Expression of Functional GABA<sub>A</sub> Receptors in Isolated Human Insulinoma Cells

Glassmeier, Günter; Höpfner, Michael; Buhr, H. J.; Lemmer, K.; Riecken, Ernst–Otto; Stein, Harald; Quabbe, Hans-Jürgen; Rancsò, Christoph; Wiedenmann, Bertram; Scherübl, Hans

doi:10.1111/j.1749-6632.1998.tb11138.x

Cited by 18 publications

(10 citation statements)

References 12 publications

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“…1), which is consistent with previously reported studies in isolated human insulinoma cells [13] and rat pancreatic beta cells [15]. Since GABA is localised mainly within the pancreatic beta cells [32], identification of GABA A Rs in the beta cells suggests that the GABA-GABA A R system may serve as both an autocrine and paracrine modulator in the islets.…”

Section: Discussionsupporting

confidence: 80%

“…Other studies demonstrate that both GABA and GABA A R agonists have no detectable effect on insulin secretion in perfused rat pancreas [22,23]. However, GABA-induced increases in insulin release were observed in rat pancreas and isolated human insulinoma cells [13,24,25].…”

Section: Introductionmentioning

confidence: 98%

“…In the pancreas, GABA is primarily produced by insulin-secreting beta cells [9][10][11] and probably by the glucagon-containing alpha cells [9,12]. GABA A Rs are expressed in both beta and alpha cells [13][14][15], suggesting that GABA modulates pancreatic endocrine function in an autocrine and paracrine manner [16][17][18]. In pancreatic beta cells, GABA is associated with synaptic-like microvesicles that are distinct from the insulin-containing large dense-core vesicles [10,11].…”

Section: Introductionmentioning

confidence: 99%

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Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration

et al. 2006

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Aims/hypothesis: The role of gamma-aminobutyric acid (GABA) and A-type GABA receptors (GABA A Rs) in modulating islet endocrine function has been actively investigated since the identification of GABA and GABA A Rs in the pancreatic islets. However, the reported effects of GABA A R activation on insulin secretion from islet beta cells have been controversial. Methods: This study examined the hypothesis that the effect of GABA on beta cell insulin secretion is dependent on glucose concentration. Results: Perforated patchclamp recordings in INS-1 cells demonstrated that GABA, at concentrations ranging from 1 to 1,000 μmol/l, induced a transmembrane current (I GABA ) which was sensitive to the GABA A R antagonist bicuculline. The current-voltage relationship revealed that I GABA reversed at −42±2.2 mV, independently of glucose concentration. Nevertheless, the glucose concentration critically controlled the membrane potential (V M ), i.e., at low glucose (0 or 2.8 mmol/l) the endogenous V M of INS-1 cells was below the I GABA reversal potential and at high glucose (16.7 or 28 mmol/l), the endogenous V M of INS-1 cells was above the I GABA reversal potential. Therefore, GABA dose-dependently induced membrane depolarisation at a low glucose concentration, but hyperpolarisation at a high glucose concentration. Consistent with electrophysiological findings, insulin secretion assays demonstrated that at 2.8 mmol/l glucose, GABA increased insulin secretion in a dose-dependent fashion (p<0.05, n=7). This enhancement was blocked by bicuculline (p<0.05, n=4). In contrast, in the presence of 28 mmol/l glucose, GABA suppressed the secretion of insulin (p<0.05, n=5). Conclusions/interpretation: These findings indicate that activation of GABA A Rs in beta cells regulates insulin secretion in concert with changes in glucose levels.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration

et al. 2006

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“…Abdominal obesity is associated with an increase in insulin resistance, which might offer an explanation for the fact that obese women with PCO are more likely to be hirsute and have menstrual irregularities than those who are lean [30]. However, with respect to clincial findings and 14.0 (± 33.6) 6.0 (± 1.7) 16.6 (± 38.5) 10.5 (± 9.0) 6.0 (± 1.7) 11.0 (± 9) NS 1, 2, 3 Proinsulin (pmol/l) 7.5 (± 3.3) 6.5 (± 3.9) 7.8 (± 3. laboratory data the whole group of women with PCO did not reveal significant differences compared with the women without PCO. Furthermore we could not find an increase in menstrual disturbances or of the incidence of PCO in women with VPA treatment compared with the CBZ group, as had been described in the published studies of Isojärvi, et al [18,19,20].…”

Section: Discussionmentioning

confidence: 89%

“…Valproate is a fatty acid derivative and thus might modulate insulin secreation as well as insulin sensitivity [7,15,23,32]. Moreover, GABA-ergic mechanisms were found to pancreatic islet function [14,33]. The increased appetite and weight gain reported by some patients on valproate might then be a consequence of an increase in postprandial insulin secretion.…”

Section: Discussionmentioning

confidence: 97%

Polycystic ovaries, obesity and insulin resistance in women with epilepsy

Luef¹,

Abraham²,

Haslinger³

et al. 2002

Journal of Neurology

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In order to investigate the possible role of valproic acid therapy in the development of obesity, hyperinsulinism and polycystic ovaries (PCOs), we have studied metabolic parameters and ovarian morphology in epileptic women. A total of 105 women, who were treated for at least 2 years with valproate (n = 52) or carbamazepine monotherapy (n = 53), were included in the examination. Menstrual disturbances were reported by 29 (28 %) of the women, 12 (11 %) of the VPA treated women, and 17 (16 %) in the CBZ group. On ultrasound scan polycystic ovaries were found in 28 patients (27 %) of the whole study population, of whom 13 (12 %) received VPA and 15 (14 %) CBZ. The mean body mass index (BMI) was significantly higher in the VPA group (24.4 kg/m(2) +/- 4.1) than in CBZ treated patients (22.9 kg/m(2) +/- 2.4;p < 0.022), and serum triglycerides tended to be increased, while total cholesterol values (178.9 +/- 30.5) and LDL-cholesterol values (92.6 +/- 27.4) were significantly lower in the valproate group, than in the carbamazepine group (207.1 +/- 43.0 vs 115.1 +/- 42.0; p < 0.001). Postprandial insulin, C-peptide and proinsulin levels were significantly higher in VPA treated patients compared with those treated with CBZ, while no differences could be found in the fasting state. In conclusion we could thus demonstrate that the frequency of PCOs in 27 % of epileptic women seems to be similar to that in the general population with a frequency of 20-30 %. The development of PCOs did not reveal a difference with the administration of VPA or CBZ. With respect to the metabolic side-effects of VPA therapy our data indicate that VPA increases glucose stimulated pancreatic insulin secretion, which might be followed by an increase in body weight.

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Differential expression of GABAA receptor π subunit in cultured rat alveolar epithelial cells

et al. 2005

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Although type A gamma-aminobutyric acid (GABA) receptors (ligand-gated Cl(-) channels) have been extensively studied in the central nervous system, no information is available on this receptor in lung cells. We have examined the expression of GABA(A) receptor pi-subunit (GABRP) during the trans-differentiation between rat alveolar epithelial type II cells and type I cells. Rat alveolar type II cells, when cultured on plastic plates, gradually trans-differentiated into type-I-like cells and lost their GABRP mRNA expression. However, the GABRP mRNA was partially retained in the type II cells cultured on Matrigel. Keratinocyte growth factor (a mitogen of type II cells) increased GABRP expression. A detached collagen gel maintained the GABRP mRNA to a level close to that of the freshly isolated type II cells. An air-liquid interface culture system, mimicking in vivo conditions in the lung, significantly up-regulated the expression of GABRP mRNA and protein. mRNAs of the GABA(A) receptor alpha1-, alpha3-, beta2-, gamma2-, and gamma3-subunits were also detected in rat type II cells. These results suggest that GABRP expression is differentially regulated by culture substrata, growth factor, detached gel, and an air-apical surface.

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Expression of Functional GABA_A Receptors in Isolated Human Insulinoma Cells

Cited by 18 publications

References 12 publications

Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration

Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration

Polycystic ovaries, obesity and insulin resistance in women with epilepsy

Differential expression of GABAA receptor π subunit in cultured rat alveolar epithelial cells

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Expression of Functional GABAA Receptors in Isolated Human Insulinoma Cells

Cited by 18 publications

References 12 publications

Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration

Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration

Polycystic ovaries, obesity and insulin resistance in women with epilepsy

Differential expression of GABAA receptor π subunit in cultured rat alveolar epithelial cells

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Expression of Functional GABA_A Receptors in Isolated Human Insulinoma Cells