Children’s Nutrition Research Center Staff Publications
Language
English
Publication Date
11-1-2022
Journal
Journal of Clinical Investigation
DOI
10.1172/JCI152961
PMID
36107630
PMCID
PMC9621133
PubMedCentral® Posted Date
11-1-2022
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Humans, Steroid 12-alpha-Hydroxylase, Insulin Resistance, Insulin, Haploinsufficiency, Bile Acids and Salts, Cholic Acid, Glucose, Endocrinology, Insulin signaling
Published Open-Access
yes
Recommended Citation
Zhong, Shiqi; Chèvre, Raphael; Castaño Mayan, David; et al., "Haploinsufficiency of CYP8B1 Associates With Increased Insulin Sensitivity in Humans" (2022). Children’s Nutrition Research Center Staff Publications. 243.
https://digitalcommons.library.tmc.edu/staff_pub/243
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Dietetics and Clinical Nutrition Commons, Endocrinology, Diabetes, and Metabolism Commons, Nutrition Commons