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【bio-news】TXNIP：高糖毒性引起β细胞凋亡的关键
Objective: In diabetes, glucose-toxicity affects different organ systems including pancreatic islets where it leads to beta cell apoptosis, but the mechanisms are not fully understood. Recently, we identified thioredoxin-interacting protein (TXNIP) as a pro-apoptotic beta cell factor that is induced by glucose raising the possibility that TXNIP may play a role in beta cell glucose-toxicity.
Resarch Design And Methods: To assess the effects of glucose on TXNIP expression and apoptosis and define the role of TXNIP, we used INS-1 beta cells, primary mouse islets, obese, diabetic BTBR.ob mice and a unique mouse model of TXNIP-deficiency (HcB-19) harboring a natural nonsense mutation in the TXNIP gene.
Results: Incubation of INS-1 cells at 25mM glucose for 24h led to a 18-fold increase in TXNIP protein as assessed by immunoblotting. This was accompanied by increased apoptosis as demonstrated by a 12-fold induction of cleaved caspase-3. Overexpression of TXNIP revealed that TXNIP induces the intrinsic mitochondrial pathway of apoptosis. Islets of diabetic BTBR.ob mice also demonstrated increased TXNIP and apoptosis as did isolated wild-type islets incubated at high glucose. In contrast, TXNIP-deficient HcB-19 islets were protected against glucose-induced apoptosis as measured by TUNEL and caspase-3, indicating that TXNIP is a required causal link between glucose-toxicity and beta cell death.
Conclusions: These findings shed new light onto the molecular mechanisms of beta cell glucose-toxicity and apoptosis, demonstrate that TXNIP induction plays a critical role in this vicious cycle and suggest that inhibition of TXNIP may represent a novel approach to reduce glucotoxic beta cell loss.
http://diabetes.diabetesjournals.org/cgi/content/abstract/db07-0715v2 硫氧还原交互作用蛋白(TXNIP) 基因是细胞氧化还原过程中的调控子，在胰岛素抵抗或糖尿病鼠中高表达。研究发现，高糖情况下TXNIP 基因的表达增强，TXNIP 的增加可使Bax 表达增强，Bcl-2 表达下降，并促进caspase 的激活和β细胞凋亡。
转载 最近再看凋亡的文献，正好也有这篇就顺变翻一下吧。
THIOREDOXIN-INTERACTING PROTEIN: A CRITICAL LINK BETWEEN GLUCOSE TOXICITY AND BETA CELL APOPTOSIS
硫氧还原交互作用蛋白(TXNIP)：糖毒性与β细胞凋亡之间的重要联系
Objective: In diabetes, glucose-toxicity affects different organ systems including pancreatic islets where it leads to beta cell apoptosis, but the mechanisms are not fully understood. Recently, we identified thioredoxin-interacting protein (TXNIP) as a pro-apoptotic beta cell factor that is induced by glucose raising the possibility that TXNIP may play a role in beta cell glucose-toxicity.
目的：在糖尿病中，糖毒性影响包括胰岛细胞在内的众多器官。糖毒性对胰岛细胞的影响导致β细胞的凋亡，但是具体的机制目前尚未完全明确。最近，我们发现硫氧还原交互作用蛋白(TXNIP)是促进β细胞凋亡的因子，血糖升高诱导硫氧还原交互作用蛋白(TXNIP)表达，且硫氧还原交互作用蛋白(TXNIP)可能在β细胞糖毒性中起重要作用。
Resarch Design And Methods: To assess the effects of glucose on TXNIP expression and apoptosis and define the role of TXNIP, we used INS-1 beta cells, primary mouse islets, obese, diabetic BTBR.ob mice and a unique mouse model of TXNIP-deficiency (HcB-19) harboring a natural nonsense mutation in the TXNIP gene.
研究设计与试验方法：我们使用了胰腺肿瘤β-细胞(INS-1)，小鼠胰岛原代培养细胞，肥胖小鼠，BTB糖尿病小鼠，OB小鼠，和唯一的硫氧还原交互作用蛋白(TXNIP)缺陷的小鼠模型(HcB-19 此模型存在天然的TXNIP无效突变)，用来评价高糖对硫氧还原交互作用蛋白(TXNIP)表达、细胞凋亡以及明确硫氧还原交互作用蛋白(TXNIP)在其中所起的作用。
Results: Incubation of INS-1 cells at 25mM glucose for 24h led to a 18-fold increase in TXNIP protein as assessed by immunoblotting. This was accompanied by increased apoptosis as demonstrated by a 12-fold induction of cleaved caspase-3. Overexpression of TXNIP revealed that TXNIP induces the intrinsic mitochondrial pathway of apoptosis. Islets of diabetic BTBR.ob mice also demonstrated increased TXNIP and apoptosis as did isolated wild-type islets incubated at high glucose. In contrast, TXNIP-deficient HcB-19 islets were protected against glucose-induced apoptosis as measured by TUNEL and caspase-3, indicating that TXNIP is a required causal link between glucose-toxicity and beta cell death.
结果：免疫印迹法发现胰腺肿瘤β-细胞(INS-1)在浓度为25mM的高糖培养基中培养24小时以后，硫氧还原交互作用蛋白(TXNIP)蛋白表达增加18倍。Caspase－3的表达也增加了12倍，说明细胞的凋亡与硫氧还原交互作用蛋白(TXNIP)的增加是伴随存在的。硫氧还原交互作用蛋白(TXNIP)的过度表达显示：硫氧还原交互作用蛋白(TXNIP)诱导内源性的线粒体凋亡途径。BTBR糖尿病小鼠以及ob小鼠的胰岛也发现，硫氧还原交互作用蛋白(TXNIP)及凋亡同时增加，体外分离的野生型胰岛在高糖培养基中培养后也有相似的情况。相反，在硫氧还原交互作用蛋白(TXNIP)缺陷小鼠HcB-19的胰岛中却发现：硫氧还原交互作用蛋白(TXNIP)缺陷对高糖诱导的细胞凋亡有保护作用（β细胞的凋亡通过TUNEL法以及测定caspase－3反映），这表明硫氧还原交互作用蛋白(TXNIP)是联系糖毒性与β细胞凋亡的必要联系。
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作者:admin@医学,生命科学 2011-08-23 17:36
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