GABA promotes human β-cell proliferation and modulates glucose homeostasis

  1. Qinghua Wang1,2,3
  1. 1Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Ontario, Canada
  2. 2Departments of Physiology and Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  3. 3Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, China
  4. 4Department of Surgery, McGill University, and Human Islet Transplantation Laboratory, McGill University Health Centre, Montreal, Quebec, Canada
  5. 5Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
  6. 6Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Health Science Center, Gainesville, FL
  7. 7Department of Laboratory Medicine and Pathobiology, University of Toronto, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Canada.
  1. Corresponding author: Qinghua Wang, E-mail: qinghua.wang{at}utoronto.ca
  1. * These authors contributes equally in this study. (JZ’s present address: Dept of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China)

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-gamma 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 GABAAR and GABABR. This activated the PI3K-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.

  • Received January 31, 2014.
  • Accepted June 23, 2014.

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  1. Diabetes
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