Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans
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 a...
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-11-01
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| Series: | The Journal of Clinical Investigation |
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| Online Access: | https://doi.org/10.1172/JCI152961 |
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| author | 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. Hayden Ching-Yu Cheng Shaji Chacko Jason Flannick Xueling Sim Hong Chang Tan Roshni R. Singaraja |
| author_facet | 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. Hayden Ching-Yu Cheng Shaji Chacko Jason Flannick Xueling Sim Hong Chang Tan Roshni R. Singaraja |
| author_sort | Shiqi Zhong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:10:08Z |
| format | Article |
| id | doaj.art-d03f46bd050f440897a9444be497521e |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:10:08Z |
| publishDate | 2022-11-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-d03f46bd050f440897a9444be497521e2023-11-07T16:19:30ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-11-0113221Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humansShiqi ZhongRaphael ChèvreDavid Castaño MayanMaria CorlianòBlake J. CochranKai Ping SemTheo H. van DijkJianhe PengLiang Juin TanSiddesh V. HartimathBoominathan RamasamyPeter ChengAlbert K. GroenFolkert KuipersJulian L. GoggiChester DrumRob M. van DamRu San TanKerry-Anne RyeMichael R. HaydenChing-Yu ChengShaji ChackoJason FlannickXueling SimHong Chang TanRoshni R. SingarajaBACKGROUND 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.https://doi.org/10.1172/JCI152961Endocrinology |
| spellingShingle | 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. Hayden Ching-Yu Cheng Shaji Chacko Jason Flannick Xueling Sim Hong Chang Tan Roshni R. Singaraja Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans The Journal of Clinical Investigation Endocrinology |
| title | Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans |
| title_full | Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans |
| title_fullStr | Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans |
| title_full_unstemmed | Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans |
| title_short | Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans |
| title_sort | haploinsufficiency of cyp8b1 associates with increased insulin sensitivity in humans |
| topic | Endocrinology |
| url | https://doi.org/10.1172/JCI152961 |
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