title: GABA promotes human β-cell proliferation and modulates glucose homeostasis.
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.
authors.affiliation: Division 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.
authors.forename: Indri
authors.initials: I
authors.lastname: Purwana
authors.affiliation: Division 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.
authors.forename: Juan
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Division 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.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.affiliation: Departments of Physiology and Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marielle
authors.initials: M
authors.lastname: Deurloo
authors.affiliation: Division 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.
authors.forename: Dong Ok
authors.initials: DO
authors.lastname: Son
authors.affiliation: Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Zhaoyun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division 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.
authors.forename: Christie
authors.initials: C
authors.lastname: Liang
authors.affiliation: Division 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.
authors.forename: Eddie
authors.initials: E
authors.lastname: Shen
authors.affiliation: Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Akshaya
authors.initials: A
authors.lastname: Tadkase
authors.affiliation: Departments of Physiology and Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Zhong-Ping
authors.initials: ZP
authors.lastname: Feng
authors.affiliation: Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Surgery, McGill University, and Human Islet Transplantation Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Craig
authors.initials: C
authors.lastname: Hasilo
authors.affiliation: Department of Surgery, McGill University, and Human Islet Transplantation Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Paraskevas
authors.affiliation: Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Rita
authors.initials: R
authors.lastname: Bortell
authors.affiliation: Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida Health Science Center, Gainesville, FL.
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Prud'homme
authors.affiliation: Division 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.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental; D018682:GABA Agents / Q000494:pharmacology*; D005934:Glucagon / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D018682:GABA Agents; D007328:Insulin; D005680:gamma-Aminobutyric Acid; D005934:Glucagon