ArticleDiabetes2011
Susceptibility of glucokinase-MODY mutants to inactivation by oxidative stress in pancreatic β-cells.
Article in Diabetes, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 14 citations in OpenAlex.
- Glucose-dependent partitioning of arginine to the urea cycle protects β-cells from inflammation.Nature metabolism · 2020Article
- Reducing Glucokinase Activity to Enhance Insulin Secretion: A Counterintuitive Theory to Preserve Cellular Function and Glucose Homeostasis.Frontiers in endocrinology · 2020Article
- Molecular and cellular regulation of human glucokinase.Archives of biochemistry and biophysics · 2019Review
- Chronic alcohol consumption potentiates the development of diabetes through pancreatic β-cell dysfunction.World journal of biological chemistry · 2015Review
- Glutathione s-transferase m1 and t1 gene polymorphisms are not associated with increased risk of gestational diabetes mellitus development.The West Indian medical journal · 2014Article
- Glucagon induces translocation of glucokinase from the cytoplasm to the nucleus of hepatocytes by transfer between 6-phosphofructo 2-kinase/fructose 2,6-bisphosphatase-2 and the glucokinase regulatory protein.Biochimica et biophysica acta · 2014Article
- A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators.Nature structural & molecular biology · 2014Article
- GCK-MODY diabetes associated with protein misfolding, cellular self-association and degradation.Biochimica et biophysica acta · 2012Article
- Thermal stability of glucokinase (GK) as influenced by the substrate glucose, an allosteric glucokinase activator drug (GKA) and the osmolytes glycerol and urea.Biochimica et biophysica acta · 2012Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveThe posttranslational regulation of glucokinase (GK) differs in hepatocytes and pancreatic β-cells. We tested the hypothesis that GK mutants that cause maturity-onset diabetes of the young (GK-MODY) show compromised activity and posttranslational regulation in β-cells. RESEARCH DESIGN AND
methodsActivity and protein expression of GK-MODY and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) mutants were studied in β-cell (MIN6) and non-β-cell (H4IIE) models. Binding of GK to phosphofructo-2-kinase, fructose-2,6-bisphosphatase (PFK2/FBPase2) was studied by bimolecular fluorescence complementation in cell-based models.
resultsNine of 11 GK-MODY mutants that have minimal effect on enzyme kinetics in vitro showed decreased specific activity relative to wild type when expressed in β-cells. A subset of these were stable in non-β-cells but showed increased inactivation in conditions of oxidative stress and partial reversal of inactivation by dithiothreitol. Unlike the GK-MODY mutants, four of five GK-PHHI mutants had similar specific activity to wild type and Y214C had higher activity than wild type. The GK-binding protein PFK2/FBPase2 protected wild-type GK from oxidative inactivation and the decreased stability of GK-MODY mutants correlated with decreased interaction with PFK2/FBPase2.
conclusionsSeveral GK-MODY mutants show posttranslational defects in β-cells characterized by increased susceptibility to oxidative stress and/or protein instability. Regulation of GK activity through modulation of thiol status may be a physiological regulatory mechanism for the control of GK activity in β-cells.
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