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Diabetes. 2014 Dec;63(12):4197-205. doi: 10.2337/db14-0153. Epub 2014 Jul 9.

GABA promotes human β-cell proliferation and modulates glucose homeostasis.

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  • 1Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada Departments of Physiology and Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
  • 2Departments of Physiology and Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
  • 3Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China.
  • 4Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
  • 5Department of Surgery, McGill University, and Human Islet Transplantation Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.
  • 6Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
  • 7Department of Pathology, Immunology and Laboratory Medicine, University of Florida Health Science Center, Gainesville, FL.
  • 8Department of Laboratory Medicine and Pathobiology, University of Toronto, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
  • 9Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada Departments of Physiology and Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China qinghua.wang@utoronto.ca.

Abstract

γ-Aminobutyric acid (GABA) exerts protective and regenerative effects on mouse islet β-cells. However, in humans it is unknown whether it can increase β-cell mass and improve glucose homeostasis. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-γ mice with streptozotocin-induced diabetes. GABA treatment increased grafted β-cell proliferation, while decreasing apoptosis, leading to enhanced β-cell mass. This was associated with increased circulating human insulin and reduced glucagon levels. Importantly, GABA administration lowered blood glucose levels and improved glucose excursion rates. We investigated GABA receptor expression and signaling mechanisms. In human islets, GABA activated a calcium-dependent signaling pathway through both GABA A receptor and GABA B receptor. This activated the phosphatidylinositol 3-kinase-Akt and CREB-IRS-2 signaling pathways that convey GABA signals responsible for β-cell proliferation and survival. Our findings suggest that GABA regulates human β-cell mass and may be beneficial for the treatment of diabetes or improvement of islet transplantation.

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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