2. Academic Validation
  3. Anti-apoptotic activity of human matrix metalloproteinase-2 attenuates diabetes mellitus

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

  • Metabolism. 2018 May;82:88-99. doi: 10.1016/j.metabol.2018.01.016.
Kota Nishihama 1,  Taro Yasuma 2,  Yutaka Yano 1,  Corina N D' Alessandro-Gabazza 3,  Masaaki Toda 4,  Josephine A Hinneh 4,  Prince Baffour Tonto 4,  Atsuro Takeshita 1,  Toshiaki Totoki 5,  Rumi Mifuji-Moroka 5,  Tetsu Kobayashi 6,  Motoh Iwasa 5,  Yoshiyuki Takei 5,  John Morser 7,  Isaac Cann 8,  Esteban C Gabazza 9
Affiliations

Affiliations

  • 1 Department of Diabetes, Metabolism and Endocrinology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan.
  • 2 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.
  • 3 Department of Immunology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan; Microbiome Metabolic Engineering Theme, Carl R. Woese Biology Institute for Genomic Biology, Department of Animal Sciences, Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.
  • 4 Department of Immunology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan.
  • 5 Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan.
  • 6 Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan.
  • 7 Division of Hematology, Stanford School of Medicine, 269 Campus Drive, CCSR 1155, Stanford, CA 94305-5156, United States.
  • 8 Microbiome Metabolic Engineering Theme, Carl R. Woese Biology Institute for Genomic Biology, Department of Animal Sciences, Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.
  • 9 Department of Immunology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan. Electronic address: gabazza@doc.medic.mie-u.ac.jp.
PMID: 29366755 DOI: 10.1016/j.metabol.2018.01.016
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.

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