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Title: Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans
Authors: Zhong, 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 
Keywords: Endocrinology
Insulin signaling
Steroid 12-alpha-Hydroxylase
Insulin Resistance
Bile Acids and Salts
Cholic Acid
Issue Date: 1-Nov-2022
Publisher: American Society for Clinical Investigation
Citation: Zhong, 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.
Abstract: BACKGROUNDCytochrome 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.
Source Title: The Journal of clinical investigation
ISSN: 00219738
DOI: 10.1172/JCI152961
Appears in Collections:Staff Publications

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