THIOREDOXIN-INTERACTING PROTEIN: A CRITICAL LINK BETWEEN GLUCOSE TOXICITY AND BETA CELL APOPTOSIS
THIOREDOXIN-INTERACTING PROTEIN: A CRITICAL LINK BETWEEN GLUCOSE TOXICITY AND BETA CELL APOPTOSIS
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发表时间：
2007
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通讯作者：
Junqin Chen;Geetu Saxena;Imran N. Mungrue;A. Lusis;A. Shalev
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作者：
Junqin Chen;Geetu Saxena;Imran N. Mungrue;A. Lusis;A. Shalev
目的：在糖尿病中，葡萄糖毒性会影响不同的器官系统，包括胰岛导致β细胞凋亡，但这些机制尚未完全了解。最近，我们确定硫氧还蛋白相互作用蛋白（TXNIP）是一种促凋亡β细胞因子，该因子是由葡萄糖诱导的，从而提高了TXNIP可能在β细胞葡萄糖毒性中起作用的可能性。 RESARCH设计和方法：为了评估葡萄糖对TXNIP表达和凋亡的影响，并定义了TXNIP的作用，我们使用了INS-1β细胞，原代小鼠胰岛，肥胖，糖尿病BTBR.OB小鼠和TXNIP-独特的小鼠模型缺乏症（HCB-19）在TXNIP基因中含有天然的废话突变。结果：通过免疫印迹评估，在25mm葡萄糖下孵育25mm葡萄糖的24小时导致TXNIP蛋白增加18倍。这伴随着凋亡的增加，如裂解的caspase-3诱导12倍。 TXNIP的过表达表明TXNIP诱导凋亡的内在线粒体途径。糖尿病BTBR.OB小鼠的胰岛也表现出增加的TxNIP和凋亡增加，而在高葡萄糖下孵育的分离的野生型胰岛也是如此。相反，通过TUNEL和CASPASE-3测量的TXNIP缺陷HCB-19胰岛受到葡萄糖诱导的凋亡的保护，表明TXNIP是葡萄糖毒性和β细胞死亡之间所需的因果关系。结论：这些发现为β细胞葡萄糖毒性和凋亡的分子机制提供了新的启示，表明TXNIP诱导在此恶性循环中起着至关重要的作用，并表明抑制TXNIP可能代表了一种新的方法来减少葡萄毒性β细胞损失。
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.