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葡萄糖激酶 - MODY 突变体对胰岛 β 细胞氧化应激失活的敏感性。

Susceptibility of glucokinase-MODY mutants to inactivation by oxidative stress in pancreatic β-cells.

机构信息

Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, U.K.

出版信息

Diabetes. 2011 Dec;60(12):3175-85. doi: 10.2337/db11-0423. Epub 2011 Oct 25.

DOI:10.2337/db11-0423
PMID:22028181
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3219952/
Abstract

OBJECTIVE

The 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 METHODS

Activity 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.

RESULTS

Nine 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.

CONCLUSIONS

Several 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.

摘要

目的

葡萄糖激酶（GK）在肝细胞和胰腺β细胞中的翻译后调控存在差异。我们检验了这样一个假说，即导致青年发病型糖尿病（MODY）的 GK 突变体在β细胞中表现出活性降低和翻译后调控受损。

研究设计和方法

在β细胞（MIN6）和非β细胞（H4IIE）模型中研究了 GK-MODY 和婴儿持续性高胰岛素血症低血糖（PHHI）突变体的活性和蛋白表达。通过双分子荧光互补在基于细胞的模型中研究了 GK 与磷酸果糖-2-激酶、果糖-2,6-二磷酸酶（PFK2/FBPase2）的结合。

结果

在体外对酶动力学影响最小的 11 个 GK-MODY 突变体中的 9 个，当在β细胞中表达时，其比野生型的特定活性降低。这些突变体中有一部分在非β细胞中稳定，但在氧化应激条件下失活增加，二硫苏糖醇可部分逆转失活。与 GK-MODY 突变体不同，5 个 GK-PHHI 突变体中的 4 个具有与野生型相似的比活性，而 Y214C 的比活性高于野生型。结合蛋白 PFK2/FBPase2 保护野生型 GK 免受氧化失活，而 GK-MODY 突变体稳定性降低与与 PFK2/FBPase2 的相互作用降低有关。

结论

几种 GK-MODY 突变体在β细胞中表现出翻译后缺陷，其特征为对氧化应激和/或蛋白不稳定性的敏感性增加。通过调节巯基状态来调节 GK 活性可能是β细胞中 GK 活性的生理调节机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/7127d5706f0f/3175fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/eff97be1a50e/3175fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/2b14652647d1/3175fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/0ec2fc03a535/3175fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/949fbe197e69/3175fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/b5eb44d1a526/3175fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/7127d5706f0f/3175fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/eff97be1a50e/3175fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/2b14652647d1/3175fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/0ec2fc03a535/3175fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/949fbe197e69/3175fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/b5eb44d1a526/3175fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e46/3219952/7127d5706f0f/3175fig6.jpg

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