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2015年9月9日讯 /生物谷BIOON/ –近日，来自美国俄克拉荷马大学的华人科学家在国际学术期刊diabetes上发表了一项最新研究进展，他们发现抗衰老基因Klotho能够抑制β细胞凋亡， 而异常的细胞凋亡是造成1型糖尿病发病过程中合成胰岛素的β细胞死亡的主要原因。因此这项研究对于1型糖尿病治疗具有重要提示意义。
在这项研究中，研究人员检测到最近发现的抗衰老基因Klotho基因在胰腺β细胞中也有表达。非常有趣的是，Klotho基因发生单染色体缺失会加重STZ诱导的糖尿病模型（一种1型糖尿病模型）出现高血糖症，葡萄糖不耐受，胰岛内储存的胰岛素减少，β细胞凋亡增加等症状。而在β细胞内特异性表达Klotho基因可以减弱β细胞的凋亡，并阻止STZ诱导的1型糖尿病发生。
研究人员对其中的机制进行了研究，他们利用培养的MIN6 β细胞发现Klotho会促进细胞黏附到胶原IV，增加FAK和Akt的磷酸化并抑制caspase 3的剪切，这表明Klotho能够通过消除STZ以及TNF a诱导的对FAK和Akt磷酸化的抑制作用，激活整合素β1-FAK/Akt信号途径以抑制caspase 3的功能剪切，进而阻止β细胞发生凋亡。
研究人员还利用自身免疫性1型糖尿病动物模型进行了进一步研究，结果发现在β细胞内特异性表达mKL可以改善葡萄糖耐受性，减缓β细胞凋亡，并增强β细胞内胰岛素的储存以及血浆中的胰岛素水平。
综上所述，这项研究发现抗衰老基因Klotho可以通过激活整合素β1-FAK/Akt信号途径抑制β细胞凋亡，对于1型糖尿病治疗具有重要提示意义。（基因宝jiyinbao.com）
Anti-aging Gene Klotho Attenuates Pancreatic β Cell Apoptosis in Type I Diabetes
Yi Lin and Zhongjie Sun
Apoptosis is the major cause of death of insulin-producing β cells in type 1 diabetes mellitus (T1DM). Klotho is a recently discovered anti-aging gene. We found that klotho gene is expressed in pancreatic β cells. Interestingly, halplodeficiency of Klotho (KL+/-) exacerbated streptozotocin (STZ)-induced diabetes (a model of T1DM), including hyperglycemia, glucose intolerance, diminished islet insulin storage, and increased apoptotic β cells. Conversely, in vivo β cell-specific expression of mouse Klotho gene (mKL) attenuated β cell apoptosis and prevented STZ-induced diabetes. mKL promoted cell adhesion to collagen IV, increased FAK and Akt phosphorylation, and inhibited Caspase 3 cleavage in cultured MIN6 β cells. mKL abolished STZ- and TNFα-induced inhibition of FAK and Akt phosphorylation, Caspase 3 cleavage, and β cell apoptosis. These promoting effects of Klotho can be abolished by blocking integrin β1. Therefore, these cell-based studies indicated that klotho protected β cells by inhibiting β cell apoptosis through activation of the integrin β1-FAK/Akt pathway leading to inhibition of Caspase 3 cleavage. In an autoimmune T1DM model (NOD), we showed that in vivo β cell-specific expression of mKL improved glucose tolerance, attenuated β cell apoptosis, enhanced insulin storage in β cells, and increased plasma insulin levels. The beneficial effect of Klotho gene delivery is likely due to attenuation of T cell infiltration in pancreatic islets in NOD mice. Overall, our results demonstrate for the first time that Klotho protected β cells in T1DM via attenuating apoptosis.