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...
Gespeichert in:
Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2012-06, Vol.61 (6), p.1479 |
---|---|
Hauptverfasser: | , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | 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. |
---|---|
ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/db11-0815 |