Anti-apoptotic activity of human matrix metalloproteinase-2 attenuates diabetes mellitus
Anti-apoptotic activity of human matrix metalloproteinase-2 attenuates diabetes mellitus
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DOI：
10.1016/j.metabol.2018.01.016
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发表时间：
2018-05-01
影响因子：
9.8
通讯作者：
Gabazza, Esteban C.
中科院分区：
文献类型：
--
作者：
Nishihama, Kota;Yasuma, Taro;Gabazza, Esteban C.
背景：糖尿病的慢性进展与β细胞凋亡引起的胰岛质量减少有关。糖尿病患者的循环基质金属蛋白酶2（MMP 2）增加，然而，生理意义仍然难以捉摸。这项研究测试的假设，MMP 2抑制细胞凋亡，包括胰岛β-cells.Methods：样本从糖尿病患者和新开发的转基因小鼠过度表达人MMP 2（hMMP 2）被利用，糖尿病是诱导与streptozotocin.Results：循环hMMP 2显着增加，糖尿病患者相比，对照组和显着相关的血清C-肽水平。与糖尿病野生型小鼠相比，糖尿病hMMP 2转基因小鼠在血糖、葡萄糖耐量和胰岛素分泌方面表现出显著改善。重要的是，与野生型对应物相比，小鼠中增加的hMMP 2水平与胰岛β细胞凋亡的显著减少相关，并且hMMP 2的抑制剂逆转了这种对糖尿病的缓解活性。与对照相比，hMMP 2在β细胞中诱导的Akt和BAD的活化增加，将该信号传导途径与hMMP 2的抗凋亡活性联系起来，该性质可被hMMP 2抑制剂和针对整合素β 3的抗体逆转。总的来说，这项研究表明，hMMP 2的表达增加可能通过保护胰岛β细胞免于凋亡来减轻糖尿病的严重程度，这是通过整合素-介导的Akt/BAD途径的激活。(C)2018爱思唯尔公司All rights reserved.
Background: Chronic progression of diabetes is associated with decreased pancreatic islet mass due to apoptosis of beta-cells. Patients with diabetes have increased circulating matrix metalloproteinase-2 (MMP2); however, the physiological significance has remained elusive. This study tested the hypothesis that MMP2 inhibits cell apoptosis, including islet beta-cells.Methods: Samples from diabetic patients and newly developed transgenic mice overexpressing human MMP2 (hMMP2) were harnessed, and diabetes was induced with streptozotocin.Results: Circulating hMMP2 was significantly increased in diabetic patients compared to controls and significantly correlated with the serum C-peptide levels. The diabetic hMMP2 transgenic mice showed significant improvements in glycemia, glucose tolerance and insulin secretion compared to diabetic wild type mice. Importantly, the increased hMMP2 levels in mice correlated with significant reduction in islet beta-cell apoptosis compared to wild-type counterparts, and an inhibitor of hMMP2 reversed this mitigating activity against diabetes. The increased activation of Akt and BAD induced by hMMP2 in beta-cells compared to controls, links this signaling pathway to the anti-apoptotic activity of hMMP2, a property that was reversible by both an hMMP2 inhibitor and antibody against integrin-beta 3.Conclusion: Overall, this study demonstrates that increased expression of hMMP2 may attenuate the severity of diabetes by protecting islet beta-cells from apoptosis through an integrin-mediated activation of the Akt/BAD pathway. (C) 2018 Elsevier Inc. All rights reserved.