Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans

Shiqi Zhong, Raphael Chèvre, 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. HaydenChing Yu Cheng, Shaji Chacko, Jason Flannick, Xueling Sim, Hong Chang Tan, Roshni R. Singaraja*

*Corresponding author voor dit werk

    OnderzoeksoutputAcademicpeer review

    16 Citaten (Scopus)
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    Samenvatting

    BACKGROUND. Cytochrome P450 family 8 subfamily B member 1 (CYP8B1) generates 12α-hydroxylated bile acids (BAs) that are associated with insulin resistance in humans.

    METHODS. To determine whether 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 with age-, sex-, 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 mutation-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 found 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. Biomedical Research Council/National Medical Research Council of Singapore.

    Originele taal-2English
    Artikelnummere152961
    Aantal pagina's12
    TijdschriftThe Journal of Clinical Investigation
    Volume132
    Nummer van het tijdschrift21
    DOI's
    StatusPublished - 1-nov.-2022

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