Maternal serum Sortilin-1 level as a potential biomarker for intrahepatic cholestasis of pregnancy.

Objective: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease related to pregnancy in women. Sortilin-1 is a sorting receptor belonging to the vacuolar protein sorting 10 (Vps10p) domain family, and recent studies have shown that Sortilin-1 has a distinct role in the pathogenesis of biliary fibrosis and cirrhosis. We aimed to evaluate maternal serum Sortilin-1 level as a potential biomarker in pregnant women with intrahepatic cholestasis.Materials and methods: A prospective observational cohort study was conducted. We enrolled 80 pregnant women, 49 with the diagnosis of intrahepatic cholestasis of pregnancy and 31 healthy controls. Then, we measured maternal serum Sortilin-1 levels using an enzyme-linked immunosorbent assay method and compared them between groups.Results: The mean Sortilin-1 level in the ICP group was higher than control group (3.3 ± 1.7 ng/mL vs. 2.0 ± 0.6 ng/mL, respectively, p < .001). The receiver operating characteristic curve (ROC) analysis based on maternal serum Sortilin-1 levels to predict the presence of ICP was 85.3% controls [area under the curve (AUC), 0.853; 95% CI, 0.738-0.938, p < .001]. The optimal cutoff value of Sortilin-1 was 2.24 ng/mL (71.4% sensitivity and 74.2% specificity) to detect intrahepatic cholestasis of pregnancy.Conclusion: Elevated maternal serum Sortilin-1 levels are associated with ICP and can be used as a disease biomarker. Sortilin-1 levels can be combined with total bile acids, transaminases, and blood coagulation profile in the follow-up of ICP.

Fasting and refeeding triggers specific changes in bile acid profiles and gut microbiota.

BACKGROUND: Bile acids (BAs) are closely related to nutrient supply and modified by gut microbiota. Gut microbiota perturbations shape BA composition, which further affects host metabolism. METHODS: We investigated BA profiles in plasma, feces, and liver of mice fed ad libitum, fasted for 24 h, fasted for 24 h and then refed for 24 h using ultraperformance liquid chromatography coupled to tandem mass spectrometry. Gut microbiota was measured by 16S rRNA gene sequencing. Expressions of BA biosynthesis-related genes in the liver and BA reabsorption-related genes in the ileum were analyzed. FINDINGS: Compared with the controls, unconjugated primary BAs (PBAs) and unconjugated secondary BAs (SBAs) in plasma were decreased whereas conjugated SBAs in plasma, unconjugated PBAs, unconjugated SBAs and conjugated SBAs in feces, and unconjugated SBAs in liver were increased in the fasting mice. The expression of BA biosynthesis-related genes in the liver and BA reabsorption-related genes in the ileum were decreased in the fasting mice compared with the controls. Compared with the controls, Akkermansia, Parabacteroides, Muribaculum, Eubacterium_coprostanoligenes and Muribaculaceae were increased in the fasting mice whereas Lactobacillus and Bifidobacterium were decreased. All these changes in BAs and gut microbiota were recovered under refeeding. Akkermansia was negatively correlated with plasma levels of unconjugated PBAs, unconjugated SBAs and glucose, whereas it was positively correlated with plasma conjugated SBAs, fecal unconjugated PBAs, and fecal unconjugated SBAs. CONCLUSIONS: We characterized the BA profiles, gut microbiota, and gene expression responsible for BA biosynthesis and intestinal reabsorption to explore their rapid changes in response to food availability. Our study highlighted the rapid effect of nutrient supply on BAs and gut microbiota.

Saxagliptin alters bile acid profiles and yields metabolic benefits in drug-naïve overweight or obese type 2 diabetes patient.

BACKGROUND: The aim of the present study was to investigate the metabolic benefits of saxagliptin and its effects on serum bile acids (BAs) in normal weight and overweight/obese drug-naïve type 2 diabetes (T2D) patients. METHODS: In all, 282 drug-naïve T2D patients (123 normal weight [NW], with body mass index [BMI] between 19.0 and <25.0 kg/m2 ; 159 overweight/obese [OW/OB], with BMI ≥25.0 kg/m2 ) were enrolled in the study and treated with saxagliptin 5 mg daily for 24 weeks. Serum BAs were assayed by liquid chromatography with tandem mass spectrometry. RESULTS: At 24 weeks, HbA1c was significantly reduced in both groups, but the HbA1c levels were lower in the OW/OB than NW group. Moreover, significant decreases were seen at 24 weeks in C-reactive protein (CRP), aspartate aminotransferase, alanine aminotransferase, waist circumference, and systolic blood pressure in the OW/OB group. Interestingly, cholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid (GDCA), and glycoursodeoxycholic acid (GUDCA) were increased in both groups after treatment, whereas chenodeoxycholic acid and deoxycholic acid (DCA) were specifically increased in the OW/OB group. Increased DCA and GDCA concentrations were significantly associated with decreased HbA1c or fasting blood glucose and CRP levels, whereas increased GDCA and GUDCA concentrations were associated with decreased waist circumference in the OW/OB group during treatment. In the NW group, increased GUDCA concentrations were significantly associated with a decrease in HbA1c. CONCLUSIONS: Type 2 diabetes patients with OW/OB exhibited greater improvement in glycemic control and additional metabolic benefits after saxagliptin treatment. Saxagliptin significantly increased the BA pool, and DCA and GDCA were associated with metabolic improvements in OW/OB T2D patients.

Plasma bile acid changes in type 2 diabetes correlated with insulin secretion in two-step hyperglycemic clamp.

BACKGROUND: Bile acids (BAs) conduct crucial signals in human metabolism. Correlations between changes in plasma BA concentrations, insulin secretion defects, and progression of type 2 diabetes mellitus (T2DM) in humans have not been sufficiently investigated. This study explored the trajectories of changes in human plasma BA concentrations and their association with insulin secretion dynamics during a two-step hyperglycemic clamp. METHODS: Eleven healthy subjects with normal glucose tolerance (NGT) and 33 drug-naïve T2DM subjects were enrolled in the study. The two-step hyperglycemic clamp consisted of a classic clamp as Step 1 with fasting, followed by a Step 2 clamp after ingestion of a carbohydrate meal, illustrating basal and incretin-amplified insulin responses to glucose. Plasma BA were assayed using liquid chromatography-tandem mass spectrometry. Nine T2DM subjects were followed-up, and the two-step clamp was repeated after 3 months sulfonylurea treatment. RESULTS: Ursodeoxycholic acid (UDCA) was lower and lithocholic acid (LCA) and taurocholic acid (TCA) were higher in T2DM compared with NGT subjects. The dynamics of plasma UDCA concentrations and the UDCA/LCA ratio was positively correlated with insulin secretion in T2DM subjects and were corrected after treatment. Moreover, fasting ratios of UDCA/LCA and unconjugated/conjugated BAs were correlated with the first phase of insulin secretion in T2DM subjects. CONCLUSION: The abnormal BA composition in T2DM subjects and its correlation with insulin secretion during the clamp suggest an interaction between BA signals and insulin secretion capacity, and the potential to use fasting plasma BA composition indices to predict and evaluate the progression and prognosis of T2DM.