Hyocholic acid (HCA) and its derivatives are found in trace amounts in human blood but constitute approximately 76% of the bile acid (BA) pool in pigs, a species known for its exceptional resistance to type 2 diabetes. Here, we show that BA depletion in pigs suppressed secretion of glucagon-like peptide-1 (GLP-1) and increased blood glucose levels. HCA administration in diabetic mouse models improved serum fasting GLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholic acid. HCA upregulated GLP-1 production and secretion in enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor (FXR), a unique mechanism that is not found in other BA species. We verified the findings in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor inhibition mouse models. Finally, we confirmed in a clinical cohort, that lower serum concentrations of HCA species were associated with diabetes and closely related to glycemic markers.

水胆酸 (HCA) 及其衍生物在人体血液中存在痕量，但占猪胆汁酸 (BA) 池的约 76%，猪胆汁酸 (BA) 以对 2 型糖尿病的出色抵抗力而闻名。在这里，我们表明猪的 BA 消耗抑制了胰高血糖素样肽-1 (GLP-1) 的分泌并增加了血糖水平。糖尿病小鼠模型中的 HCA 给药比牛磺熊去氧胆酸在更大程度上改善了血清空腹 GLP-1 分泌和葡萄糖稳态。HCA 通过同时激活 G 蛋白偶联 BA 受体 TGR5 和抑制法尼醇 X 受体 (FXR) 上调肠内分泌细胞中 GLP-1 的产生和分泌，这是在其他 BA 物种中未发现的独特机制。我们验证了 TGR5 敲除、肠道 FXR 激活、和 GLP-1 受体抑制小鼠模型。最后，我们在一个临床队列中证实，HCA 种类的较低血清浓度与糖尿病相关，并且与血糖标志物密切相关。