Triglyceride-glucose index and mortality risk in individuals with or without chronic kidney disease: Insights from a national survey of United States adults, 1999-2018.

BACKGROUND AND AIMS: The Triglyceride-Glucose Index (TyG) has been proposed as a predictor to mortality, yet its association remains incompletely understood for individuals with or without chronic kidney disease (CKD). METHODS AND RESULTS: We analyzed data from the National Health and Nutrition Examination Survey spanning the years 1999-2018. CKD was defined as eGFR level <60 ml/min/1.73 m2 or urinary albumin creatinine ratio ≥30 mg/g. We employed the Cox proportional-hazards model to evaluate the incident risk of mortality associated with TyG among both non-CKD and CKD individuals. In the current analysis, 19,426 individuals were without CKD, while 2975 individuals had CKD. The overall mean TyG was 8.65, with significant difference between non-CKD and CKD individuals (8.60 vs 8.95, P < 0.001). The TyG index exhibited linear associations with incident cardiovascular disease (CVD) mortality and all-cause mortality among non-CKD and CKD individuals, respectively. A per-unit increase in the TyG index was significantly associated with CVD mortality for both non-CKD (HR = 1.24, 95%CI = 1.09-1.41) and CKD participants (HR = 1.19, 95%CI = 1.04-1.36), with no significant difference in the associations between the two groups (P = 0.091). For both non-CKD and CKD participants, TyG index was significantly associated with CVD mortality and all-cause mortality among those with age <65, but not for those with age ≥65. CONCLUSIONS: Our findings underscore the TyG index's as a valuable predictive tool for assessing the risk of all-cause and CVD mortality in both individuals with and without CKD.

Changes in adiposity modulate the APOA5 genetic effect on blood lipids: A longitudinal cohort study.

BACKGROUND AND AIMS: The Apolipoprotein A5 (APOA5) rs662799 was significantly associated with blood lipid level at genome-wide significance level. Whether dynamic changes of adiposity influence the effect of lipid loci on long-term blood lipid profile remains unclear. We assessed interactions of 5-year body mass index (BMI) change and rs662799 genotypes with risk of incident dyslipidemia and longitudinal changes in serum lipids in a prospective cohort. METHODS: We included 4329 non-dyslipidemia participants aged ≥ 40 years at baseline from a well-defined community-based cohort and followed up for an average of 5 years. BMI and blood lipids were measured at baseline and follow-up. RESULTS: The association of each rs662799 A-allele with risk of incident dyslipidemia was stronger along with the increase in BMI change level, with the odds ratios (OR) increasing from 1.03 in the lowest tertile of BMI change (< 0.02 kg/m2) to 1.17 in the second (0.02-1.29), and 1.46 in the highest tertile (> 1.29) (pfor interaction< 0.001). Associations of each 1-unit of BMI (kg/m2) increase with incident dyslipidemia were more prominent in the AA carriers (OR = 1.50, 95%CI [1.26-1.80], p < 0.001), while much weaker in the GA (OR = 1.10) or GG carriers (OR = 1.09) (pfor interaction = 0.002). Similar results were found for the risk of incident higher triglycerides (TG) and lower high-density lipoprotein cholesterol (HDL-c), or the longitudinal changes in log10-TG (all pfor interaction ≤ 0.02). CONCLUSIONS: BMI changes significantly modulate rs662799 genetic contribution to dyslipidemia and long-term lipid profile, which provide new evidence for personalized clinical management of lipids according to individual genetic background.

New Nonalcoholic Fatty Liver Disease and Fibrosis Progression Associate With the Risk of Incident Chronic Kidney Disease.

CONTEXT: Little is known about the link between nonalcoholic fatty liver disease (NAFLD) evolution and incident chronic kidney disease (CKD). OBJECTIVE: We aim to assess the associations of NALFD status changes and NAFLD fibrosis progression with the risk of incident CKD. METHODS: We conducted a community-based prospective study that included participants aged 40 years or older and free of CKD at baseline in 2010, with follow-up evaluations after a mean of 4.4 years. NAFLD was diagnosed by ultrasonography and NAFLD fibrosis score (NFS) was used to evaluate fibrosis stage and progression. CKD was defined by estimated glomerular filtration rate or urine albumin-to-creatinine ratio. All the measurements were performed at baseline and follow-up examination. RESULTS: Among 4042 participants with 4 NAFLD status change groups, incident NAFLD was associated with an increased risk of incident CKD (odds ratio [OR] = 1.44; 95% CI, 1.003-2.06; P = 0.048) compared with non-NAFLD after adjustments for the confounders, including evolution of diabetes, hypertension, and obesity, in addition to the baseline levels. However, the risk of incident CKD was not significantly different between NAFLD resolution and persistent NAFLD. Among 534 participants in the persistent NAFLD group, fibrosis progression from low NFS to intermediate or high NFS was associated with a significantly increased risk of incident CKD compared with stable fibrosis in low NFS (OR = 2.82; 95% CI, 1.22-6.56; P = 0.016). CONCLUSION: NAFLD development and fibrosis progression are associated with increased risk of incident CKD.

Fat mass to fat-free mass ratio and the risk of non-alcoholic fatty liver disease and fibrosis in non-obese and obese individuals.

CONTEXT: Body composition may explain partially why non-obese individuals still at the risk of developing non-alcoholic fatty liver disease (NAFLD). The ratio of fat mass to fat-free mass (FM/FFM) has been proposed to assess the combined effect of different body compositions. OBJECTIVE: We aimed to investigate the associations of FM/FFM ratio with the risk of developing NAFLD and fibrosis and to identify the potential mediators according to obesity status. METHODS: This cohort study comprised 3419 adults age ≥ 40 years and free of NAFLD at baseline. Body composition was measured by bioelectrical impedance analysis. NAFLD was ascertained by ultrasonography and fibrosis was assessed by non-invasive score systems. RESULTS: For each 1 standard deviation increment in FM/FFM ratio, the odds ratio for the risk of NAFLD was 1.55 (95% confidence interval [CI] 1.23-1.95) in non-obese men, 1.33 (95% CI 1.08-1.65) in obese men, 1.42 (95% CI 1.44-1.67) in non-obese women, and 1.29 (95% CI 1.12-1.50) in obese women. Similar associations were also found between FM/FFM ratio and NAFLD with fibrosis. Mediation analysis showed that insulin resistance, triglycerides, high-density lipoprotein cholesterol, white blood cells, and total cholesterol mediated the association of FM/FFM ratio with NAFLD risk in specific sex and obesity subgroups. CONCLUSIONS: The FM/FFM ratio significantly associated with the NAFLD and fibrosis risk in both non-obese and obese individuals. Different factors may mediate the association between body composition and NAFLD risk according to different obesity status.

Fruit intake, genetic risk and type 2 diabetes: a population-based gene-diet interaction analysis.

PURPOSE: Whether the association between fruit and type 2 diabetes (T2D) is modified by the genetic predisposition of T2D was yet elucidated. The current study is meant to examine the gene-dietary fruit intake interactions in the risk of T2D and related glycemic traits. METHODS: We performed a cross-sectional study in 11,657 participants aged ≥ 40 years from a community-based population in Shanghai, China. Fruit intake information was collected by a validated food frequency questionnaire by asking the frequency of consumption of typical food items over the previous 12 months. T2D-genetic risk score (GRS) was constructed by 34 well established T2D common variants in East Asians. The risk of T2D, fasting, 2 h-postprandial plasma glucose, and glycated hemoglobin A1c associated with T2D-GRS and each individual single nucleotide polymorphisms (SNPs) were tested. RESULTS: The risk of T2D associated with each 1-point of T2D-GRS was gradually decreased from the lower fruit intake level (< 1 times/week) [the odds ratio (OR) and 95% confidence interval (CI) was 1.10 (1.07-1.13)], to higher levels (1-3 and > 3 times/week) [the corresponding ORs and 95% CIs were 1.08 (1.05-1.10) and 1.07 (1.05-1.08); P for interaction = 0.04]. Analyses for associations with fasting, 2 h-postprandial plasma glucose and glycated hemoglobin A1c demonstrated consistent tendencies (all P for interaction ≤ 0.03). The inverse associations of fruit intake with risk of T2D and glucose traits were more prominent in the higher T2D-GRS tertile. CONCLUSIONS: Fruit intakes interact with the genetic predisposition of T2D on the risk of diabetes and related glucose metabolic traits. Fruit intake alleviates the association between genetic predisposition of T2D and the risk of diabetes; the association of fruit intake with a lower risk of diabetes was more prominent in population with a stronger genetic predisposition of T2D.

Serum lipoprotein (a) associates with a higher risk of reduced renal function: a prospective investigation.

Lipoprotein (a) [Lp(a)] is a well-known risk factor for cardiovascular disease, but analysis on Lp(a) and renal dysfunction is scarce. We aimed to investigate prospectively the association of serum Lp(a) with the risk of reduced renal function, and further investigated whether diabetic or hypertensive status modified such association. Six thousand two hundred and fifty-seven Chinese adults aged ≤40 years and free of reduced renal function at baseline were included in the study. Reduced renal function was defined as estimated glomerular filtration rate <60 ml/min/1.73 m2 During a mean follow-up of 4.4 years, 158 participants developed reduced renal function. Each one-unit increase in log10-Lp(a) (milligrams per deciliter) was associated with a 1.99-fold (95% CI 1.15-3.43) increased risk of incident reduced renal function; the multivariable-adjusted odds ratio (OR) for the highest tertile of Lp(a) was 1.61 (95% CI 1.03-2.52) compared with the lowest tertile (P for trend = 0.03). The stratified analysis showed the association of serum Lp(a) and incident reduced renal function was more prominent in participants with prevalent diabetes [OR 4.04, 95% CI (1.42-11.54)] or hypertension [OR 2.18, 95% CI (1.22-3.89)]. A stronger association was observed in the group with diabetes and high Lp(a) (>25 mg/dl), indicating a combined effect of diabetes and high Lp(a) on the reduced renal function risk. An elevated Lp(a) level was independently associated with risk of incident reduced renal function, especially in diabetic or hypertensive patients.

Association of QTc Interval with Risk of Cardiovascular Diseases and Related Vascular Traits: A Prospective and Longitudinal Analysis.

Background: Prolonged heart rate corrected QT (QTc) interval was reported to be associated with cardiovascular diseases (CVDs). Objective: There exists little data on the association between QTc interval and cardiovascular risk in Asian populations. We prospectively investigated the association of QTc interval with CVDs and vascular traits in a large cohort of Chinese adults. Methods: A total of 7,605 participants aged 40 years or older from a well-defined community without CVDs at baseline were included and followed up for an average of 4.5 years. Association of baseline QTc interval with incident CVDs was evaluated using Cox regression analysis. Associations of QTc interval with brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (CIMT), and risk of microalbuminuria and peripheral arterial diseases (PAD) were secondarily examined. Results: Prolonged QTc interval (≥460 ms in women and ≥450 ms in men) was associated with 51% higher risk of total major CVDs (hazard ratio [HR] = 1.51, 95% confidence interval [CI] [1.20, 1.90]), particularly, 48% increased risk of stroke (95% CI [1.16, 1.88]). Prolonged QTc interval was positively associated with baPWV (ß = 38.10 cm/s, standard error [SE] = 8.04, P < 0.0001) and CIMT (ß = 0.01 mm, SE = 0.01, P = 0.04). Prolonged QTc interval was associated with increased risk of incident microalbuminuria (odds ratio [OR] = 1.65, 95% CI [1.21, 2.24]) and PAD (2.49, 95% CI [1.35, 4.59]). Conclusions: Prolonged QTc interval is positively and significantly associated with increased risk of CVDs and related vascular traits in Chinese population.

Serum total bile acids associate with risk of incident type 2 diabetes and longitudinal changes in glucose-related metabolic traits.

BACKGROUND: Bile acids have been found to be related to changes in gut microbiota and multiple metabolic disorders, including type 2 diabetes (T2D). We aimed to prospectively investigate associations of serum total bile acids (TBAs) with risk of incident T2D and longitudinal changes in glycemic traits. METHODS: A community-based study was conducted at baseline in 2010, including 4968 nondiabetic participants aged ≥40 years followed up for an average of 4.3 years. Incident T2D was defined by using the 1999 WHO criteria based on 75-g oral glucose tolerance tests. Multivariate Cox proportional hazards regression was used to examine the association of serum TBAs with incident T2D. Fasting plasma glucose (FPG), 2-hour postload plasma glucose (2-h PPG), and fasting serum insulin (FSI) were measured at baseline and follow-up. RESULTS: During 21 653.7 person-years of follow-up, 605 cases of incident diabetes were identified (incidence rate 2.8%). Comparing to quartile 1 of serum TBAs, quartile 2, 3, and 4 were significantly associated with a 14.2%, 15.0%, and 31.4% higher risk of incident T2D (P = .029). Each one unit of log-TBAs was associated with an increase of 0.034 mmol/L in FPG, 0.111 mmol/L in 2-h PPG, 0.023 in log-FSI, and 0.012 in log-HOMA-IR (homeostasis model assessment of insulin resistance) (all P ≤ .024). The association was attenuated after further adjustment for HOMA-IR. Mediation analysis showed that insulin resistance indicated by HOMA-IR might mediate 28.5% of indirect effect on the association of TBAs with T2D (P = .0004). CONCLUSIONS: Baseline serum TBAs were significantly associated with incident T2D and longitudinal changes in glycemic traits. Insulin resistance might partially mediate the association of TBAs and T2D.

Association between mid-upper arm circumference and cardiometabolic risk in Chinese population: a cross-sectional study.

OBJECTIVES: Upper body fat has been associated with an unfavourable cardiometabolic risk. We aimed to investigate the associations between mid-upper arm circumference (MUAC), a novel indicator of upper body fat, and a wide spectrum of cardiometabolic risk profiles in Chinese population. DESIGN AND SETTING: Cross-sectional analyses were performed using data from a well-defined community in 2014, Shanghai, China. PARTICIPANTS: A total of 6287 Chinese adults (2310 men and 3977 women) aged 40 years or older. OUTCOME MEASURES: Multivariable logistic regression model was used to examine the associations of MUAC with cardiometabolic disorders including central obesity, diabetes, hypertension, hypertriglyceridaemia, low high-density lipoprotein (HDL) cholesterol and subclinical atherosclerosis. RESULTS: In the overall participants, after multivariable adjustment, each 1 SD (3.13 cm) increment in MUAC was positively associated with central obesity (OR 2.05; 95% CI 1.85 to 2.28), hypertension (OR 1.10; 95% CI 1.03 to 1.19) and low HDL cholesterol (OR 1.10; 95% CI 1.01 to 1.22). Multivariable-adjusted ORs for subclinical atherosclerosis were gradually increased across increasing quartiles of MUAC with the lowest quartile as reference (quartile 2: OR 1.31; 95% CI 1.09 to 1.58; quartile 3: OR 1.33; 95% CI 1.10 to 1.62; quartile 4: OR 1.45; 95% CI 1.16 to 1.80; p for trend=0.005). Similar but more prominent associations were observed among women than men. In addition, MUAC was significantly interacted with diabetes (p for interaction=0.04) and insulin resistance (p for interaction=0.01) on subclinical atherosclerosis. CONCLUSION: A greater MUAC was positively associated with higher risks of several cardiometabolic disorders and subclinical atherosclerosis in Chinese adults.

Mendelian Randomization Analysis Support Causal Associations of HbA1c with Circulating Triglyceride, Total and Low-density Lipoprotein Cholesterol in a Chinese Population.

Previous observational studies supported a positive association of glycated hemoglobin A1c (HbA1c) level with serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). However, the causal relationship between HbA1c and either one of them was unclear in the East Asians. We performed a Mendelian Randomization (MR) analysis in a community-based study sample in Shanghai, China (n = 11,935). To clarify the cause-and-effect relationships of HbA1c with the four interested lipids, an Expanded HbA1c genetic risk score (GRS) with 17 HbA1c-related common variants and a Conservative score by excluding 11 variants were built and adopted as the Instrumental Variables (IVs), respectively. The Expanded HbA1c-GRS was associated with 0.19 unit increment in log-TG (P = 0.009), 0.42 mmol/L TC (P = 0.01), and 0.33 mmol/L LDL-C (P = 0.01); while the Conservative HbA1c-GRS was associated with 0.22 unit in log-TG (P = 0.03), 0.60 mmol/L TC (P = 0.01), and 0.51 mmol/L LDL-C (P = 0.007). No causal relationship was detected for HDL-C. Sensitivity analysis supported the above findings. In conclusions, MR analysis supports a causal role of increased HbA1c level in increment of circulating TG, TC, and LDL-C in a Chinese population.

Glucagon-like peptide-1 attenuates liver injury in the rat diabetes model.

The aim of present study is to examine the effect of glucagon-like peptide-1(GLP-1) on diabetes-induced liver injury and explore detailed mechanisms of GLP-1 hepatoprotective effect. 150 male Sprague-Dawley rats were randomly assigned into three groups with equal number, including Sham group, diabetes group and GLP-1 intervention group. Diabetes rat model was performed with intraperitoneal injection of streptozotocin (STZ, 65mg/kg). Fasting blood-glucose of rat model was assessed at 72h after STZ injection to verify diabetes rat model. Rats in Sham group were normally fed. Rats in GLP-1 intervention group received 2 ng/kg GLP-1 intervention, at 2, 4, 6 and 8 weeks after intervention, TUNEL staining were performed to examine apoptosis of liver tissue. PCR and Western blot were performed to examine insulin, GLP-1R, autophagy-associated gene and HDAC-1. Compared with diabetes group, insulin expression of GLP-1 intervention group increased significantly (P<0.05). TUNEL staining at different time showed apoptosis levels of liver tissues were reduced gradually after GLP-1 intervention (P<0.05). Compared with diabetes groups, the expressions of BCL2 and GLP-1R were increased, while the levels of caspase3 and LC3 were reduced in GLP-1 intervention group (P<0.05). GLP-1 treatment decreased levels of phosphorylated AKT, phosphorylated ERK1/2, and HDAC6 in liver tissues (P<0.05). GLP-1 treatment alleviated diabetes-induced liver injury via regulating autophagy. The mechanism of GLP-1 hepatoprotective effect could be via GLP-1R-ERK1/2-HDAC6 signaling pathway.

Type 2 diabetes is causally associated with depression: a Mendelian randomization analysis.

Type 2 diabetes (T2D) has been associated with a high prevalence of depression.We aimed to determine the causal relation by performing a Mendelian randomization (MR) study using 34 T2D risk genetic variants validated in East Asians as the instrumental variable (IV). An MR analysis was performed involving 11 506 participants from a large longitudinal study. The T2D genetic risk score (GRS) was built using the 34 typical T2D common variants. We used T2D_GRS as the IV estimator and performed inverse-variance weighted (IVW) and Egger MR analysis. The T2D_GRS was found to be associated with depression with an OR of 1.21 (95% CI: 1.07-1.37) after adjustments for age, sex, body mass index, current smoking and drinking, physical activity, education, and marital status. Using T2D_GRS as the IV, we similarly found a causal relationship between genetically determined T2D and depression (OR: 1.84, 95% CI: 1.25-2.70). Though we found no association between the combined effect of the genetic IVs for T2D and depression with EggerMR(OR: 0.95, 95%CI: 0.42-2.14), we found an association for T2D and depression with IVW (OR: 1.75, 95% CI: 1.31-2.46) after excluding pleiotropic SNPs. Overall, the MR analyses provide evidence inferring a potential causal relationship between T2D and depression.

Association of branched chain amino acids related variant rs1440581 with risk of incident diabetes and longitudinal changes in insulin resistance in Chinese.

AIMS: Previous genome-wide association studies reported rs1440581 was significantly associated with circulating branched chain amino acids (BCAAs) levels in Europeans. We aimed to investigate association of BCAAs related variant rs1440581 with incident T2D risk and longitudinal changes in glucose-related metabolic traits in a community-based prospective cohort of Chinese. METHODS: 6043 non-diabetic participants aged ≥ 40 years from a community-based population at baseline were included and followed-up for 5 years. The BCAAs related variant rs1440581 was genotyped. Incident T2D was defined as fasting plasma glucose (FPG) ≥ 7.0 mmol/L or taking anti-diabetic therapy. Anthropometry and biochemical measurements were evaluated at both baseline and follow-up. RESULTS: 576 (9.5%) participants developed T2D during the 5-year follow-up. Each C-allele was associated with a 20% higher risk of incident T2D (odds ratio = 1.20, 95% confidence interval [1.05, 1.36]) after adjustments for the confounders. We did not find a main effect of the variant on increase in fasting serum insulin (FSI) level or insulin resistance (IR). However, we found rs1440581 significantly modified effect of weight gain on increase in FSI and HOMA-IR. In the C-allele carriers, body mass index increase was associated with greater increase in Log10_FSI (ß ± SE 0.027 ± 0.002) and Log10_HOMA-IR (0.030 ± 0.003), as compared to T-allele (both P for interaction = 0.003). CONCLUSIONS: BCAAs related genetic variant rs1440581 was associated with an increased risk of incident T2D in a Chinese population. This variant might modify effect of weight gain on development in IR.

Urinary bisphenol A concentration and the risk of central obesity in Chinese adults: A prospective study.

BACKGROUND: Bisphenol A (BPA) exposure has been associated with diabetes and related metabolic disorders, such as obesity, but studies of the association of urinary BPA concentrations with central obesity risk are limited. The aim of this study was to prospectively investigate the association between urinary BPA and incident central obesity in a Chinese population aged ≥40 years. METHODS: The study followed 888 participants from Shanghai, China, who did not have central obesity at baseline (in 2009) for 4 years. Concentrations of BPA were measured in baseline morning spot urine samples. Central obesity was defined as waist circumference ≥90 cm in men and ≥80 cm in women. RESULTS: During a mean follow-up of 4 years, 124 (14.0%) participants developed central obesity. Each 1-unit increase in log [BPA] was positively associated with a 2.30-fold risk of incident central obesity (95% confidence interval [CI] 1.39-3.78; P < 0.001) after adjustment for confounders. Compared with the lowest tertile of urinary BPA concentration, Tertiles 2 and 3 were associated with a higher risk of incident central obesity (odds ratios 1.73 [95% CI 1.04-2.88] and 1.81 [95% CI 1.08-3.05], respectively). Stratified analysis showed significant associations of BPA with incident central obesity in women and individuals <60 years of age, with normal weight, non-smokers, non-drinkers, or non-hypertensives. CONCLUSIONS: The results indicate that higher urinary BPA concentrations may be associated with a greater risk of incident central obesity in Chinese adults. The study emphasizes the effects of BPA exposure on metabolic risk from a public health perspective.

[Correlation between serum free fatty acid level and estimated glomerular filtration rate in type 2 diabetic patients].

OBJECTIVE: To investigate the relationship between serum free fatty acid (FFA) level and glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 442 T2DM patients treated in Sir Run Run Shaw Hospital from January 2013 to June 2015 were retrospectively analyzed and divided into three groups according to estimated glomerular filtration rate (eGFR) levels using modified modification of diet in renal disease (MDRD) formula: eGFR≥90 ml·min(-1)·1.73 m(-2)group (group A, 227 cases), 60 ml·min(-1)·1.73 m(-2)≤eGFR<90 ml·min(-1)·1.73 m(-2)group (group B, 118 cases), and eGFR<60 ml·min(-1)·1.73 m(-2)group (group C, 97 cases). In addition, 50 body mass index (BMI)-matched non-diabetic subjects were selected as control group. Fasting serum FFA level was measured in each group, and its relationship with eGFR was analyzed. RESULTS: FFA level in group C[(450±203)µmol/L]was significantly higher than that in group A[(326±167)µmol/L], group B[(394±184)µmol/L]and control group[(320±90)µmol/L](all P<0.05). Meanwhile, FFA level in group B was higher compared with that in group A (P<0.05). However, no statistical difference was found in FFA level between group A and Control group (P>0.05). Multiple linear regression analysis using eGFR as the dependent variable demonstrated that uric acid (UA), FFA, triglyceride (TG), total cholesterol (TC), albuminuria, hypertension, smoking and duration of diabetes were all independent risk factors for decreased eGFR (all P<0.05). CONCLUSION: The present results suggest that increased FFA level might be involved in the development of diabetic nephropathy.