Please use this identifier to cite or link to this item: https://doi.org/10.1172/JCI152961
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dc.titleHaploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans
dc.contributor.authorZhong, S
dc.contributor.authorChèvre, R
dc.contributor.authorCastaño Mayan, D
dc.contributor.authorCorlianò, M
dc.contributor.authorCochran, BJ
dc.contributor.authorSem, KP
dc.contributor.authorvan Dijk, TH
dc.contributor.authorPeng, J
dc.contributor.authorTan, LJ
dc.contributor.authorHartimath, SV
dc.contributor.authorRamasamy, B
dc.contributor.authorCheng, P
dc.contributor.authorGroen, AK
dc.contributor.authorKuipers, F
dc.contributor.authorGoggi, JL
dc.contributor.authorDrum, C
dc.contributor.authorvan Dam, RM
dc.contributor.authorTan, RS
dc.contributor.authorRye, KA
dc.contributor.authorHayden, MR
dc.contributor.authorCheng, CY
dc.contributor.authorChacko, S
dc.contributor.authorFlannick, J
dc.contributor.authorSim, X
dc.contributor.authorTan, HC
dc.contributor.authorSingaraja, RR
dc.date.accessioned2022-11-18T03:06:46Z
dc.date.available2022-11-18T03:06:46Z
dc.date.issued2022-11-01
dc.identifier.citationZhong, S, Chèvre, R, Castaño Mayan, D, Corlianò, M, Cochran, BJ, Sem, KP, van Dijk, TH, Peng, J, Tan, LJ, Hartimath, SV, Ramasamy, B, Cheng, P, Groen, AK, Kuipers, F, Goggi, JL, Drum, C, van Dam, RM, Tan, RS, Rye, KA, Hayden, MR, Cheng, CY, Chacko, S, Flannick, J, Sim, X, Tan, HC, Singaraja, RR (2022-11-01). Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans. The Journal of clinical investigation 132 (21) : e152961-. ScholarBank@NUS Repository. https://doi.org/10.1172/JCI152961
dc.identifier.issn00219738
dc.identifier.issn15588238
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/234689
dc.description.abstractBACKGROUNDCytochrome P450 family 8 subfamily B member 1 (CYP8B1) generates 12α-hydroxylated bile acids (BAs) that are associated with insulin resistance in humans.METHODSTo 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.RESULTSMutation 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.CONCLUSIONOur findings suggest that increased circulatory CDCA due to reduced CYP8B1 activity increases skeletal muscle insulin sensitivity, contributing to increased whole-body insulin sensitization.FUNDINGBiomedical Research Council/National Medical Research Council of Singapore.
dc.publisherAmerican Society for Clinical Investigation
dc.sourceElements
dc.subjectEndocrinology
dc.subjectInsulin signaling
dc.subjectHumans
dc.subjectSteroid 12-alpha-Hydroxylase
dc.subjectInsulin Resistance
dc.subjectInsulin
dc.subjectHaploinsufficiency
dc.subjectBile Acids and Salts
dc.subjectCholic Acid
dc.subjectGlucose
dc.typeArticle
dc.date.updated2022-11-18T02:28:45Z
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.1172/JCI152961
dc.description.sourcetitleThe Journal of clinical investigation
dc.description.volume132
dc.description.issue21
dc.description.pagee152961-
dc.published.statePublished
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