Objective: We have shown previously that bile acids (BAs) directly interfere with beta-cell Ca2+ homeostasis. We evaluated now the BA-induced changes in stimulus-secretion coupling (SSC). Method: Taurochenodeoxycholic acid (TCDC) was used as lead substance. Ion currents and the membrane potential (Vm) were measured with the patch-clamp technique, cytosolic Ca2+ concentration ([Ca2+]c) by fura-2 and insulin secretion by RIA. Results: TCDC increased [Ca2+]c at threshold and high glucose concentrations. This was due to Ca2+ influx through L-type Ca2+ channels. Accordingly, glucose-induced (15 mM) insulin secretion was enhanced by 10 mM (n=24, p<=0.002) and 500 nM TCDC (n=7, p<=0.03) in steady-state incubations of 1 h. We further tested TCDC on glucose-induced electrical activity of beta-cells. The fraction of plateau phase (FOPP), i.e. the percentage of time with spike activity, increased from 27.3±4.4 % to 44.3±6.0 % in the presence of 5 mM TCDC (n=7, p<=0.001). At a threshold glucose concentration (6 mM) TCDC (10 mM) depolarized Vm and action potentials appeared (n=8, p<=0.001). The underlying depolarisation was evoked by closure of K_ATP channels by 10 mM TCDC (n=9, p<=0.0005). The specific farnesoid X receptor (FXR) agonist GW4064 activated Ca2+ influx in the same concentration range as TCDC. GW4064 (10 mM) depolarized Vm and the FOPP augmented from 46.4±4.3 % to 56.4±5.5 % (n=5, P<=0.01) and induced action potentials at a threshold glucose concentration (6-7 mM) (n=7). In addition, the BA ursodeoxycholic acid (500 nM) which does not act via the FXR did not change [Ca2+]c at 15 mM glucose (n=7). Conclusion: Certain BAs interfere at physiologic concentrations with SSC of beta-cells by inducing closure of K_ATP channels and subsequent events culminating in insulin secretion. This effect is most likely mediated by the FX-receptor. Thus, BA signalling in beta-cells may provide a further link between food intake and the control of insulin secretion.