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      γ-Aminobutyric acid (GABA) signalling in human pancreatic islets is altered in type 2 diabetes

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          Abstract

          Aims/hypothesis

          γ-Aminobutyric acid (GABA) is a signalling molecule in the interstitial space in pancreatic islets. We examined the expression and function of the GABA signalling system components in human pancreatic islets from normoglycaemic and type 2 diabetic individuals.

          Methods

          Expression of GABA signalling system components was studied by microarray, quantitative PCR analysis, immunohistochemistry and patch-clamp experiments on cells in intact islets. Hormone release was measured from intact islets.

          Results

          The GABA signalling system was compromised in islets from type 2 diabetic individuals, where the expression of the genes encoding the α1, α2, β2 and β3 GABA A channel subunits was downregulated. GABA originating within the islets evoked tonic currents in the cells. The currents were enhanced by pentobarbital and inhibited by the GABA A receptor antagonist, SR95531. The effects of SR95531 on hormone release revealed that activation of GABA A channels (GABA A receptors) decreased both insulin and glucagon secretion. The GABA B receptor antagonist, CPG55845, increased insulin release in islets (16.7 mmol/l glucose) from normoglycaemic and type 2 diabetic individuals.

          Conclusions/interpretation

          Interstitial GABA activates GABA A channels and GABA B receptors and effectively modulates hormone release in islets from type 2 diabetic and normoglycaemic individuals.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00125-012-2548-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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          Most cited references30

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          Channel-mediated tonic GABA release from glia.

          Soojung Lee, Bo-Eun Yoon, Ken Berglund … (2010)
          Synaptic inhibition is based on both tonic and phasic release of the inhibitory transmitter γ-aminobutyric acid (GABA). Although phasic GABA release arises from Ca(2+)-dependent exocytosis from neurons, the mechanism of tonic GABA release is unclear. Here we report that tonic inhibition in the cerebellum is due to GABA being released from glial cells by permeation through the Bestrophin 1 (Best1) anion channel. We demonstrate that GABA directly permeates through Best1 to yield GABA release and that tonic inhibition is eliminated by silencing of Best1. Glial cells express both GABA and Best1, and selective expression of Best1 in glial cells, after preventing general expression of Best1, fully rescues tonic inhibition. Our results identify a molecular mechanism for tonic inhibition and establish a role for interactions between glia and neurons in mediating tonic inhibition.
          Article 0 comments Cited 199 times – based on 0 reviews     Review now
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            GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition.

            Shevin T. Jacob, Rachel Jurd, S Moss (2008)
            GABA (gamma-aminobutyric acid) type A receptors (GABA(A)Rs) mediate most fast synaptic inhibition in the mammalian brain, controlling activity at both the network and the cellular levels. The diverse functions of GABA in the CNS are matched not just by the heterogeneity of GABA(A)Rs, but also by the complex trafficking mechanisms and protein-protein interactions that generate and maintain an appropriate receptor cell-surface localization. In this Review, we discuss recent progress in our understanding of the dynamic regulation of GABA(A)R composition, trafficking to and from the neuronal surface, and lateral movement of receptors between synaptic and extrasynaptic locations. Finally, we highlight a number of neurological disorders, including epilepsy and schizophrenia, in which alterations in GABA(A)R trafficking occur.
            Article 0 comments Cited 182 times – based on 0 reviews     Review now
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              Is Open Access

              Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes

              Matej Orešič, Satu Simell, Marko Sysi-Aho … (2008)
              The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward β cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.
              Article 0 comments Cited 161 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : bryndis.birnir@neuro.uu.se
                Journal
                Journal ID (nlm-ta): Diabetologia
                Journal ID (iso-abbrev): Diabetologia
                Title: Diabetologia
                Publisher: Springer-Verlag (Berlin/Heidelberg )
                ISSN (Print): 0012-186X
                ISSN (Electronic): 1432-0428
                Publication date (Electronic): 27 April 2012
                Publication date PMC-release: 27 April 2012
                Publication date (Print): July 2012
                Volume: 55
                Issue: 7
                Pages: 1985-1994
                Affiliations
                [1 ]Department of Neuroscience, Uppsala University, Box 593, 75124 Uppsala, Sweden
                [2 ]Lund University Diabetes Center, Department of Clinical Sciences, Diabetes & Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden
                [3 ]Department of Clinical Sciences, Islet Cell physiology, University Hospital Malmö, Lund University, Malmö, Sweden
                [4 ]Department of Clinical Sciences, Islet Pathophysiology, University Hospital Malmö, Lund University, Malmö, 20502 Sweden
                [5 ]Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, 75185 Sweden
                Article
                Publisher ID: 2548
                DOI: 10.1007/s00125-012-2548-7
                PMC ID: 3369140
                PubMed ID: 22538358
                SO-VID: 90b1b08a-bfb3-4beb-90fa-0460d66df69a
                Copyright © © The Author(s) 2012
                History
                Date received : 12 October 2011
                Date accepted : 7 March 2012
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © Springer-Verlag 2012

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: type 2 diabetes,human islets,gene expression,γ-aminobutyric acid
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: type 2 diabetes, human islets, gene expression, γ-aminobutyric acid

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