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bioRxiv · 10.1101/503532

Hyocholic acid species and the risk of type 2 diabetes

Zheng, X.·Chen, T.·Jiang, R.·Zhao, A.·Huang, F.·Zhang, Y.·Han, X.·Li, M.·Wei, M.·You, Y.·Wang, S.·Ma, X.·Bao, Y.·Jiang, M.·Liu, J.·Zhao, Q.·Ge, K.·Dong, B.·Li, D.·Liang, D.·Lei, S.·Li, Y.·Lan, K.·Lu, A.·Zhang, W.·Wang, C.·Yu, H.·Rajani, C.·Panee, J.·Xie, G.·Jia, W.
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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.

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Zheng, X., Chen, T., Jiang, R., Zhao, A., Huang, F., Zhang, Y., Han, X., Li, M., Wei, M., You, Y., Wang, S., Ma, X., Bao, Y., Jiang, M., Liu, J., Zhao, Q., Ge, K., Dong, B., Li, D., Liang, D., Lei, S., Li, Y., Lan, K., Lu, A., Zhang, W., Wang, C., Yu, H., Rajani, C., Panee, J., Xie, G., Jia, W.. 2018-12-21. Hyocholic acid species and the risk of type 2 diabetes. https://doi.org/10.1101/503532

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