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Acta Physiologica 2009; Volume 195, Supplement 669
The 88th Annual Meeting of The German Physiological Society
3/22/2009-3/25/2009
Giessen, Germany
BILE ACIDS AFFECT ELECTRICAL ACTIVITY AND [CA2+]C IN PANCREATIC BETA CELLS
Abstract number: P426
Drews1 G., Horth1 K., Dufer1 M., Krippeit-Drews1 P.
1Pharmakologie und Toxikologie, Pharmazeutisches Institut, Tbingen
Bile acids (BAs) are involved in cholesterol metabolism and facilitate digestion and absorption of dietary lipids. During the last years it became clear that BAs function as signalling molecules in several metabolic pathways. Especially in the liver BAs affect insulin action and thus interfere with glucose homeostasis.
We studied the effects of BAs on stimulus-secretion coupling to test whether BAs directly influence pancreatic beta cell function.
Taurochenodeoxycholic acid (Ta) at a low concentration (500 nM) yielded a significant increase of the cytosolic Ca2+ concentration ([Ca2+]c) (239% 56%, n=9, p<0,05) in isolated islet cells perifused with 15 mM glucose. In addition, Ta (10 mM) induced oscillations in [Ca2+]c (n=5) at a sub-threshold glucose concentration (5 mM). Experiments with the SERCA blocker thapsigargin did not affect the Ta-induced rise in [Ca2+]c (n=5), but the L-type Ca2+ channel blocker nifedipine completely suppressed it (n=4). This denotes that Ta activates Ca2+ influx. To analyse the mechanism underlying the Ta-induced rise in [Ca2+]c we tested the influence of Ta on the membrane potential (Vm). Decreasing the glucose concentration from 10 mM to 6 mM hyperpolarized Vm and action potentials ceased. The subsequent addition of Ta (10 mM) depolarized Vm and action potentials reappeared (n=8, p<0,001). Since BAs are ligands of the nuclear farnesoid X receptor (FXR), we tested whether the effects of Ta on beta cell stimulus-secretion coupling are mediated by this receptor. The specific FXR agonist GW4064 had very similar effects as Ta and acted in the same concentration range. GW4064 (500 nM) increased [Ca2+]c (197% 19%, n=13, p<0,001) at a supra-threshold glucose concentration (15 mM). The stimulating effects of Ta and GW4064 on [Ca2+]c (15 mM glucose) could be blocked by the FXR antagonist guggulsterone (n=9 and n=5, respectively). Similar to Ta, GW4064 (10 mM) induced action potentials at a sub-threshold glucose concentration (67 mM) (n=7).
We conclude that BAs at physiologic concentrations interfere with stimulus-secretion coupling pointing to a new signalling pathway in beta cells possibly mediated by the FXR receptor.
To cite this abstract, please use the following information:
Acta Physiologica 2009; Volume 195, Supplement 669 :P426