title: γ-Aminobutyric acid regulates both the survival and replication of human β-cells.
abstract: γ-Aminobutyric acid (GABA) has been shown to inhibit apoptosis of rodent β-cells in vitro. In this study, we show that activation of GABAA receptors (GABAA-Rs) or GABAB-Rs significantly inhibits oxidative stress-related β-cell apoptosis and preserves pancreatic β-cells in streptozotocin-rendered hyperglycemic mice. Moreover, treatment with GABA, or a GABAA-R- or GABAB-R-specific agonist, inhibited human β-cell apoptosis following islet transplantation into NOD/scid mice. Accordingly, activation of GABAA-Rs and/or GABAB-Rs may be a useful adjunct therapy for human islet transplantation. GABA-R agonists also promoted β-cell replication in hyperglycemic mice. While a number of agents can promote rodent β-cell replication, most fail to provide similar activities with human β-cells. In this study, we show that GABA administration promotes β-cell replication and functional recovery in human islets following implantation into NOD/scid mice. Human β-cell replication was induced by both GABAA-R and GABAB-R activation. Hence, GABA regulates both the survival and replication of human β-cells. These actions, together with the anti-inflammatory properties of GABA, suggest that modulation of peripheral GABA-Rs may represent a promising new therapeutic strategy for improving β-cell survival following human islet transplantation and increasing β-cells in patients with diabetes.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California.
authors.forename: Jide
authors.initials: J
authors.lastname: Tian
authors.forename: Hoa
authors.initials: H
authors.lastname: Dang
authors.forename: Zheying
authors.initials: Z
authors.lastname: Chen
authors.forename: Alice
authors.initials: A
authors.lastname: Guan
authors.forename: Yingli
authors.initials: Y
authors.lastname: Jin
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001418:Baclofen / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009118:Muscimol / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D001418:Baclofen