Question:

Development of type 2 diabetes mellitus coincides with alterations in the size and composition of the bile acid (BA) pool. We have recently shown that the BA taurochenodeoxycholic acid increases insulin release via FXR-dependent inhibition of K_ATP channels.

Methods:

Islets were isolated from wildtype (WT) and FXR knockout (FXR-KO) mice. [Ca²⁺]c was determined by fura-2 fluorescence and insulin release was quantified by a radioimmunoassay. High fat diet (HFD) was applied to WT and FXR-KO mice for 12 weeks.

Results:

The BAs taurochenodeoxycholate (TCDC), chenodeoxycholate (CDC), and glycochenodeoxycholate (GCDC) increased glucose-induced insulin release after 1 h of incubation. These effects were absent in islets lacking the BA receptor FXR. In agreement with a stimulatory effect on insulin release TCDC, CDC and GCDC augmented [Ca²⁺]_c. However, in beta-cells of FXR-KO the BAs had no influence on [Ca²⁺]_c. The effect of TCDC on insulin secretion was mimicked by the FXR agonist GW4064 and prevented by the FXR antagonist guggulsterone. Ursochenodeoxycholate (UDC) that has no affinity to FXR showed inhibitory and stimulatory effects, respectively, depending on the incubation time. The FXR-KO protected against HFD-induced impairment of fasting glucose concentration and glucose tolerance (12 weeks HFD). These effects were not due to differences in body weight or insulin resistance.

Conclusion:

BAs that activate FXR increase insulin secretion. Surprisingly, under HFD conditions the FXR-KO mice profit from the lack of this receptor, seemingly contradictory to the in vitro data. Obviously, the nutritional status of the animals critically determines the effects of FXR on glucose tolerance.