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Hyocholic acid (HCA) and its derivatives are found in trace amounts in human blood but constitute approximately 76% of the bile acid (BA) pool in pigs, a species known for its exceptional resistance to type 2 diabetes. Here, we show that BA depletion in pigs suppressed secretion of glucagon-like peptide-1 (GLP-1) and increased blood glucose levels. HCA administration in diabetic mouse models improved serum fasting GLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholic acid. HCA upregulated GLP-1 production and secretion in enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor (FXR), a unique mechanism that is not found in other BA species. We verified the findings in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor inhibition mouse models. Finally, we confirmed in a clinical cohort, that lower serum concentrations of HCA species were associated with diabetes and closely related to glycemic markers. [Display omitted] • HCA is the primary BA in pigs, a species known for its exceptional resistance to T2DM • Serum HCA levels are inversely correlated with glucose levels in humans with T2DM • HCA exhibit strong effects on glucose regulation in the pig and diabetic mouse models • HCA promote GLP-1 secretion via simultaneously activating TGR5 and inhibiting FXR Pigs are routinely raised on obesogenic diets yet are resistant to the development of T2DM. Zheng et al. report that a group of bile acids, hyocholic acid and its derivatives (HCAs), the primary bile acids in pigs, are inversely correlated with glucose levels in subjects with T2DM. They further discover that HCAs promote GLP-1 production and secretion through a distinct TGR5 and FXR signaling mechanism. [ABSTRACT FROM AUTHOR]

Serum uric acid (SUA) levels are highly heritable and an increased SUA level is one of important risk factors for gout, diabetes, metabolic syndrome, and cardiovascular diseases. The genetic variants underlying SUA remains largely unexplored. The aim was to explore new genetic variants underlying SUA in Chinese Han. We performed a genome-wide association study of SUA levels in Han Chinese. The discovery set contained 1634 samples and subsequent replication was comprised of 1649 females and 1169 males. 2620 subjects were recruited in the detailed analysis of rs671, alcohol drinking and SUA. We found a genome-wide significant association between SUA level and the SNP rs671 at ALDH2 ( P  = 1.2 × 10 −10 ) in the merged data. In addition, we also replicated the signal from rs3733590 at SLC2A9 ( P  = 1.0 × 10 −10 ). In males, about 0.21% to 1.95% of the total variance for SUA can be explained by rs671 using linear regression models in four independent cohorts. Of those, 56.75% to 93.51% might be explained by altering alcohol consumption due to rs671. No statistical association of rs671 and SUA was observed in females ( P  = 0.409). Furthermore, we observed a causal relationship between alcohol consumption and SUA in males using rs671 as an instrumental variable ( P  = 5.1 × 10 −4 ). We replicated the previous findings in SLC2A9 . Our evidence supported that rs671 was associated with SUA by affecting alcohol consumption in males. This finding strongly suggests a role for alcohol consumption in the development of hyperuricaemia and uric acid related traits. [ABSTRACT FROM AUTHOR]