Background: 

Bile acids (BAs) function as signalling molecules in several metabolic pathways mainly in the liver to affect insulin action and to interfere with glucose homeostasis. The aim of the study was to test whether BAs influence stimulus-secretion coupling in pancreatic beta-cells.

Methodology: 

Ion currents and the membrane potential (V_m) of mouse beta-cells were measured with the patch-clamp technique, cytosolic Ca²⁺ concentration ([Ca²⁺]_c) by fura-2 and insulin secretion by RIA.

Results: 

Taurochenodeoxycholic acid (TCDC) increased [Ca²⁺]_c (n=9, p<=0.012) in physiological concentrations which resulted in enhanced glucose-induced insulin secretion (GIIS) (n=7, p<=0.025). V_m was depolarised and beta-cell electrical activity was stimulated by TCDC due to inhibition of K_ATP current (n=9, p<=0.0005). In excised i/o patches TCDC had no effect (n=11). It is known that BAs interact with the nuclear farnesoid X receptor (FXR) that is involved in the regulation of glucose and energy homeostasis. The specific FXR agonist GW4064 mimicked the effects of TCDC on stimulus-secretion coupling. GW4064 depolarized V_m (n=5, p<=0.0065), triggered Ca²⁺ influx and enhanced GIIS (n=10, p<=0.029). In contrast, ursodeoxycholat (UDC) that had a much lower affinity to FXR than TCDC did not change [Ca²⁺]_c (n=7). Likewise, all effects could be suppressed by the FXR antagonist guggulsterone indicating that FXR activation is indispensable for the stimulatory effects of TCDC. In islets of SUR1-KO mice (n=8) lacking functional K_ATP channels and FXR-KO mice (n=6) TCDC did not alter GIIS.

Conclusion: 

The results provide evidence for a novel link between FXR activation and inhibition of K_ATP channels. BA signalling in beta-cells may provide a further link between food intake and the control of insulin secretion.