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

Taneera J, Jin Z, Jin Y, Muhammed SJ, Zhang E, Lang S, Salehi A, Korsgren O, Renström E, Groop L, Birnir B - Diabetologia (2012)

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

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences, Lund University Diabetes Center, University Hospital Malmö, Lund University, Malmö, Sweden.

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.

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Related in: MedlinePlus

GABAA channel and GABAB receptor antagonists increase hormone release in pancreatic islets from normoglycaemic and type 2 diabetic individuals. a Insulin release was increased in 1 mmol/l glucose (1G) but decreased in 16.7 mmol/l glucose (16.7G) in islets from type 2 diabetic individuals (black bar) compared with those from normoglycaemic individuals (grey bar). SR95531, a GABAA channel antagonist, at a concentration of 10 μmol/l did not modulate insulin release. b Glucagon release was increased in 16.7 but not 1 mmol/l glucose in islets from type 2 diabetic individuals compared with those from normoglycaemic donors. SR95531 (10 μmol/l) increased glucagon release at both glucose concentrations in islets from type 2 diabetic and normoglycaemic individuals. c Insulin release was increased by the GABAB antagonist, CGP55845 (10 μmol/l) in 16.7 but not 1 mmol/l glucose in islets from type 2 diabetic and normoglycaemic individuals. d Glucagon release was not affected by CGP55845 (10 μmol/l). Grey bars: n = 19–31 from four to six normoglycaemic individuals. Black bars: n = 19 from three type 2 diabetic donors. Data are presented as mean ± SEM; *p < 0.05, ***p < 0.001. e Correlation of the α1 GABAA subunit gene expression with insulin secretion measured at 16.7 mmol/l glucose and HbA1c level. A negative correlation with HbA1c (black circles; n = 51; R = 0.3724; p = 0.0071) and no correlation with insulin (grey circles; n = 53; R = 0.1655; p = 0.2363) were observed. Correlation analysis was performed using non-parametric Spearman’s test. f Correlation of the α2 GABAA subunit gene expression with insulin secretion measured at 16.7 mmol/l glucose and HbA1c level. A negative correlation with HbA1c (black circles; n = 51; R = 0.6453; p < 0.0001) and positive correlation with insulin (grey circles; n = 53; R = 0.4790; p = 0.0003) were observed. Correlation analysis was performed using non-parametric Spearman’s test. NB To convert values for HbA1c in % into mmol/mol, subtract 2.15 and multiply by 10.929
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Fig5: GABAA channel and GABAB receptor antagonists increase hormone release in pancreatic islets from normoglycaemic and type 2 diabetic individuals. a Insulin release was increased in 1 mmol/l glucose (1G) but decreased in 16.7 mmol/l glucose (16.7G) in islets from type 2 diabetic individuals (black bar) compared with those from normoglycaemic individuals (grey bar). SR95531, a GABAA channel antagonist, at a concentration of 10 μmol/l did not modulate insulin release. b Glucagon release was increased in 16.7 but not 1 mmol/l glucose in islets from type 2 diabetic individuals compared with those from normoglycaemic donors. SR95531 (10 μmol/l) increased glucagon release at both glucose concentrations in islets from type 2 diabetic and normoglycaemic individuals. c Insulin release was increased by the GABAB antagonist, CGP55845 (10 μmol/l) in 16.7 but not 1 mmol/l glucose in islets from type 2 diabetic and normoglycaemic individuals. d Glucagon release was not affected by CGP55845 (10 μmol/l). Grey bars: n = 19–31 from four to six normoglycaemic individuals. Black bars: n = 19 from three type 2 diabetic donors. Data are presented as mean ± SEM; *p < 0.05, ***p < 0.001. e Correlation of the α1 GABAA subunit gene expression with insulin secretion measured at 16.7 mmol/l glucose and HbA1c level. A negative correlation with HbA1c (black circles; n = 51; R = 0.3724; p = 0.0071) and no correlation with insulin (grey circles; n = 53; R = 0.1655; p = 0.2363) were observed. Correlation analysis was performed using non-parametric Spearman’s test. f Correlation of the α2 GABAA subunit gene expression with insulin secretion measured at 16.7 mmol/l glucose and HbA1c level. A negative correlation with HbA1c (black circles; n = 51; R = 0.6453; p < 0.0001) and positive correlation with insulin (grey circles; n = 53; R = 0.4790; p = 0.0003) were observed. Correlation analysis was performed using non-parametric Spearman’s test. NB To convert values for HbA1c in % into mmol/mol, subtract 2.15 and multiply by 10.929

Mentions: In islets from both normoglycaemic and type 2 diabetic donors, 16.7 mmol/l glucose stimulated insulin secretion and reduced glucagon secretion relative to the secretion observed in response to 1 mmol/l glucose (ESM Fig. 2). To study the effects of GABA on insulin and glucagon release, we examined the effects of the GABAA and GABAB antagonists, SR95531 (10 μmol/l, Fig. 5a, b) and CGP55845 (10 μmol/l, Fig. 5c, d), on hormone secretion in islets from normoglycaemic and type 2 diabetic individuals incubated with basal (1 mmol/l) or high-concentration (16.7 mmol/l) glucose.Fig. 5


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

Taneera J, Jin Z, Jin Y, Muhammed SJ, Zhang E, Lang S, Salehi A, Korsgren O, Renström E, Groop L, Birnir B - Diabetologia (2012)

GABAA channel and GABAB receptor antagonists increase hormone release in pancreatic islets from normoglycaemic and type 2 diabetic individuals. a Insulin release was increased in 1 mmol/l glucose (1G) but decreased in 16.7 mmol/l glucose (16.7G) in islets from type 2 diabetic individuals (black bar) compared with those from normoglycaemic individuals (grey bar). SR95531, a GABAA channel antagonist, at a concentration of 10 μmol/l did not modulate insulin release. b Glucagon release was increased in 16.7 but not 1 mmol/l glucose in islets from type 2 diabetic individuals compared with those from normoglycaemic donors. SR95531 (10 μmol/l) increased glucagon release at both glucose concentrations in islets from type 2 diabetic and normoglycaemic individuals. c Insulin release was increased by the GABAB antagonist, CGP55845 (10 μmol/l) in 16.7 but not 1 mmol/l glucose in islets from type 2 diabetic and normoglycaemic individuals. d Glucagon release was not affected by CGP55845 (10 μmol/l). Grey bars: n = 19–31 from four to six normoglycaemic individuals. Black bars: n = 19 from three type 2 diabetic donors. Data are presented as mean ± SEM; *p < 0.05, ***p < 0.001. e Correlation of the α1 GABAA subunit gene expression with insulin secretion measured at 16.7 mmol/l glucose and HbA1c level. A negative correlation with HbA1c (black circles; n = 51; R = 0.3724; p = 0.0071) and no correlation with insulin (grey circles; n = 53; R = 0.1655; p = 0.2363) were observed. Correlation analysis was performed using non-parametric Spearman’s test. f Correlation of the α2 GABAA subunit gene expression with insulin secretion measured at 16.7 mmol/l glucose and HbA1c level. A negative correlation with HbA1c (black circles; n = 51; R = 0.6453; p < 0.0001) and positive correlation with insulin (grey circles; n = 53; R = 0.4790; p = 0.0003) were observed. Correlation analysis was performed using non-parametric Spearman’s test. NB To convert values for HbA1c in % into mmol/mol, subtract 2.15 and multiply by 10.929
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Fig5: GABAA channel and GABAB receptor antagonists increase hormone release in pancreatic islets from normoglycaemic and type 2 diabetic individuals. a Insulin release was increased in 1 mmol/l glucose (1G) but decreased in 16.7 mmol/l glucose (16.7G) in islets from type 2 diabetic individuals (black bar) compared with those from normoglycaemic individuals (grey bar). SR95531, a GABAA channel antagonist, at a concentration of 10 μmol/l did not modulate insulin release. b Glucagon release was increased in 16.7 but not 1 mmol/l glucose in islets from type 2 diabetic individuals compared with those from normoglycaemic donors. SR95531 (10 μmol/l) increased glucagon release at both glucose concentrations in islets from type 2 diabetic and normoglycaemic individuals. c Insulin release was increased by the GABAB antagonist, CGP55845 (10 μmol/l) in 16.7 but not 1 mmol/l glucose in islets from type 2 diabetic and normoglycaemic individuals. d Glucagon release was not affected by CGP55845 (10 μmol/l). Grey bars: n = 19–31 from four to six normoglycaemic individuals. Black bars: n = 19 from three type 2 diabetic donors. Data are presented as mean ± SEM; *p < 0.05, ***p < 0.001. e Correlation of the α1 GABAA subunit gene expression with insulin secretion measured at 16.7 mmol/l glucose and HbA1c level. A negative correlation with HbA1c (black circles; n = 51; R = 0.3724; p = 0.0071) and no correlation with insulin (grey circles; n = 53; R = 0.1655; p = 0.2363) were observed. Correlation analysis was performed using non-parametric Spearman’s test. f Correlation of the α2 GABAA subunit gene expression with insulin secretion measured at 16.7 mmol/l glucose and HbA1c level. A negative correlation with HbA1c (black circles; n = 51; R = 0.6453; p < 0.0001) and positive correlation with insulin (grey circles; n = 53; R = 0.4790; p = 0.0003) were observed. Correlation analysis was performed using non-parametric Spearman’s test. NB To convert values for HbA1c in % into mmol/mol, subtract 2.15 and multiply by 10.929
Mentions: In islets from both normoglycaemic and type 2 diabetic donors, 16.7 mmol/l glucose stimulated insulin secretion and reduced glucagon secretion relative to the secretion observed in response to 1 mmol/l glucose (ESM Fig. 2). To study the effects of GABA on insulin and glucagon release, we examined the effects of the GABAA and GABAB antagonists, SR95531 (10 μmol/l, Fig. 5a, b) and CGP55845 (10 μmol/l, Fig. 5c, d), on hormone secretion in islets from normoglycaemic and type 2 diabetic individuals incubated with basal (1 mmol/l) or high-concentration (16.7 mmol/l) glucose.Fig. 5

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

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences, Lund University Diabetes Center, University Hospital Malmö, Lund University, Malmö, Sweden.

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.

Show MeSH
Related in: MedlinePlus