Hyocholic acid species and the risk of type 2 diabetes

Xiaojiao Zheng; Tianlu Chen; Runqiu Jiang; Aihua Zhao; Fengjie Huang; Yunjing Zhang; Xiaolong Han; Mengci Li; Meilin Wei; Yijun You; Shouli Wang; Xiaojing Ma; Yuqian Bao; Miao Jiang; Jiajian Liu; Qing Zhao; Kun Ge; Bing Dong; Defa Li; Dandan Liang; Sha Lei; Yitao Li; Ke Lan; Aiping Lü; Weituo Zhang; Congrong Wang; Haoyong Yu; Cynthia Rajani; Jun Panee; Guoxiang Xie

doi:10.1101/503532

Systems BiologybioRxivDec 21, 2018

Preprint

Hyocholic acid species and the risk of type 2 diabetes

Xiaojiao Zheng iD, Tianlu Chen iD, Runqiu Jiang iD, Aihua Zhao iD, Fengjie Huang iD, Yunjing Zhang iD, Xiaolong Han, Mengci Li iD, Meilin Wei iD, Yijun You iD, Shouli Wang iD, Xiaojing Ma iD, Yuqian Bao iD, Miao Jiang iD, Jiajian Liu iD, Qing Zhao iD, Kun Ge, Bing Dong iD, Defa Li iD, Dandan Liang iD, Sha Lei iD, Yitao Li iD, Ke Lan iD, Aiping Lü iD, Weituo Zhang, , Wei Jia iD

Abstract

Hyocholic acid (HCA) and its derivatives are found in only trace amounts in human blood, but constitute approximately 76 % of the bile acid (BA) pool in the pig, a species known for its exceptional resistance to type 2 diabetes mellitus (T2DM). Here we show that HCA species play a crucial role in maintaining glucose homeostasis and preventing T2DM. We found that in two cohort studies (n=1,213), both obesity and diabetes were associated with lower serum concentrations of HCA species. Serum HCA levels in apparently healthy individuals (n=132) were found to be strong predictors for metabolic health 10 years later. Oral administration of HCA increased serum fasting GLP-1, to a greater extent than metformin, in healthy and diabetic mouse models. HCA upregulated GLP-1 secretion in intestinal enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor, a unique mechanism that is not found in other BA species.

PDF DOI