Search

BACKGROUND. Cytochrome P450 family 8 subfamily B member 1 (CYP8B1) generates 12[alpha]-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 12[alpha]-hydroxylated/non-12[alpha]-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 mutationcarrier 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., Introduction Bile acids (BAs) are products of cholesterol catabolism, accounting for approximately 50% of daily cholesterol turnover in humans, and act as surfactants to promote intestinal lipid absorption (1). The [...]

Prior experimental work showed that Bi 2 Se 3 , as a sister compound of the best room-temperature thermoelectric material Bi 2 Te 3 , has remarkably improved thermoelectric performance by Sb-Br codoping. But the relationship between its crystalline structure and thermoelectric properties is still unclear to date. Here, we use first-principles calculations to explore the possible reasons for such improvement. The electronic structures of Bi 2- x Sb x (Se 1- y Br y ) 3 ( x = 0, 1, 2; y = 0, 0.08) are systematically investigated. Significant effects of 8% Br codoping in BiSbSe 3 are found. First, the Br atom acts as an electron donor, thus greatly increasing the carrier concentration. Second, similar to the effect of Sb doping, Br codoping further improves greatly the degeneracy of the conduction band edge, which leads to a remarkably increased density-of-states effective mass without deterioration of the carrier mobility, and simultaneously preserves a large Seebeck coefficient of ∼-254 μV K -1 at 800 K. In addition, the Br codoping softens the chemical bonds, which enhances anharmonic scattering and further reduces the lattice thermal conductivity. We predict that the maximum zT of BiSb(Se 0.92 Br 0.08 ) 3 at 800 K can reach 0.96 with the carrier concentration of 9.22 × 10 19 cm -3 . This study rationalizes a potential strategy to improve the thermoelectric performance of Bi 2 Se 3 -based thermoelectric materials., Competing Interests: The authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)