Nutrient regulation of gamma-aminobutyric acid release from islet beta cells

Smismans, Annick; Schuit, Frans; Pipeleers, Daniël

doi:10.1007/s001250050843

Cited by 72 publications

(103 citation statements)

References 26 publications

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“…Based on the histochemical observations of Sorenson (16) and the biochemical results of Pipeleers and coworkers (40,41) with sorted islet cells, one can safely assume that the observations pertain specifically to beta cells. The apparent rates of interconversion are comparable with the rates of glucose conversion to alanine, aspartate, and glutamate, suggesting that the pathway is relatively active and plays a prominent role in intermediary metabolism of pancreatic beta cells during glucose stimulation, in agreement with independent reports (42).…”

Section: Discussionmentioning

confidence: 99%

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

Nissim

Chen

et al. 2008

Journal of Biological Chemistry

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Pancreatic beta cells are hyper-responsive to amino acids but have decreased glucose sensitivity after deletion of the sulfonylurea receptor 1 (SUR1) both in man and mouse. It was hypothesized that these defects are the consequence of impaired integration of amino acid, glucose, and energy metabolism in beta cells. We used gas chromatography-mass spectrometry methodology to study intermediary metabolism of SUR1 knock-out (SUR1 ؊/؊ ) and control mouse islets with D-[U-13 C]glucose as substrate and related the results to insulin secretion. The levels and isotope labeling of alanine, aspartate, glutamate, glutamine, and ␥-aminobutyric acid (GABA) served as indicators of intermediary metabolism. We found that the GABA shunt of SUR1 ؊/؊ islets is blocked by about 75% and showed that this defect is due to decreased glutamate decarboxylase synthesis, probably caused by elevated free intracellular calcium. Glutaminolysis stimulated by the leucine analogue D,L-␤-2-amino-2-norbornane-carboxylic acid was, however, enhanced in SUR1 ؊/؊ and glyburide-treated SUR1 ؉/؉ islets. Glucose oxidation and pyruvate cycling was increased in SUR1 ؊/؊ islets at low glucose but was the same as in controls at high glucose. Malic enzyme isoforms 1, 2, and 3, involved in pyruvate cycling, were all expressed in islets. High glucose lowered aspartate and stimulated glutamine synthesis similarly in controls and SUR1 ؊/؊ islets. The data suggest that the interruption of the GABA shunt and the lack of glucose regulation of pyruvate cycling may cause the glucose insensitivity of the SUR1 ؊/؊ islets but that enhanced basal pyruvate cycling, lowered GABA shunt flux, and enhanced glutaminolytic capacity may sensitize the beta cells to amino acid stimulation.The pancreatic beta cells function as the predominant sensors and regulators of glucose, amino acid, and fatty acid levels of the mammalian organism, including man, by adjusting the minute to minute rate of insulin secretion such that these fuels are maintained at physiologically optimal blood concentrations under all nutritional conditions including feeding and fasting. This process of fuel-sensing and stimulation of insulin secretion requires that the various stimuli are transported into the beta cells and are metabolized to generate coupling factors that trigger and sustain the secretion of the hormone from large stores of insulin granules (1-4). The diverse specific pathways that allow access to metabolism for glucose, amino acids, and fatty acids converge to a complex network of intermediary metabolism represented by the citric acid cycle, a considerable variety of metabolite and cofactor shuttles including the GABA 2 shunt, and the processes of electron transport and oxidative phosphorylation, to mention just a few outstanding features of the biochemical maze of the beta cell.In the present study we have used uniformly labeled D-[13 C]glucose and GC-MS methods to explore the role of intermediary metabolism of pancreatic islets isolated from normal and sulfonylurea receptor 1 (SUR1) knock-out...

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Section: Discussionmentioning

confidence: 99%

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

Nissim

Chen

et al. 2008

Journal of Biological Chemistry

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“…However, the mode of action of GABA as an intercellular chemical transmitter, especially the timing for its appearance with the receptor-accessible manner in islet, was less understood. Previous studies on GABA release have been performed after a long incubation period, around a day (31,38,39). Under such conditions, amounts of GABA release may reflect the metabolic state of ␤ cells but not directly reflect the rate of GABA secretion through exocytosis of SLMVs.…”

Section: Discussionmentioning

confidence: 99%

Secretory Granule-mediated Co-secretion ofl-Glutamate and Glucagon Triggers Glutamatergic Signal Transmission in Islets of Langerhans

Hayashi

Yamada

Uehara

et al. 2003

Journal of Biological Chemistry

126

158

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L-Glutamate is the major excitatory neurotransmitter in the central nervous system and plays important roles in many neuronal processes such as fast synaptic transmission and neuronal plasticity (1, 2). To use L-glutamate as an intercellular signaling molecule, neuronal cells develop the glutamatergic system. Thus, L-glutamate is accumulated in synaptic vesicles through vesicular glutamate transporters (VGLUTs), 1 and is secreted through exocytosis. The released L-glutamate binds to the receptor so as to transmit signals intercellularly. The excess amount of L-glutamate in synaptic cleft is sequestrated through plasma membrane-type glutamate transporter. Recent evidence has indicated that peripheral non-neuronal tissues also possess the glutamatergic system and use L-glutamate as an intercellular transmitter (3). The islet of Langerhans, a pancreatic miniature organ for the hormones regulating the blood glucose level, is composed of four major types of endocrine cells, i.e. insulin-secreting ␤ cells, glucagon-secreting ␣ cells, somatostatin-secreting ␦ cells, and pancreatic polypeptide-secreting F cells. These islet cells expresses functional glutamate receptors and plasma membrane-type glutamate transporter (4 -11), suggesting that L-glutamate functions as an intercellular transmitter in islet. In fact, L-glutamate has been shown to affect secretion of insulin or glucagon from islet cells, isolated islets, or perfused pancreas (4 -11). However, the role of L-glutamate as an intercellular chemical transmitter in the islets has been long controversial, mainly because critical issues, i.e. where, when, and how L-glutamate appears in the islets and what happens upon stimulation of glutamate receptors in the islets, remain unresolved.Recent findings indicate that brain-specific Na ϩ -dependent inorganic phosphate cotransporter (12) and its isoform, differentiation-associated Na ϩ -dependent inorganic phosphate cotransporter (13), function as VGLUTs and are thus abbreviated as VGLUT1 and VGLUT2, respectively (14 -21). These VGLUTs seem to be potential probes for the site of L-glutamate release in peripheral tissues as well as the central nervous system since these transporters are essential for L-glutamate signal output. We have shown that VGLUT2 is expressed in ␣TC6 cells, clonal ␣ cells, and islet ␣ cells, but not in ␤ or ␦ cells (18). These results are consistent with the occurrence of Ca 2ϩ -dependent exocytosis of L-glutamate from ␣TC6 cells (22) and suggest that ␣ cells are the sites of L-glutamate signal appearance.During course of the study, we noticed that the expression and subcellular localization of VGLUTs are of extraordinary

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“…Measurement of insulin secretion after treatment Freshly isolated small islets (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) were plated in clusters in 60-90 μl respectively of M199 medium in half-diameter 96-well plates. Islets were incubated for 60 min with test reagents, as above, or left untreated.…”

Section: Methodsmentioning

confidence: 99%

“…The highest concentration of GABA peripherally is found in beta cells of the pancreatic islet [19], at levels comparable with those observed in GABAergic brain nuclei [19,20]. Work by others indicates GABA is released from beta cells in response to nutrients and depolarisation through a calcium-regulated secretion pathway [21][22][23][24]. Using electrophysiology, Wendt et al estimated that concentrations of GABA within the islet reach levels sufficient for GABA to act as a paracrine signal [25].…”

Section: Introductionmentioning

confidence: 92%

Regulation of pancreatic islet cell survival and replication by γ-aminobutyric acid

et al. 2007

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Aims/hypothesis Pancreatic islets have evolved remarkable, though poorly understood mechanisms to modify beta cell mass when nutrient intake fluctuates or cells are damaged. We hypothesised that appropriate and timely adjustments in cell number occur because beta cells release proliferative signals to surrounding cells when stimulated by nutrients and 'bleed' these growth factors upon injury. Materials and methods In rat pancreatic islets, we measured DNA content, insulin content, insulin secretion after treatment, immunoblots of apoptotic proteins and the uptake of nucleoside analogues to assess the ability of γ-aminobutyric acid (GABA), which is highly concentrated in beta cells, to act as a growth and survival factor. This focus is supported by work from others demonstrating that GABA increases cell proliferation in the developing nervous system, acts as a survival factor for differentiated neurons and, interestingly, protects plants under stress. Results Our results show that DNA, insulin content and insulin secretion are higher in freshly isolated islets treated with GABA or GABA B receptor agonists. Exposure to GABA upregulated the anti-apoptotic protein B-cell chronic lymphocytic leukaemia XL and limited activation of caspase 3 in islets. The cellular proliferation rate in GABA-treated islets was twice that of untreated controls. Conclusions/interpretation We conclude that GABA serves diverse purposes in the islet, meeting a number of functional criteria to act as an endogenous co-regulator of beta cell mass.

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Nutrient regulation of gamma-aminobutyric acid release from islet beta cells

Cited by 72 publications

References 26 publications

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

Secretory Granule-mediated Co-secretion ofl-Glutamate and Glucagon Triggers Glutamatergic Signal Transmission in Islets of Langerhans

Regulation of pancreatic islet cell survival and replication by γ-aminobutyric acid

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