Thioredoxin-interacting protein deficiency induces Akt/Bcl-xL signaling and pancreatic beta-cell mass and protects against diabetes
Thioredoxin-interacting protein deficiency induces Akt/Bcl-xL signaling and pancreatic beta-cell mass and protects against diabetes
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DOI：
10.1096/fj.08-111690
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发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Shalev, Anath
中科院分区：
文献类型：
--
作者：
Chen, Junqin;Hui, Simon T.;Shalev, Anath
通过细胞凋亡的胰腺β细胞损失代表糖尿病发病机制中的关键因素;然而，目前没有有效的方法来阻断该过程并保持内源性β细胞群。为了研究硫氧还蛋白相互作用蛋白（TXNIP）的作用，我们最近发现了一种促凋亡β细胞因子，我们使用HcB-19（TXNIP无义突变）和β细胞特异性TXNIP敲除（bTKO）小鼠。有趣的是，HcB-19小鼠表现出增加的肥胖，但具有较低的血糖水平和增加的胰腺β细胞质量（如通过形态测定法评估的）。此外，HcB-19小鼠对链脲佐菌素诱导的糖尿病具有抗性。当与肥胖、胰岛素抵抗和糖尿病小鼠杂交时，双突变BTBRlep（ob/ob）txnip（hcb/hcb）甚至更肥胖，但可防止糖尿病和β细胞凋亡，导致β细胞质量增加3倍。β细胞特异性TXNIP缺失也增加了β细胞质量（P < 0.005），并保护免受糖尿病，末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）显示，在链脲佐菌素治疗的bTKO小鼠中，β细胞凋亡减少了50倍。我们进一步发现，TXNIP缺陷诱导Akt/Bcl-xL信号传导并抑制线粒体β细胞死亡，这表明这些机制可能介导TXNIP缺陷的β细胞保护作用。这些结果表明，降低β细胞TXNIP表达可以作为一种新的策略，用于治疗1型和2型糖尿病，通过促进内源性β细胞存活。
Pancreatic beta-cell loss through apoptosis represents a key factor in the pathogenesis of diabetes; however, no effective approaches to block this process and preserve endogenous beta-cell mass are currently available. To study the role of thioredoxin-interacting protein (TXNIP), a proapoptotic beta-cell factor we recently identified, we used HcB-19 (TXNIP nonsense mutation) and beta-cell-specific TXNIP knockout (bTKO) mice. Interestingly, HcB-19 mice demonstrate increased adiposity, but have lower blood glucose levels and increased pancreatic beta-cell mass (as assessed by morphometry). Moreover, HcB-19 mice are resistant to streptozotocin-induced diabetes. When intercrossed with obese, insulin-resistant, and diabetic mice, double-mutant BTBRlep(ob/ob) txnip(hcb/hcb) are even more obese, but are protected against diabetes and beta-cell apoptosis, resulting in a 3-fold increase in beta-cell mass. Beta-cell-specific TXNIP deletion also enhanced beta-cell mass (P < 0.005) and protected against diabetes, and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) revealed a similar to 50-fold reduction in beta-cell apoptosis in streptozotocin-treated bTKO mice. We further discovered that TXNIP deficiency induces Akt/Bcl-xL signaling and inhibits mitochondrial beta-cell death, suggesting that these mechanisms may mediate the beta-cell protective effects of TXNIP deficiency. These results suggest that lowering beta-cell TXNIP expression could serve as a novel strategy for the treatment of type 1 and type 2 diabetes by promoting endogenous beta-cell survival.