Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans.

Albert K Groen, Roshni R Singaraja, Hong Chang Tan, Jason Flannick, Shaji Chacko, Ching-Yu Cheng, Michael R Hayden, Kerry-Anne Rye, Ru San Tan, Rob M van Dam, Chester Drum, Julian L Goggi, Folkert Kuipers, Xueling Sim, Peter Cheng, Boominathan Ramasamy, Siddesh V Hartimath, Liang Juin Tan, Jianhe Peng, Theo H van Dijk, Kai Ping Sem, Blake J Cochran, Maria Corlianò, David Castaño Mayan, Raphael Chèvre, Shiqi Zhong

Journal: The Journal of clinical investigation 2022;132(21):e152961

PMID: 36107630

Free Full Text on American Society for Clinical Investigation View on PubMed

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.

Address: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Singapore.; Cardiovascular Research Institute, National University Health System, Singapore.; School of Medical Sciences, University of New South Wales, Sydney, Australia.; Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Netherlands.; Experimental Therapeutics Centre and.; Singapore Bioimaging Consortium, A*STAR, Singapore.; Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.; Department of Cardiology, National Heart Centre, Singapore.; Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada.; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.; Ophthalmology and Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore.; USDA/ARS Children's Nutrition Research Centre, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.; Program in Metabolism and.; Program in Medical & Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.; Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; Department of Endocrinology, Singapore General Hospital, Singapore.

DOI: 10.1172/JCI152961