Department of Diabetes, Metabolism and Endocrinology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan.
Department of Diabetes, Metabolism and Endocrinology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan; Department of Immunology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan.
Metabolism. 2018 May;82:88-99. doi: 10.1016/j.metabol.2018.01.016. Epub 2018 Jan 31.
Chronic progression of diabetes is associated with decreased pancreatic islet mass due to apoptosis of β-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 β-cells.
Samples from diabetic patients and newly developed transgenic mice overexpressing human MMP2 (hMMP2) were harnessed, and diabetes was induced with streptozotocin.
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 β-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 β-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-β3.
Overall, this study demonstrates that increased expression of hMMP2 may attenuate the severity of diabetes by protecting islet β-cells from apoptosis through an integrin-mediated activation of the Akt/BAD pathway.
糖尿病的慢性进展与β细胞凋亡导致胰岛质量下降有关。糖尿病患者循环中的基质金属蛋白酶-2（MMP2）增加；然而，其生理意义仍不清楚。本研究检验了 MMP2 抑制细胞凋亡，包括胰岛β细胞的假说。
利用糖尿病患者和过表达人 MMP2（hMMP2）的新开发转基因小鼠的样本，并使用链脲佐菌素诱导糖尿病。
与对照组相比，糖尿病患者的循环 hMMP2 显着增加，并且与血清 C 肽水平显着相关。与糖尿病野生型小鼠相比，糖尿病 hMMP2 转基因小鼠的血糖、葡萄糖耐量和胰岛素分泌均显着改善。重要的是，与野生型相比，小鼠中 hMMP2 水平的增加与胰岛β细胞凋亡的显着减少相关，并且 hMMP2 的抑制剂逆转了这种对糖尿病的缓解作用。与对照组相比，hMMP2 在β细胞中诱导 Akt 和 BAD 的激活增加，将这种信号通路与 hMMP2 的抗凋亡活性联系起来，这种特性可被 hMMP2 抑制剂和整合素-β3 抗体逆转。
总的来说，这项研究表明，hMMP2 的表达增加可能通过整合素介导的 Akt/BAD 途径的激活来保护胰岛β细胞免于凋亡，从而减轻糖尿病的严重程度。
