uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
gamma-Aminobutyric acid (GABA) signalling in human pancreatic islets is altered in type 2 diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
Show others and affiliations
2012 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 7, 1985-1994 p.Article in journal (Refereed) Published
Abstract [en]

gamma-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. 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. The GABA signalling system was compromised in islets from type 2 diabetic individuals, where the expression of the genes encoding the alpha 1, alpha 2, beta 2 and beta 3 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. Interstitial GABA activates GABA(A) channels and GABA(B) receptors and effectively modulates hormone release in islets from type 2 diabetic and normoglycaemic individuals.

Place, publisher, year, edition, pages
2012. Vol. 55, no 7, 1985-1994 p.
Keyword [en]
gamma-Aminobutyric acid, Gene expression, Human islets, Type 2 diabetes
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-178541DOI: 10.1007/s00125-012-2548-7ISI: 000305215200017OAI: oai:DiVA.org:uu-178541DiVA: diva2:542429
Note

De tre första författarna delar förstaförfattarskapet.

Available from: 2012-08-01 Created: 2012-07-31 Last updated: 2017-12-07Bibliographically approved
In thesis
1. The Cross-Talk between GABA Signalling and Metabolic Hormones in the Brain and Pancreatic Islets
Open this publication in new window or tab >>The Cross-Talk between GABA Signalling and Metabolic Hormones in the Brain and Pancreatic Islets
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

GABA is a well-known neurotransmitter that can be synthesized in the central nervous system (CNS) and, interestingly, also in pancreatic islets. Once released, GABA activates GABA-A channels tonically or transiently resulting in different physiological functions. The pancreatic islets are important micro-organs composed of mainly α, β and δ cells secreting the metabolic hormones, namely insulin, glucagon and somatosatin, respectively. When insulin is secreted from pancreatic β cells, it can enter the blood and travel to the target tissues including the brain where the insulin receptor is prominently expressed such as in the hippocampus. It has been suggested that insulin regulates hippocampal function and, thereby, possibly modulates cognition. However, how this comes about is not understood. On the other hand, GABA secreted from the pancreatic β cells can regulate the islet cells via the para or autocrine loop. Nevertheless, in order to elucidate the details of GABA effects on cellular function, more insight into the pharmacological characteristics of GABA-A receptors, the physiological concentration of GABA and activation types of the GABA-receptors are required. We, therefore, used the whole-cell and single-channel patch-clamp technique to record from cells in the hippocampal slice and pancreatic islets for studying the function of GABA-A receptors and how they are modified by hormones, GABA or drugs. RT-qPCR was utilized to profile the expression of GABA-A receptors in the intact tissues. We also initiated the patch-clamp combined single-cell RT-PCR in the intact rat and human islets to investigate the cell-specific function of GABA-A receptors.

We have shown in acute rat hippocampal slices that 1 nM insulin “turns on” extrasynaptic GABA-A receptors in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity in the pM range. The benzodiazepines, flumazenil and zolpidem, are inverse agonists. The results demonstrated an unexpected hormonal control of the inhibitory channel subtype expressed and excitability of hippocampal neurons.

In the intact rat islets, the GABA-evoked tonic currents were present in the α cells and may contribute to keeping the resting membrane potential of α cells population at hyperpolarized membrane potential and, thereby, making it more difficult to depolarize the cells. In the human, the GABA signaling system was compromised in islets from type 2 diabetic individuals, where the expression of genes encoding the α1, α2, β2 and β3 GABA-A receptor subunits were down-regulated. GABA originating within the islets evoked tonic currents in the α, β and δ cells. However, transient current was observed only in δ cells, which implies a rapid regulation of somatostatin secretion by GABA. The effects of SR95531 on hormone release revealed that activation of GABA-A receptors decreased both insulin and glucagon secretion. The data is important for understanding the mechanism underlying GABA regulation of hormones secretion in human islets.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 40 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 947
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-209532 (URN)978-91-554-8795-9 (ISBN)
Public defence
2013-12-12, lecture hall A1:111a, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2013-11-21 Created: 2013-10-21 Last updated: 2014-01-23

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Jin, ZheJin, YangKorsgren, OlleBirnir, Bryndis

Search in DiVA

By author/editor
Jin, ZheJin, YangKorsgren, OlleBirnir, Bryndis
By organisation
PhysiologyClinical Immunology
In the same journal
Diabetologia
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 935 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf