LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis.

Inhibition of immunocyte infiltration and activation has been suggested to effectively ameliorate nonalcoholic steatohepatitis (NASH). Paired immunoglobulin-like receptor B (PirB) and its human ortholog receptor, leukocyte immunoglobulin-like receptor B (LILRB2), are immune-inhibitory receptors. However, their role in NASH pathogenesis is still unclear. Here, we demonstrate that PirB/LILRB2 regulates the migration of macrophages during NASH by binding with its ligand angiopoietin-like protein 8 (ANGPTL8). Hepatocyte-specific ANGPTL8 knockout reduces MDM infiltration and resolves lipid accumulation and fibrosis progression in the livers of NASH mice. In addition, PirB-/- bone marrow (BM) chimeras abrogate ANGPTL8-induced MDM migration to the liver. And yet, PirB ectodomain protein could ameliorate NASH by sequestering ANGPTL8. Furthermore, LILRB2-ANGPTL8 binding-promoted MDM migration and inflammatory activation are also observed in human peripheral blood monocytes. Taken together, our findings reveal the role of PirB/LILRB2 in NASH pathogenesis and identify PirB/LILRB2-ANGPTL8 signaling as a potential target for the management or treatment of NASH.

Associations between metabolic score for visceral fat and the risk of cardiovascular disease and all-cause mortality among populations with different glucose tolerance statuses.

AIMS: To investigate the associations between metabolic score for visceral fat (METS-VF) and clinical outcomes among populations with different glucose tolerance statuses. METHODS: We analysed 6827 participants aged ≥ 40 years with different glucose tolerance statuses from a cohort study. The associations between METS-VF and cardiovascular disease (CVD) events and all-cause mortality were assessed using Cox regression, restricted cubic spline and receiver operating characteristic curves. RESULTS: During a follow-up of 5.00 years, there were 338 CVD events and 307 subjects experienced all-cause death. The METS-VF quartile (Quartile 4 versus 1) was significantly related to CVD events [adjusted HRs and 95% CIs: 5.75 (2.67-12.42), 2.80 (1.76-4.48), and 3.31 (1.28-8.54) for subjects with normal glucose tolerance, prediabetes and diabetes, respectively] and all-cause mortality [adjusted HRs and 95% CIs: 2.80 (1.43-5.49), 4.15 (2.45-7.01), and 4.03 (1.72-9.42), respectively]. Restricted cubic spline suggested a dose-response association of METS-VF with the risk of CVD events and all-cause mortality. The area under curve for CVD events and all-cause mortality was higher for METS-VF than for the other obesity and IR indexes in subjects with different glucose tolerance statuses. CONCLUSIONS: The METS-VF was associated with an increased risk of CVD events and all-cause mortality and could be used as a predictive index of the risk of CVD events and all-cause mortality among populations with different glucose tolerance statuses.

Predictive values of metabolic score for insulin resistance on risk of major adverse cardiovascular events and comparison with other insulin resistance indices among Chinese with and without diabetes mellitus: Results from the 4C cohort study.

AIMS/INTRODUCTION: To investigate the relationship between the metabolic score for insulin resistance (METS-IR) index and major adverse cardiac events (MACEs) and to compare its ability to predict MACEs with other IR indices including homeostatic model assessment for IR (HOMA-IR) and triglyceride glucose (TyG) index-related parameters. MATERIALS AND METHODS: We conducted a cohort study enrolling 7,291 participants aged ≥40 years. Binary logistic regression and restricted cubic splines were performed to determine the association between METS-IR and MACEs, and the receiver operating curve (ROC) was utilized to compare the predictive abilities of IR indices and to determine the optimal cut-off points. RESULTS: There were 348 (4.8%) cases of MACEs during a median follow-up of 3.8 years. Compared with participants with a METS-IR in the lowest quartile, the multivariate-adjusted RRs and 95% CIs for participants with a METS-IR in the highest quartile were 1.47 (1.05-2.77) in all participants, 1.42 (1.18-2.54) for individuals without diabetes, and 1.75 (1.11-6.46) for individuals with diabetes. Significant interactions were found between the METS-IR and the risk of MACEs by sex in all participants and by age and sex in individuals without diabetes (all P values for interaction < 0.05). In the ROC analysis, the METS-IR had a higher AUC value than other indices for predicting MACEs in individuals with diabetes and had a comparable or higher AUC than other indices for individuals without diabetes. CONCLUSIONS: The METS-IR can be an effective clinical indicator for identifying MACEs, as it had superior predictive power when compared with other IR indices in individuals with diabetes.

Dose-response association between sedentary time and incident of diabetes in Chinese middle-aged and older adults: The 4C study.

AIMS: To investigate the dose-response relationship of total sedentary time with incident diabetes in Chinese middle-aged and older adults. METHODS: The present study followed 100,525 participants aged ≥ 40 years old from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was a prospective study conducted in 25 communities across mainland China. Associations between sedentary time and incident diabetes were assessed with Cox regression and restricted cubic splines. RESULTS: During a median follow-up of 3.8 years, 7,529 participants developed diabetes. After adjustment for multiple variables, high levels of sedentary time (≥ 30 h/week) was associated with increased risk for developing diabetes (hazards ratio, 1.08; 95 % confidence intervals 1.02, 1.14) compared with low levels of sedentary time (<20 h/week). Restricted cubic spline analyses revealed an inverted U-shaped relation between sedentary time with diabetes. Subgroup analyses found that the observed association remained significant in subgroup of individuals with body mass index (BMI) ≥ 25 kg/cm2 or diastolic blood pressure (DBP) ≥ 90 mm Hg. However, the significant association was diminished in participants with sufficient physical activity (PA) (P = 0.22). CONCLUSIONS: The multicenter, population-based, prospective study suggested an inverted U-shaped relation between sedentary time with diabetes. PA alleviated the deleterious effects associated with sedentary time.

Association of Circulating ANGPTL8 Levels With Renal Dysfunction: A Case-Control Study.

Background: Chronic kidney disease (CKD) is recognized as a major public health problem with high morbidity and mortality worldwide. Recently, angiopoietin-like protein 8 (ANGPTL8) was found to regulate lipid metabolism. Previous studies suggested that serum ANGPTL8 levels increased in patients with diabetes, especially in diabetic patients with albuminuria. This study aimed to investigate the association between circulating levels of ANGPTL8 and kidney function in the general population. Methods: The subjects were patients with renal dysfunction [estimated glomerular filtration rate (eGFR) <60/min/1.73 m2] from Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal study (the REACTION study). Each case was matched by age, sex, and body mass index (BMI) with one control whose eGFR was ≥ 90 ml/min/1.73 m2. The case and control groups were compared using a paired t-test. Binary logistic regression analysis was used to calculate the odds ratio (OR) of renal dysfunction (RD). Results: Among 135 case-control pairs, circulating ANGPTL8 levels were elevated in patients with RD compared to control subjects [799.96 (410.12-1086.44) vs. 609.58 (365.13-740.06) pg/ml, p < 0.05]. Partial correlations showed that ANGPTL8 levels were negatively correlated with eGFR (r = -0.26, p < 0.05). Multivariable-adjusted binary logistic regression analysis showed that elevated ANGPTL8 levels were associated with an increased risk of RD (OR in quartile 4 vs. 1, 3.80; 95% CI, 1.71-8.41). Interestingly, the association between ANGPTL8 levels and RD was consistent with the overall findings in both nondiabetic individuals (OR, 1.44; 95% CI, 1.09 to 1.91) and diabetic patients (OR, 2.71; 95% CI, 1.13-6.49) in the subgroup analyses. Furthermore, the estimates for this association were also significant in females (OR, 2.12; 95% CI, 1.33-3.37), individuals aged > 60 years (OR, 1.55; 95% CI, 1.16-2.07), individuals with a BMI <24 (OR, 1.66; 95% CI, 1.16-2.39), and individuals without hyperlipidaemia (OR, 1.61; 95% CI, 1.16-2.23) (all p-values <0.05). Conclusion: Elevated circulating ANGPTL8 levels were associated with increased risk of RD in the general population, especially among females, individuals aged > 60 years, individuals with a BMI < 24, individuals without diabetes mellitus, individuals with diabetes mellitus (DM), and individuals without hyperlipidaemia. This finding implies that ANGPTL8 may play a role in the pathological process of RD.

Circulating ANGPTL8 levels and risk of kidney function decline: Results from the 4C Study.

BACKGROUND: ANGPTL8, an important regulator of lipid metabolism, was recently proven to have additional intracellular and receptor-mediated functions. This study aimed to investigate circulating levels of ANGPTL8 and its potential association with the risk of kidney function decline in a cohort study. METHODS: We analysed 2,311 participants aged 40 years old and older from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Kidney function decline was defined as an estimated glomerular filtration rate (eGFR) less than 60 mL per minute per 1.73 m2 of body surface area, a decrease in eGFR of ≥ 30% from baseline, chronic kidney disease (CKD)-related hospitalization or death, or end-stage renal disease. The association between baseline ANGPTL8 levels and kidney function decline was assessed using multivariable-adjusted Cox proportional hazards models, and inverse possibility of treatment weight (IPTW) was utilized to prevent overfitting. RESULTS: There were 136 (5.9%) cases of kidney function decline over a median of 3.8 years of follow-up. We found that serum ANGPTL8 levels at baseline were elevated in individuals with kidney function decline compared to those without kidney function decline during follow-up (718.42 ± 378.17 vs. 522.04 ± 283.07 pg/mL, p < 0.001). Compared with the first quartile, multivariable-adjusted hazard ratio (95% confidence intervals [CIs]) for kidney function decline was 2.59 (95% CI, 1.41-4.77) for the fourth ANGPTL8 quartile. Furthermore, compared with patients in the first ANGPTL8 quartile, those in the fourth ANGPTL8 quartile were more likely to report a higher stage of CKD (relative risk: 1.33; 95% CI, 1.01-1.74). The conclusions of the regression analyses were not altered in the IPTW models. Multivariable-adjusted restricted cubic spline analyses suggested a linear relationship of ANGPTL8 with kidney function decline (p for nonlinear trend = 0.66, p for linear trend < 0.001). CONCLUSIONS: Participants with higher circulating ANGPTL8 levels were at increased risk for kidney function decline, highlighting the importance of future studies addressing the pathophysiological role of ANGPTL8 in CKD.

Changes in thyroid function during controlled ovarian hyperstimulation (COH) and its impact on assisted reproduction technology (ART) outcomes: a systematic review and meta-analysis.

BACKGROUND: To investigate the thyroid function changes during controlled ovarian hyperstimulation (COH) and ascertain its impact on reproductive outcomes. METHODS: We conducted meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was performed to identify studies reported changes in thyroid parameters during COH. We analyzed thyroid-stimulating hormone (TSH) levels, free thyroxin (fT4) levels, changes in estrogens (E2), thyroxine-binding globulin (TBG), relative risks (RRs) of clinical pregnancy rate (CPR), live birth rate (LBR), and mean difference (MD) of TSH increment between the miscarriage group and ongoing pregnancy group. RESULTS: This meta-analysis included fifteen individual studies (n = 1665 subjects). At the end of COH, the mean TSH (2.53 mIU/L; 95% CI, 2.19 to 2.88; I2 = 92.9%) exceeded the upper limit (2.5 mIU/L) and remained above the threshold until one month following embryo transfer (ET). Thyroxin decreased from baseline to the end of COH (-0.18 ng/l; 95% CI, -0.35 to 0.00; I2 = 92.2%). The CPR and LBR of patients with TSH exceeding the cutoff after COH were significantly lower than those of patients with TSH below the threshold (CPR: RR, 0.62; 95% CI, 0.47 to 0.82; I2 = 0.0% and LBR: RR, 0.64; 95% CI, 0.44 to 0.92; I2 = 0.0%). The MD of the increment in TSH levels between the miscarriage and ongoing pregnancy groups was 0.40 mIU/L (95% CI, 0.15 to 0.65; I2 = 0.0%). CONCLUSIONS: This meta-analysis shows that TSH increases and fT4 decreases during COH. COH-induced thyroid disorder impairs reproductive outcomes.

Durability of glycaemic control in type 2 diabetes: A systematic review and meta-analysis for its association with body weight changes.

AIMS: To analyse quantitatively the association between the durability of glycaemic control and body weight changes during treatment. MATERIALS AND METHODS: This study adhered to an appropriate methodology according to Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Studies with follow-ups >12 months, and final and intermediate assessments of haemoglobin A1c (HbA1c) and body weight were included. Four outcomes assessing therapeutic durability were extracted and synthesized using Stata statistical software, including changes in HbA1c, goal-achievement rate, failure rate and coefficient of failure (CoF). RESULTS: After 8.9 months of treatment, HbA1c levels declined from 8.03% [95% confidence interval (CI), 7.91-8.15; I2 = 99.2%] to 7.15% (95% CI, 7.02-7.27; I2 = 99.4%) and then gradually increased up to 7.72% (95% CI, 7.50-7.94; I2 = 99.0%) 5 years later. The goal-achievement rate decreased from 54.8% (after 1 year of treatment) to 19.4% 5 years later. The CoF was 0.123 ± 0.022%/year (P < .001). After stratification, the CoFs were 0.224 ± 0.025%/year (P < .001) for weight gain, 0.137 ± 0.034%/year (P < .001) for neutral weight and -0.024 ± 0.032%/year (P = .450) for weight loss. After stratification by treatment approaches, the CoFs were 0.45%/year for insulin, 0.43%/year for sulphonylurea, 0.34%/year for thiazolidinediones, 0.29%/year for metformin, 0.16% for glucagon-like polypeptide-1 receptor agonists, 0.12% for surgery, -0.03% for sodium-glucose cotransporter-2 inhibitors and -0.21% for dipeptidyl peptidase-IV inhibitors. CONCLUSION: Modest weight loss with a goal of 2-3% of body weight should be recommended to improve therapeutic durability and prevent beta-cell deterioration.

Predictive values of ANGPTL8 on risk of all-cause mortality in diabetic patients: results from the REACTION Study.

BACKGROUND: Angiopoietin-like protein 8 (ANGPTL8), an important regulator of lipid metabolism, is increased in diabetes and is associated with insulin resistance. However, the role of ANGPTL8 in the outcomes of diabetic patients remains unclear. This study aimed to investigate circulating levels of ANGPTL8 in participants with and without diabetes and its potential associations with clinical outcomes in a 5 year cohort study. METHODS: Propensity-matched cohorts of subjects with and without diabetes from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A longitudinal (REACTION) study were generated on the basis of age, sex and body mass index at baseline. The primary outcome was all-cause mortality. The secondary outcomes were a composite of new-onset major adverse cardiovascular events, hospitalization for heart failure, and renal dysfunction (eGFR < 60/min/1.73 m2). RESULTS: We identified 769 matched pairs of diabetic patients and control subjects. Serum ANGPTL8 levels were elevated in patients with diabetes compared to control subjects (618.82 [Formula: see text] 318.08 vs 581.20 [Formula: see text] 299.54 pg/mL, p = 0.03). Binary logistic regression analysis showed that elevated ANGPTL8 levels were associated with greater risk ratios (RRs) of death (RR in quartile 4 vs. quartile 1, 3.54; 95% CI 1.32-9.50) and renal dysfunction (RR in quartile 4 vs. quartile 1, 12.43; 95% CI 1.48-104.81) only in diabetic patients. Multivariable-adjusted restricted cubic spline analyses revealed a significant, linear relationship between ANGPTL8 and all-cause mortality in diabetic patients (p for nonlinear trend = 0.99, p for linear trend = 0.01) but not in control subjects (p for nonlinear trend = 0.26, p for linear trend = 0.80). According to ROC curve analysis, the inclusion of ANGPTL8 in QFrailty score significantly improved its predictive performance for mortality in patients with diabetes. CONCLUSION: Serum ANGPTL8 levels were associated with an increased risk of all-cause mortality and could be used as a potential biomarker for the prediction of death in patients with diabetes.