Bile Acids Acutely Stimulate Insulin Secretion of Mouse β-Cells via Farnesoid X Receptor Activation and KATP Channel Inhibition
- Martina Düfer1⇓,
- Katrin Hörth1,
- Rebecca Wagner1,
- Björn Schittenhelm1,
- Susanne Prowald1,
- Thomas F.J. Wagner2,
- Johannes Oberwinkler3,
- Robert Lukowski1,
- Frank J. Gonzalez4,
- Peter Krippeit-Drews1 and
- Gisela Drews1
- 1Department of Pharmacology, Institute of Pharmacy, University of Tübingen, Tübingen, Germany
- 2Department of Cell Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California
- 3Institute of Physiology and Pathophysiology, University of Marburg, Marburg, Germany
- 4National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Corresponding author: Martina Düfer, .
M.D. and K.H. contributed equally to this study.
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+ (KATP) 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 Ca2+ concentration ([Ca2+]c). These effects were blunted by guggulsterone. Sodium ursodeoxycholate, which has a much lower affinity to FXR than TCDC, had no effect on [Ca2+]c and insulin secretion. FXR activation by TCDC is suggested to inhibit KATP current. The decline in KATP 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 KATP channel inhibition.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0815/-/DC1.
- Received June 15, 2011.
- Accepted February 7, 2012.
- © 2012 by the American Diabetes Association.
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