohistochemistry using antibodies to insulin-like growth factor1, insulin-like growth factor2 (IGF2), insulin-like growth factor one receptor-a epidermal growth factor receptor, transforming growth factor-b1 and 2, and transforming growth factor-b receptor type 3. Fifty-two surgically excised pancreatic specimens from patients with benign exocrine tumors and no evidence of hypoglycemia were used as controls. There was increased IGF2, insulin-like growth factor receptor1 receptor-a and transforming growth factor-b receptor 3 expression in islets from nesidioblastosis patients compared to controls. Peliosis-type vascular ectasia was more common in nesidioblastosis patients compared to controls. These findings suggest that increased production of growth factors and growth factor receptors may contribute to the development of nesidioblastosis in adults.

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Familial Hyperinsulinism Caused by an Activating Glucokinase Mutation

Cited by 536 publications

References 25 publications

Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators

Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

Hyperinsulinemic hypoglycemia with nesidioblastosis: histologic features and growth factor expression

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