Bile acids acutely stimulate insulin secretion of mouse ?-cells via farnesoid X receptor activation and K(ATP) channel inhibition.

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Bile acids acutely stimulate insulin secretion of mouse ?-cells via farnesoid X receptor activation and K(ATP) channel inhibition.

Diabetes. 2012 Jun;61(6):1479-89

Authors: D�fer M, H�rth K, Wagner R, Schittenhelm B, Prowald S, Wagner TF, Oberwinkler J, Lukowski R, Gonzalez FJ, Krippeit-Drews P, Drews G

Abstract
Type 2 diabetes mellitus is associated with alterations in bile acid (BA) signaling. The aim of our study was to test whether pancreatic ?-cells contribute to BA-dependent regulation of glucose homeostasis. Experiments were performed with islets from wild-type, farnesoid X receptor (FXR) knockout (KO), and ?-cell ATP-dependent K(+) (K(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 ?-cells and enhanced cytosolic Ca(2+) concentration ([Ca(2+)](c)). These effects were blunted by guggulsterone. Sodium ursodeoxycholate, which has a much lower affinity to FXR than TCDC, had no effect on [Ca(2+)](c) and insulin secretion. FXR activation by TCDC is suggested to inhibit K(ATP) current. The decline in K(ATP) channel activity by TCDC was only observed in ?-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 ?-cell function. The effect is mediated by FXR by nongenomic elements, suggesting a novel link between FXR activation and K(ATP) channel inhibition.

PMID: 22492528 [PubMed - indexed for MEDLINE]

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