title: GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes.
abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by insulitis and islet β-cell loss. Thus, an effective therapy may require β-cell restoration and immune suppression. Currently, there is no treatment that can achieve both goals efficiently. We report here that GABA exerts antidiabetic effects by acting on both the islet β-cells and immune system. Unlike in adult brain or islet α-cells in which GABA exerts hyperpolarizing effects, in islet β-cells, GABA produces membrane depolarization and Ca(2+) influx, leading to the activation of PI3-K/Akt-dependent growth and survival pathways. This provides a potential mechanism underlying our in vivo findings that GABA therapy preserves β-cell mass and prevents the development of T1D. Remarkably, in severely diabetic mice, GABA restores β-cell mass and reverses the disease. Furthermore, GABA suppresses insulitis and systemic inflammatory cytokine production. The β-cell regenerative and immunoinhibitory effects of GABA provide insights into the role of GABA in regulating islet cell function and glucose homeostasis, which may find clinical application.
authors.affiliation: Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada M5B 1W8.
authors.forename: Nepton
authors.initials: N
authors.lastname: Soltani
authors.forename: Hongmin
authors.initials: H
authors.lastname: Qiu
authors.forename: Mila
authors.initials: M
authors.lastname: Aleksic
authors.forename: Yelena
authors.initials: Y
authors.lastname: Glinka
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Yiming
authors.initials: Y
authors.lastname: Li
authors.forename: Nina
authors.initials: N
authors.lastname: Zhang
authors.forename: Rabindranath
authors.initials: R
authors.lastname: Chakrabarti
authors.forename: Tiffany
authors.initials: T
authors.lastname: Ng
authors.forename: Tianru
authors.initials: T
authors.lastname: Jin
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Lu
authors.forename: Zhong-Ping
authors.initials: ZP
authors.lastname: Feng
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Prud'homme
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006943:Hyperglycemia / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology* / Q000502:physiology
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D005680:gamma-Aminobutyric Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt