Bile acids acutely stimulate insulin secretion of mouse [beta]-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 [beta]-cells contribute to BA-dependent regulation of glucose homeostasis. Experiments were performed with islets from wild-type, farnesoid X receptor (FXR) knockout (KO), and [beta]-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 [beta]-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 [beta]-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 [beta]-cell function. The effect is mediated by FXR by nongenomic elements, suggesting a novel link between FXR activation and [K.sub.ATP] channel inhibition.