Department of Pharmacology, Institute of Pharmacy, University of Tübingen, Tübingen, Germany.
Diabetes. 2012 Jun;61(6):1479-89. doi: 10.2337/db11-0815. Epub 2012 Apr 9.
Type 2 diabetes mellitus is associated with alterations in bile acid (BA) signaling. The aim of our study was to test whether pancreatic β-cells contribute to BA-dependent regulation of glucose homeostasis. Experiments were performed with islets from wild-type, farnesoid X receptor (FXR) knockout (KO), and β-cell ATP-dependent K(+) (K(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 β-cells and enhanced cytosolic Ca(2+) concentration (Ca(2+)). These effects were blunted by guggulsterone. Sodium ursodeoxycholate, which has a much lower affinity to FXR than TCDC, had no effect on Ca(2+) and insulin secretion. FXR activation by TCDC is suggested to inhibit K(ATP) current. The decline in K(ATP) channel activity by TCDC was only observed in β-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 β-cell function. The effect is mediated by FXR by nongenomic elements, suggesting a novel link between FXR activation and K(ATP) channel inhibition.
2 型糖尿病与胆汁酸（BA）信号转导的改变有关。我们的研究目的是测试胰岛β细胞是否有助于 BA 依赖的葡萄糖稳态调节。分别用野生型、法尼醇 X 受体（FXR）敲除（KO）和胰岛β细胞三磷酸腺苷依赖性钾（KATP）通道基因 SUR1（ABCC8）KO 小鼠的胰岛进行实验。牛磺胆酸钠（TCDC）增加葡萄糖诱导的胰岛素分泌。这种作用被 FXR 激动剂 GW4064 模拟，被 FXR 拮抗剂 guggulsterone 抑制。TCDC 和 GW4064 刺激β细胞的电活动并增强细胞浆 Ca2+浓度([Ca2+]（c）)。这些作用被 guggulsterone 减弱。牛磺熊脱氧胆酸钠（TCDC 的亲和力比 TCDC 低得多）对 [Ca2+]（c）和胰岛素分泌没有影响。TCDC 对 FXR 的激活被认为抑制 KATP 电流。TCDC 对 KATP 通道活性的下降仅在代谢完整的β细胞中观察到，并被 guggulsterone 逆转。TCDC 没有改变 SUR1-KO 或 FXR-KO 小鼠胰岛的胰岛素分泌。TCDC 没有改变胰岛细胞凋亡。这是第一项研究表明 BA 对β细胞功能具有急性作用。该作用通过非基因组元件介导 FXR，提示 FXR 激活和 KATP 通道抑制之间存在新的联系。
