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gamma-Aminobutyric acid (GABA) signalling in human pancreatic islets is altered in type 2 diabetes
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
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2012 (Engelska)Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, nr 7, s. 1985-1994Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2012. Vol. 55, nr 7, s. 1985-1994
Nyckelord [en]
gamma-Aminobutyric acid, Gene expression, Human islets, Type 2 diabetes
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-178541DOI: 10.1007/s00125-012-2548-7ISI: 000305215200017OAI: oai:DiVA.org:uu-178541DiVA, id: diva2:542429
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Tillgänglig från: 2012-08-01 Skapad: 2012-07-31 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Ingår i avhandling
1. The Cross-Talk between GABA Signalling and Metabolic Hormones in the Brain and Pancreatic Islets
Öppna denna publikation i ny flik eller fönster >>The Cross-Talk between GABA Signalling and Metabolic Hormones in the Brain and Pancreatic Islets
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2013. s. 40
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 947
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-209532 (URN)978-91-554-8795-9 (ISBN)
Disputation
2013-12-12, lecture hall A1:111a, BMC, Husargatan 3, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2013-11-21 Skapad: 2013-10-21 Senast uppdaterad: 2014-01-23

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