Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans

Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans

Journal of Clinical Investigation

10.1172/JCI152961

http://dx.doi.org/10.1172/jci152961

Shiqi Zhong, Raphael Chevre, David Castaño Mayan, Maria Corlianò, Blake J. Cochran, Kai Ping Sem, Theo H. van Dijk, Jianhe Peng, Liang Juin Tan, Siddesh V. Hartimath, Boominathan Ramasamy, Peter Cheng, Albert K. Groen, Folkert Kuipers, Julian L. Goggi, Chester Drum, Rob M. van Dam, Ru San Tan, Kerry-Anne Rye, Michael R. Hayden, Ching-Yu Cheng, Shaji Chacko, Jason Flannick, Xueling Sim, Hong Chang Tan, Roshni R. Singaraja

General Medicine

15 September 2022

Zhong, S., Chèvre, R., Castaño Mayan, D., Corlianò, M., Cochran, B. J., Sem, K. P., van Dijk, T. H., Peng, J., Tan, L. J., Hartimath, S. V., Ramasamy, B., Cheng, P., Groen, A. K., Kuipers, F., Goggi, J. L., Drum, C., van Dam, R. M., Tan, R. S., Rye, K.-A., … Singaraja, R. R. (2022). Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans. Journal of Clinical Investigation, 132(21). https://doi.org/10.1172/jci152961

Abstract Background: Cytochrome P450 Family 8 Subfamily B Member 1 (CYP8B1) generates 12α-hydroxylated bile acids (BAs) which were associated with insulin resistance in humans. Methods: To determine if reduced CYP8B1 activity improves insulin sensitivity, we sequenced CYP8B1 in individuals without diabetes and identified carriers of complete loss-of-function (CLOF) mutations utilizing functional assays. Results: Mutation carriers had lower plasma 12α-hydroxylated:non-12α-hydroxylated BA and cholic acid (CA):chenodeoxycholic acid (CDCA) ratios compared to age-, gender- and BMI-matched controls. During insulin clamps, hepatic glucose production was suppressed to a similar magnitude by insulin, but glucose infusion rates to maintain euglycemia were higher in mutation carriers, indicating increased peripheral insulin sensitivity. Consistently, a polymorphic CLOF CYP8B1 mutation associated with lower fasting insulin in the AMP-T2D-GENES study. Exposure of primary human muscle cells to carrier CA:CDCA ratios demonstrated increased FOXO1 activity, and upregulation of both insulin signaling and glucose uptake, which were mediated by increased CDCA. Inhibition of FOXO1 attenuated the CDCA-mediated increase in muscle insulin signaling and glucose uptake. We find that reduced CYP8B1 activity associates with increased insulin sensitivity in humans. Conclusion: Our findings suggest that increased circulatory CDCA due to reduced CYP8B1 activity increases skeletal muscle insulin sensitivity, contributing to increased whole-body insulin sensitization. Funding: This study was funded by BMRC/NMRC Bench and Bedside grant (BnB13Dec011) to HCT and RRS.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Medical Research Council (NMRC)/ Biomedical Research Council (BMRC) - Bench and Bedside grant
Grant Reference no. : BnB13Dec011

https://oar.a-star.edu.sg/communities-collections/articles/18730

1558-8238

Institute of Bioengineering and Bioimaging