Anti-apoptotic activity of human matrix metalloproteinase-2 attenuates diabetes mellitus

Abstract

Background: 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.

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 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.

Conclusion: 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.

Keywords: Akt signaling pathway; Apoptosis; Diabetes; Integrins; Islet β-cell; Metalloproteinases.