Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans

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Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans
Title:
Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans
Other Titles:
Journal of Clinical Investigation
Publication Date:
15 September 2022
Citation:
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:
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.
License type:
Attribution 4.0 International (CC BY 4.0)
Funding Info:
This research / project is supported by the National Medical Research Council (NMRC)/ Biomedical Research Council (BMRC) - Bench and Bedside grant
Grant Reference no. : BnB13Dec011
Description:
ISSN:
1558-8238
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