Bile acids acutely stimulate insulin secretion of mouse β-cells via farnesoid X receptor activation and [K.sub.ATP] channel inhibition

Type 2 diabetes mellitus is associated with alterations in bile acid (BA) signaling. The aim of our study was to test whether pancreatic β-cells contribute to BA-dependent regulation of glucose homeostasis. Experiments were performed with islets from wild-type, farnesoid X receptor (FXR) knockout (K...

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Veröffentlicht in:Diabetes (New York, N.Y.) N.Y.), 2012-06, Vol.61 (6), p.1479
Hauptverfasser: Dufer, Martina, Horth, Katrin, Wagner, Rebecca, Schittenhelm, Bjorn, Prowald, Susanne, Wagner, Thomas F.J, Oberwinkler, Johannes, Lukowski, Robert, Gonzalez, Frank J, Krippeit-Drews, Peter, Drews, Gisela
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container_end_page
container_issue 6
container_start_page 1479
container_title Diabetes (New York, N.Y.)
container_volume 61
creator Dufer, Martina
Horth, Katrin
Wagner, Rebecca
Schittenhelm, Bjorn
Prowald, Susanne
Wagner, Thomas F.J
Oberwinkler, Johannes
Lukowski, Robert
Gonzalez, Frank J
Krippeit-Drews, Peter
Drews, Gisela
description Type 2 diabetes mellitus is associated with alterations in bile acid (BA) signaling. The aim of our study was to test whether pancreatic β-cells contribute to BA-dependent regulation of glucose homeostasis. Experiments were performed with islets from wild-type, farnesoid X receptor (FXR) knockout (KO), and β-cell ATP-dependent [K.sup.+] ([K.sub.ATP]) channel gene SUR1 (ABCC8) KO mice, respectively. Sodium taurochenodeoxycholate (TCDC) increased glucose-induced insulin secretion. This effect was mimicked by the FXR agonist GW4064 and suppressed by the FXR antagonist guggulsterone. TCDC and GW4064 stimulated the electrical activity of β-cells and enhanced cytosolic [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.c]). These effects were blunted by guggulsterone. Sodium ursodeoxycholate, which has a much lower affinity to FXR than TCDC, had no effect on [[[Ca.sup.2+]].sub.c] and insulin secretion. FXR activation by TCDC is suggested to inhibit [K.sub.ATP] current. The decline in [K.sub.ATP] channel activity by TCDC was only observed in β-cells with intact metabolism and was reversed by guggulsterone. TCDC did not alter insulin secretion in islets of SUR1-KO or FXR-KO mice. TCDC did not change islet cell apoptosis. This is the first study showing an acute action of BA on β-cell function. The effect is mediated by FXR by nongenomic elements, suggesting a novel link between FXR activation and [K.sub.ATP] channel inhibition.
doi_str_mv 10.2337/db11-0815
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The decline in [K.sub.ATP] channel activity by TCDC was only observed in β-cells with intact metabolism and was reversed by guggulsterone. TCDC did not alter insulin secretion in islets of SUR1-KO or FXR-KO mice. TCDC did not change islet cell apoptosis. This is the first study showing an acute action of BA on β-cell function. 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The aim of our study was to test whether pancreatic β-cells contribute to BA-dependent regulation of glucose homeostasis. Experiments were performed with islets from wild-type, farnesoid X receptor (FXR) knockout (KO), and β-cell ATP-dependent [K.sup.+] ([K.sub.ATP]) channel gene SUR1 (ABCC8) KO mice, respectively. Sodium taurochenodeoxycholate (TCDC) increased glucose-induced insulin secretion. This effect was mimicked by the FXR agonist GW4064 and suppressed by the FXR antagonist guggulsterone. TCDC and GW4064 stimulated the electrical activity of β-cells and enhanced cytosolic [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.c]). These effects were blunted by guggulsterone. Sodium ursodeoxycholate, which has a much lower affinity to FXR than TCDC, had no effect on [[[Ca.sup.2+]].sub.c] and insulin secretion. FXR activation by TCDC is suggested to inhibit [K.sub.ATP] current. 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source Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals; PubMed Central
subjects Bile acids
Pancreatic beta cells
Physiological aspects
Potassium channels
title Bile acids acutely stimulate insulin secretion of mouse β-cells via farnesoid X receptor activation and [K.sub.ATP] channel inhibition
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