Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucokinase (GK) is a glycolytic key enzyme that functions as a glucose sensor in the pancreatic beta-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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PMID:Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. 1527 2

Glucokinase and phosphorylase both have a high control strength over hepatocyte glycogen metabolism and are potential therapeutic targets for type 2 diabetes. We tested whether combined phosphorylase inactivation and glucokinase activation is a more effective strategy for controlling hepatic glycogen metabolism than single-site targeting. Activation of glucokinase by enzyme overexpression combined with selective dephosphorylation of phosphorylase-a by an indole carboxamide that favors the T conformation of phosphorylase caused a greater stimulation of glycogen synthesis than the sum of either treatment alone. This result is explained by the complementary roles of elevated glucose-6-phosphate (G6P; a positive modulator) and depleted phosphorylase-a (a negative modulator) in activating glycogen synthase and also by synergistic inactivation of phosphorylase-a by glucokinase activation and the indole carboxamide. Inactivation of phosphorylase-a by the indole carboxamide was counteracted by 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside, which is metabolized to an AMP analog; this effect was reversed by G6P. Our findings provide further evidence for the inverse roles of G6P and AMP in regulating the activation state of hepatic phosphorylase. It is proposed that dual targeting of glucokinase and phosphorylase-a enables improved potency and efficacy in controlling hepatic glucose metabolism.
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PMID:Increased potency and efficacy of combined phosphorylase inactivation and glucokinase activation in control of hepatocyte glycogen metabolism. 1573 35

As the rate-limiting controller of glucose metabolism, glucokinase represents the primary beta-cell "glucose sensor." Inactivation of both glucokinase (GK) alleles results in permanent neonatal diabetes; inactivation of a single allele causes maturity-onset diabetes of the young type 2 (MODY-2). Similarly, mice lacking both alleles (GK(-/-)) exhibit severe neonatal diabetes and die within a week, whereas heterozygous GK(+/-) mice exhibit markedly impaired glucose tolerance and diabetes, resembling MODY-2. Glucose metabolism increases the cytosolic [ATP]-to-[ADP] ratio, which closes ATP-sensitive K(+) channels (K(ATP) channels), leading to membrane depolarization, Ca(2+) entry, and insulin exocytosis. Glucokinase insufficiency causes defective K(ATP) channel regulation, which may underlie the impaired secretion. To test this prediction, we crossed mice lacking neuroendocrine glucokinase (nGK(+/-)) with mice lacking K(ATP) channels (Kir6.2(-/-)). Kir6.2 knockout rescues perinatal lethality of nGK(-/-), although nGK(-/-)Kir6.2(-/-) animals are postnatally diabetic and still die prematurely. nGK(+/-) animals are diabetic on the Kir6.2(+/+) background but only mildly glucose intolerant on the Kir6.2(-/-) background. In the presence of glutamine, isolated nGK(+/-)Kir6.2(-/-) islets show improved insulin secretion compared with nGK(+/-)Kir6.2(+/+). The significant abrogation of nGK(-/-) and nGK(+/-) phenotypes in the absence of K(ATP) demonstrate that a major factor in glucokinase deficiency is indeed altered K(ATP) signaling. The results have implications for understanding and therapy of glucokinase-related diabetes.
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PMID:ATP-sensitive K+ channel signaling in glucokinase-deficient diabetes. 1618 94

Glucokinase (GK) is a molecular sensor that regulates glucose induced insulin secretion in pancreatic beta-cells and glucose homeostasis in the liver via catalysis of glucose to glucose-6-phosphate. The recent discovery and development of small molecule glucokinase activators represents a potentially important development for the management of type 2 diabetes. Since the discovery of the first orally active small molecule GK activator RO0281675, a number of research groups have reported the identification of potent activators. In this review, the biological significance of GK in whole body glucose homeostasis is briefly described coupled with the recent progress regarding the identification of novel small molecule GK activators.
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PMID:Small molecule glucokinase activators as glucose lowering agents: a new paradigm for diabetes therapy. 1678 25

As the prevalence of type 2 diabetes mellitus is increasing at an alarming rate, effective nutritional and exercise strategies for the prevention of this disease are required. Specific dietary components with antidiabetic efficacy could be one aspect of these strategies. This study investigated the antidiabetic effects of the most abundant green tea catechin, epigallocatechin gallate (EGCG, TEAVIGO), in rodent models of type 2 diabetes mellitus and H4IIE rat hepatoma cells. We assessed glucose and insulin tolerance in db/db mice and ZDF rats after they ingested EGCG. Using gene microarray and real-time quantitative RT-PCR we investigated the effect of EGCG on gene expression in H4IIE rat hepatoma cells as well as in liver and adipose tissue of db/db mice. EGCG improved oral glucose tolerance and blood glucose in food-deprived rats in a dose-dependent manner. Plasma concentrations of triacylglycerol were reduced and glucose-stimulated insulin secretion was enhanced. In H4IIE cells, EGCG downregulated genes involved in gluconeogenesis and the synthesis of fatty acids, triacylgycerol, and cholesterol. EGCG decreased the mRNA expression of phosphoenolpyruvate carboxykinase in H4IIE cells as well as in liver and adipose tissue of db/db mice. Glucokinase mRNA expression was upregulated in the liver of db/db mice in a dose-dependent manner. This study shows that EGCG beneficially modifies glucose and lipid metabolism in H4IIE cells and markedly enhances glucose tolerance in diabetic rodents. Dietary supplementation with EGCG could potentially contribute to nutritional strategies for the prevention and treatment of type 2 diabetes mellitus.
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PMID:Epigallocatechin gallate supplementation alleviates diabetes in rodents. 1698 19

Glucokinase (GK) plays a key role in the control of blood glucose homeostasis. We identified a small molecule GK activator, compound A, that increased the glucose affinity and maximal velocity (V(max)) of GK. Compound A augmented insulin secretion from isolated rat islets and enhanced glucose utilization in primary cultured rat hepatocytes. In rat oral glucose tolerance tests, orally administrated compound A lowered plasma glucose elevation with a concomitant increase in plasma insulin and hepatic glycogen. In liver, GK activity is acutely controlled by its association to the glucokinase regulatory protein (GKRP). In order to decipher the molecular aspects of how GK activator affects the shuttling of GK between nucleus and cytoplasm, the effect of compound A on GK-GKRP interaction was further investigated. Compound A increased the level of cytoplasmic GK in both isolated rat primary hepatocytes and the liver tissues from rats. Experiments in a cell-free system revealed that compound A interacted with glucose-bound free GK, thereby impairing the association of GK and GKRP. On the other hand, compound A did not bind to glucose-unbound GK or GKRP-associated GK. Furthermore, we found that glucose-dependent GK-GKRP interaction also required ATP. Given the combined prominent role of GK on insulin secretion and hepatic glucose metabolism where the GK-GKRP mechanism is involved, activation of GK has a new therapeutic potential in the treatment of type 2 diabetes.
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PMID:An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism. 1702 92

Using the metabolic stimulus-secretion coupling of pancreatic beta cells as an example, this review illustrates how new strategies in the treatment of type 2 diabetes mellitus can be developed from the results of basic research. Metabolic stimulus-secretion coupling presupposes the metabolizing of those stimuli of insulin secretion that have the properties of nutritional substances. Changes in the ATP/ADP ratio within the beta cells will then trigger the release of insulin granules from them. Glucokinase, a glucose phosphorylating enzyme, functions as a metabolic glucose sensor, which couples changes in physiological glucose concentration in the pancreatic beta cells and in the liver to the intermediary metabolism, i.e. glycolysis, the citrate cycle and respiratory-chain phosphorylation. In this way insulin secretion and hepatic metabolism are positively influenced. Several pharmaceutical companies (Roche, Merck, Astra-Zeneca, Lilly) have recently developed first examples of glucokinase-activating compounds and demonstrated in animal models their efficacy in the treatment of type 2 diabetes mellitus. These glucokinase activators prevent glucokinase from changing into a catalytically inactive structure. They also increase glucose affinity of the enzyme and stabilize a catalytically active form of glucokinase proteins. In this way glucokinase activators increase glucose-induced insulin secretion and inhibit hepatic glucogenesis. Glucokinase activators are an interesting innovation in the future treatment of type 2 diabetes, because their action on beta cells and the liver is caused by changes in blood glucose concentration.
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PMID:[New aspects of pancreatic beta cell functions and their possible therapeutic applications]. 1713 75

Monogenic diabetes results from one or more mutations in a single gene which might hence be rare but has great impact leading to diabetes at a very young age. It has resulted in great challenges for researchers elucidating the aetiology of diabetes and related features in other organ systems, for clinicians specifying a diagnosis that leads to improved genetic counselling, predicting of clinical course and changes in treatment, and for patients to altered treatment that has lead to coming off insulin and injections with no alternative (Glucokinase mutations), insulin injections being replaced by tablets (e.g. low dose in HNFalpha or high dose in potassium channel defects -Kir6.2 and SUR1) or with tablets in addition to insulin (e.g. metformin in insulin resistant syndromes). Genetic testing requires guidance to test for what gene especially given limited resources. Monogenic diabetes should be considered in any diabetic patient who has features inconsistent with their current diagnosis (unspecified neonatal diabetes, type 1 or type 2 diabetes) and clinical features of a specific subtype of monogenic diabetes (neonatal diabetes, familial diabetes, mild hyperglycaemia, syndromes). Guidance is given by clinical and physiological features in patient and family and the likelihood of the proposed mutation altering clinical care. In this article, I aimed to provide insight in the genes and mutations involved in insulin synthesis, secretion, and resistance, and to provide guidance for genetic testing by showing the clinical and physiological features and tests for each specified diagnosis as well as the opportunities for treatment.
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PMID:Monogenic diabetes in children and young adults: Challenges for researcher, clinician and patient. 1718 87

About 2-5% of all pregnant women develop gestational diabetes mellitus (GDM) during their pregnancies and the prevalence has increased considerably during the last decade. GDM is a heterogeneous disorder that is defined as carbohydrate intolerance with onset or first recognition during pregnancy. It is manifested when pancreatic beta cells are no longer able to compensate for the increased insulin resistance during pregnancy, but the pathogenesis of the disease is still largely unknown. GDM is considered to result from interaction between genetic and environmental risk factors. Genetic predisposition to GDM has been suggested since GDM clusters in families. Also, women with mutations in MODY (Maturity onset diabetes of the young) genes often present with GDM. In addition, common variants in several candidate genes (e.g. potassium inwardly rectifying channel subfamily J, member 11 [KCNJ11], Glucokinase [GCK], Hepatocyte nuclear factor-1alpha [HNF1A] etc.) have been demonstrated to increase the risk of GDM. Old age, obesity and high fat diet represent some important non-genetic factors. There are several approaches to search for genes predisposing to a polygenic disease like GDM including linkage and association studies, expression profiling and animal models. A combination of several methods is usually necessary. Identification of the underlying genetic causes of GDM will eventually give a better view of the mechanisms that contribute to the pathophysiology of the disease. Furthermore, it may improve options to possibly prevent GDM and complications for the mother and her child. This review focuses on the genetics of GDM and possible implications in clinical practice.
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PMID:Genetics of gestational diabetes mellitus. 1734 48

Glucokinase (GCK) plays a key role in glucose metabolism. GCK mutations are known as a pathogenic cause of maturity-onset diabetes of the young type 2 (MODY2). These mutations are also found in gestational diabetics. The aim of our study was to assess the variability of the GCK gene in the Czech diabetic and control populations. We screened all 10 exons specific for the pancreatic isoform of glucokinase (1a and 2-10) including the intron flanking regions in 722 subjects (in 12 patients with an unrecognised type of MODY and their 10 family members, 313 patients with diabetes mellitus type 2 (DM2), 141 gestational diabetics (GDM), 130 healthy offspring of diabetic parents, and 116 healthy controls without family history of DM2). In two MODY families we identified two mutations in exon 2 of the GCK gene: a novel mutation Val33Ala and the previously described mutation Glu40Lys. In other subgroups (excluding MODY families) we detected only intronic variants and previously described polymorphisms in exons 6 (Tyr215Tyr) and 7 (Ser263Ser), we did not find any known GCK pathogenic mutation. We observed no difference in the frequencies of GCK polymorphisms between Czech diabetic (DM2, GDM) and non-diabetic populations.
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PMID:Screening of mutations and polymorphisms in the glucokinase gene in Czech diabetic and healthy control populations. 1827 87


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