Microplastics (MPs) are emerging environmental contaminants with potential hepatotoxicity, yet direct epidemiological evidence linking internal MP exposure to liver injury is scarce, particularly in individuals with type 2 diabetes (T2D). In this cross-sectional study nested within the METAL2 cohort, we aimed to characterize blood microplastic profiles in patients with T2D and to determine whether specific MP polymers are associated with hepatic steatosis and fibrosis risk, with experimental validation of the identified polymer. In patients with T2D, multiple MP polymers were detectable in blood, with polyvinyl chloride (PVC), polyamide 66 (PA66), and polystyrene (PS) being the most prevalent. Although PVC constituted the largest proportion of total MP burden, PS showed the most consistent nominal positive liver-related signal in the human analyses, including higher levels in participants with elevated fibrosis risk and higher FIB-4 and ALT in the highest exposure quartile. Experimental validation in diabetic mice demonstrated that PS microplastics markedly exacerbated hepatic steatosis, inflammation, and collagen deposition, leading to overt liver fibrosis. Mechanistically, PS-MPs exposure disrupted hepatic lipid homeostasis and concurrently activated the NLRP3 inflammasome and the TGF-β1/Smad signaling pathway, promoting inflammatory amplification and hepatic stellate cell activation. This integrated human and experimental study provides preliminary evidence that circulating PS-associated signals are linked to liver-related indices in T2D, while experimental findings support the biological plausibility that PS exposure may aggravate hepatic injury under diabetic conditions.

Immune checkpoint molecules (ICMs) are a class of surface proteins predominantly expressed on immune cells that play a key role in maintaining immune homeostasis by regulating the functions of T cells and other immune cells. Beyond their established immunoregulatory roles, emerging evidence indicates that ICMs are also involved in metabolic regulation. Within the tumor microenvironment (TME), tumour-derived ICMs have been shown to modulate glucose, amino acid, and lipid metabolism in infiltrating T cells, thereby influencing their metabolic reprogramming and functional states. Certain ICMs expressed on immune cells may directly regulate systemic metabolism through cell-intrinsic, immune-independent mechanisms. Moreover, specific ICMs are constitutively expressed in key metabolic tissues, such as pancreatic islets, liver, and adipose tissue, where they are thought to contribute to the maintenance of systemic metabolic homeostasis. Clinically, host metabolic status can affect the efficacy of immune checkpoint inhibitor (ICI) therapies. Conversely, ICI treatment can lead to metabolism-related adverse effects, such as ICI-associated diabetes (ICI-DM), which may extend beyond classic autoimmune insulin-dependent diabetes. Accumulating evidence suggests that ICMs can exert direct regulatory roles in metabolism independent of their canonical immune functions. Elucidating how ICMs regulate metabolism could, on the one hand, improve ICI therapy by maintaining metabolic homeostasis and preventing T cell exhaustion, and on the other hand, facilitate the development of novel therapeutic strategies for metabolic diseases that simultaneously target metabolic and inflammatory pathways. This review synthesises current knowledge on the metabolic roles and regulatory mechanisms of ICMs.

Mitochondrial redox imbalance and defective oxidative phosphorylation are central features of lipotoxic cardiac injury, but whether diet-related chemical exposures perturb cardiomyocyte mitochondrial gene-expression machinery remains unclear. Here, we investigated whether sucralose promotes cardiac redox-metabolic remodeling and lipid accumulation involving MRPL12-associated mitoribosomal impairment. Male C57BL/6J mice were exposed to sucralose in drinking water for 28 weeks; hiPSC-derived cardiomyocytes were used for mechanistic assays, and hiPSC-derived cardiomyocytes and H9c2 cardiomyoblast-like cells were used for lipid-accumulation assays under palmitic acid/oleic acid-induced lipid-loading conditions. Chronic sucralose exposure was associated with cardiac dysfunction, myocardial lipid accumulation, mitochondrial structural injury, ATP depletion, oxidative stress-associated signals, reduced glutathione redox buffering capacity, and reduced oxidative phosphorylation (OXPHOS) protein abundance. Quantitative cardiac proteomics identified mitochondrial ribosome- and oxidative phosphorylation-related changes, with MRPL12 emerging as a candidate mechanistic node. In cardiomyocytes, sucralose reduced MRPL12 abundance, altered the distribution of 39S/55S-enriched mitoribosomal fractions, suppressed residual nascent protein synthesis under cytosolic translation-suppressed conditions, reduced mitochondrially encoded OXPHOS proteins, impaired mitochondrial respiration, and aggravated lipid accumulation. Restoration of MRPL12 in cardiomyocytes or mouse hearts partially attenuated sucralose-associated redox-bioenergetic impairment, lipid deposition, and cardiac remodeling. Conversely, siRNA-mediated MRPL12 knockdown phenocopied key sucralose-associated abnormalities, including reduced abundance of mtDNA-encoded OXPHOS subunits, impaired respiration, increased mitochondrial superoxide-associated signal, and lipid accumulation. These findings support MRPL12-associated mitoribosomal impairment as a contributing mechanism linking sucralose exposure to mitochondrial redox-bioenergetic dysfunction and metabolic remodeling in the heart.

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic loss of the Y chromosome (mLOY) are age-related somatic genomic mutations linked to mortality, yet their independent and combined associations with mortality remain incompletely characterized. We analyzed 205,543 UK Biobank men with CHIP and mLOY status derived from genomic data and followed them for all-cause and cause-specific mortality. During a median follow-up of 15.3 years, 28,164 deaths occurred. In multivariable Cox models, CHIP was associated with higher all-cause mortality (HR 1.34, 95% CI 1.28–1.41), whereas mLOY showed a weaker association (HR 1.04, 95% CI 1.01–1.06). Men with both CHIP and mLOY had the highest absolute mortality risk (HR 1.39, 95% CI 1.27–1.52), but formal tests did not support statistically significant additive or multiplicative interaction. Similar patterns were observed across major cause-specific outcomes including cardiovascular disease mortality, cancer mortality, and respiratory mortality. Exploratory gene-specific analyses suggested heterogeneity by CHIP driver gene, with SRSF2 carriers with co-occurring mLOY showing the largest mortality estimate, although this small-subgroup finding requires replication. These findings support independent associations of CHIP and mLOY with mortality in men, while providing no clear evidence for synergistic interaction.

Objective: B7-H4 (B7S1, B7x, VTCN1) is an important immune checkpoint molecule that maintains immune homeostasis and is also expressed in pancreatic R cells. The polymorphism of B7-H4 influences the prevalence of Type 2 diabetes (T2D), suggesting a potential role of B7-H4 in the physiological function of pancreatic R cells and the pathogenesis of T2D. Methods: R-cell-specific B7-H4 knockout mice (B7-H4 cKO mice) and their wild-type littermates were used to investigate the in vivo effects of B7-H4 on pancreatic R-cell morphology and function. AAV2/8-ins2-B7H4 and a control virus were infused via the pancreatic intraduct into high- fat diet (HFD)-treated mice to elucidate the therapeutic effect of B7-H4. RNA sequencing was conducted on primary islets. A Luminex assay was used to quantify cytokine changes in B7-H4 cKO mice. Electron microscopy imaging was used to observe insulin secretory vesicles in pancreatic R cells. Results: Lesion of B7-H4 in R cells results in glucose intolerance due to reduced R-cell mass and deficient insulin secretion, whereas over- expression of B7-H4 in R cells ameliorates glucose intolerance in HFD-fed mice. Mechanistically, B7-H4 deficiency activates signal transducer and activator of transcription 5 (Stat5) signalling, which inhibits the expression of apolipoprotein F (Apof), leading to reduced cholesterol efflux and accumulated cholesterol in R cells, thereby impairing insulin processing and secretion. Overexpression of Apof in R cells or intraperitoneal injection of a Stat5 inhibitor reverses the metabolic phenotype and insulin secretion deficiency in B7-H4 cKO mice. Conclusion: Our study demonstrated that B7-H4 plays an important role in regulating R-cell mass and insulin secretion, which may shed new light on the development of novel strategies for T2D treatment. (c) 2024 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

L-Phenylalanine (L-Phe) levels are elevated in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, whether L-Phe induces liver steatosis and the underlying mechanism remain unknown. This study aimed to investigate the mechanism through which L-Phe promotes liver steatosis. We utilized human data from the UK Biobank and SPECT-China studies. Plasma/serum samples were collected for metabolomic testing to measure L-Phe levels. A rat model with L-Phe in the drinking water was established to investigate changes in hepatic lipid metabolism. In addition, BNIP3 was overexpressed both in vitro and in vivo to validate the role of L-Phe in BNIP3-mediated mitophagy associated with liver steatosis. In both populations, elevated L-Phe quartiles were associated with increased body mass index, triglyceride, and transaminase levels and increased odds of MASLD (all p < 0.05). Rats exposed to L-Phe had increased hepatic lipid deposition and decreased mitophagy in the liver. Differentially expressed proteins were enriched in the PPARα and fatty acid β-oxidation signalling pathways, with downregulation of the mitophagy marker BNIP3. Mitophagy was activated by rapamycin and then inhibited by L-Phe, indicating that elevated L-Phe promoted lipid accumulation by suppressing mitophagy. BNIP3 overexpression effectively mitigated L-Phe-induced hepatic steatosis by restoring mitophagy. Moreover, L-Phe regulates the BNIP3-mediated PPARα and AMPK/mTOR signalling pathways to promote hepatic steatosis. Our study revealed the role of L-Phe in regulating lipid metabolism and promoting liver steatosis via BNIP3-mediated mitophagy. These findings provide novel insights into the link between L-Phe and liver steatosis, suggesting potential nutritional intervention strategies for preventing MASLD.

OBJECTIVE:This research investigates the prevalence of thyroid nodules and their association with anxiety and depression disorders in Eastern China. It also investigates the potential factors influencing this relationship, focusing on demographics and thyroid function. METHODS:As part of the SPECT-China project, a cross-sectional survey was conducted with 5497 participants from both urban and rural regions in Shanghai, Zhejiang, and Jiangxi provinces. Participants received thyroid ultrasonography and laboratory tests for thyroid function, while their mental health was evaluated using the Zung Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS). Data analysis employed descriptive statistics, Student's T-test, Chi-square test, and logistic regression. RESULTS:The study found a high prevalence of TNs (57.5%) among participants, with a higher incidence in females, older individuals, and those with lower education levels. Anxiety and depression disorders were diagnosed in 4.8% and 5.2% of participants, respectively, with higher rates in females and older individuals. Logistic regression analysis, controlling for age and gender, showed no significant link between TNs and anxiety or depression disorders in the general population. However, a significant association was observed in females. No significant correlation was identified between thyroid function (as measured by TSH levels) and the presence of TNs or mental disorders. CONCLUSION:Thyroid nodules are prevalent in Eastern China, particularly among females, older individuals, and those with lower education. TNs show a significant correlation with anxiety and depression disorders in females, although not in the general population. This study emphasizes the significance of examining gender differences in the link between thyroid nodules and mental health, and calls for additional research in this domain.

Certain secretory proteins are known to be critical for maintaining the stemness of stem cells through autocrine signaling. However, the processes underlying the biogenesis, maturation, and secretion of these proteins remain largely unknown. Here we demonstrate that many secretory proteins produced by hematopoietic stem cells (HSCs) undergo exosomal maturation and release that is controlled by vacuolar protein sorting protein 33b (VPS33B). Deletion of VPS33B in either mouse or human HSCs resulted in impaired exosome maturation and secretion as well as loss of stemness. Additionally, VPS33B deficiency led to a dramatic delay in leukemogenesis. Exosomes purified from either conditioned medium or human plasma could partially rescue the defects of HSCs and leukemia-initiating cells (LICs). VPS33B co-existed in exosomes with GDI2, VPS16B, FLOT1, and other known exosome markers. Mechanistically, VPS33B interacted with the GDI2/RAB11A/RAB27A pathway to regulate the trafficking of secretory proteins as exosomes. These findings reveal an essential role for VPS33B in exosome pathways in HSCs and LICs. Moreover, they shed light on the understanding of vesicle trafficking in other stem cells and on the development of improved strategies for cancer treatment.

Background A healthy lifestyle is an important factor for preventing heart failure. However, the association between outdoor light exposure time and heart failure is still unknown. The aim of this study was to examine the association between outdoor light exposure time and the incidence of heart failure. Methods and Results This cohort study included participants from the UK Biobank recruited from 2006 to 2010 who were 40 to 70 years of age and free of heart failure at baseline. The mean follow‐up time was 12.61 years. The outdoor light exposure time was self‐reported at baseline. A restricted cubic spline was performed to examine the potential nonlinear relationship between outdoor light exposure and the incidence of heart failure. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% CIs. During a mean follow‐up of 12.61 years, 13 789 participants were first diagnosed with heart failure. There was a nonlinear (J‐shaped) trend between outdoor light time and heart failure risk. Cox proportional hazard regression models showed that, compared with participants who received an average of 1.0 to 2.5 hours of outdoor light per day, those with <1.0 hours or >2.5 hours had a higher risk of heart failure after the model was adjusted for age and sex (<1.0 hours: HR, 1.27 [95% CI, 1.18–1.36]; >2.5 hours: HR, 1.11 [95% CI, 1.07–1.15]). These associations were still significant in the fully adjusted models (<1.0 hours: HR, 1.10 [95% CI, 1.03–1.18]; >2.5 hours: HR, 1.07 [95% CI, 1.03–1.11]). Conclusions We found a J‐shaped association between outdoor light exposure time and the risk of incident heart failure, suggesting that moderate exposure to outdoor light may be a prevention strategy for heart failure.

Objectives: Early-famine exposure was reported to be associated with metabolic associated fatty liver disease (MAFLD); however, it has not been fully elucidated whether the gene-famine interaction exist in this association. We aimed to investigate the association between early-life famine exposure in different genetic risk stratifications and the risk of MAFLD in adulthood. Design, setting, participants, and measurements: The study included 8213 participants from the SPECT-China study. Famine exposure subgroups was defined according to the birth year. A genetic risk score (GRS) was constructed with single nucleotide polymorphisms associated with MAFLD in East Asians. Logistic models were used to examine the association of famine exposure and GRS with MAFLD. Results: Early-life famine exposure was positively associated with MAFLD after adjusting for multiple confounders (OR (95% CI): fetal-exposure 1.3(1.11−1.53), childhood exposure 1.12(1−1.25)). Meanwhile, with per SD increment of GRS (2.49 points), the OR(95%CI) of MAFLD was 1.1(1.04−1.16). In high GRS group, fetal-exposure was positively associated with 45% higher risk of MAFLD (1.45(1.15–1.83)). In men, neither in low or high GRS subgroups observed an association between early-life famine exposure and MAFLD. But in women with high GRS of MAFLD, fetal-exposure was positively associated with even higher risk of MAFLD (1.64(1.22–2.22)). Conclusion: The positive association between early-life famine exposure and MAFLD is intensified by high genetic susceptibility of MAFLD in women and in general population in China; while this association does not exist in men or in those with low genetic risk scores.

PURPOSE:Aging plays an important role in type 2 diabetes mellitus (T2DM). But the association between accelerated biological age and T2DM, and the mechanisms underlying this association remains unclear. Thus, this study aimed to examine the associations of biological aging with T2DM, and explore the potential mediation effect of amino acids. METHODS:This prospective cohort study included 95,773 participants in the UK Biobank who were free of diabetes at baseline. Biological age was measured from clinical traits using PhenoAgeAccel. Cox proportional hazard models were used to estimate the hazard ritios (HRs) and 95% confidence intervals (CIs), and mediation analysis was used to explore the mediation effect of amino acids. RESULTS:During a median follow-up of 14.02 years, 6,347 incident T2DM cases were recorded. After multivariable adjustment for sociodemographic characteristics, lifestyle factors, and other risk factors of T2DM, participants with older biological age were at increased risk of incident T2DM (30% increase per standard deviation of PhenoAgeAccel, 95% CI: 28.0-33.0%). Additionally, higher branched chain amino acids (BCAAs) including isoleucine and leucine, aromatic amino acids (AAAs) including phenylalanine and tyrosine, were associated with increased PhenoAgeAccel and risk of incident T2DM; while glutamine and glycine were inversely associated. Alanine, glutamine, glycine, phenylalanine, tyrosine, isoleucine, leucine, and total concentration of branched-chain amnio acids could partially explain the associations between PhenoAgeAccel and T2DM. CONCLUSION:Accelerated biological aging was associated with increased risk of incident T2DM independent of chronological age and may be a risk factor of T2DM, partially mediated by several amino acids.

AIM:To explore the relationship between proinflammatory diet, habitual salt intake and the onset of type 2 diabetes. METHODS:This prospective study was conducted among 171 094 UK Biobank participants who completed at least one 24-h dietary questionnaire and were free of diabetes at baseline. Participants were followed up until 1 March 2023 for type 2 diabetes incidence, with diagnosis information obtained from linked medical records. An Energy-adjusted Diet Inflammatory Index (E-DII) was calculated based on 28 food parameters. Habitual salt intake was determined through the self-reported frequency of adding salt to foods. The associations between E-DII, habitual salt intake and type 2 diabetes incidence were tested by the Cox proportional hazard regression model. RESULTS:Over a median follow-up period of 13.5 years, 6216 cases of type 2 diabetes were documented. Compared with participants with a low E-DII (indicative of an anti-inflammatory diet), participants with a high E-DII (indicative of a proinflammatory diet) had an 18% heightened risk of developing type 2 diabetes. The association between E-DII and type 2 diabetes tends to be linear after adjustment for major confounders. Participants with a proinflammatory diet and always adding salt to foods had the highest risk of type 2 diabetes incidence (hazard ratio 1.60, 95% confidence interval 1.32-1.94). CONCLUSIONS:Our findings indicate that a proinflammatory diet and higher habitual salt intake were associated with an increased risk of type 2 diabetes. These results support the public health promotion of an anti-inflammatory diet and reducing salt intake to prevent the onset of type 2 diabetes.

BackgroundImmune disorders are key heart failure (HF) triggers, but little is known about whether the status of immunity affects the incidence of HF. To explore this, we used blood cell counts and derived ratios to investigate the association between immunity status markers and HF incidence.MethodsThe number and proportion of peripheral blood leucocytes in a physiological state are related to the body’s immune status. Neutrophils, monocytes, SII (systemic immune-inflammatory index), NLR (neutrophil-to-lymphocyte ratio), and PLR (platelet-to-lymphocyte ratio) serve as innate immunity status markers, while lymphocytes and LMR (lymphocyte-to-monocyte ratio) serve as specific immunity status markers. 330 362 UK Biobank (UKB) participants were finally examined. Cox proportional hazard models were used to explore the relationship between immunity status markers and HF incidence. Flexible parametric survival models were used to capture time-varying relationships between blood cell ratios and HRs for HF. Subgroup analyses were conducted by age, sex, and body mass index. Finally, sensitivity analyses were performed to validate the results.ResultsDuring a median follow-up of 14.1 years, 9611 (2.9%) participants developed HF. Neutrophils, monocytes, SII, and NLR were positively associated with HF incidence, with fully adjusted per SD increment HR (95% CI) of 1.20 (1.17 to 1.22), 1.09 (1.07 to 1.12), 1.12 (1.10 to 1.14), and 1.16 (1.14 to 1.18), respectively. Platelets, lymphocytes, and LMR were inversely correlated with HF incidence, with fully adjusted per SD increment HR (95% CI) of 0.97 (0.95 to 1.00), 0.97 (0.95 to 0.99), and 0.90 (0.88 to 0.92), respectively.ConclusionsThe innate immunity status markers were positively associated with HF incidence, while specific immunity status markers exhibited an inverse association, offering novel insights for HF prediction and intervention.

Objective: Chronic low-grade inflammation of the pancreatic islets is the characteristic of type 2 diabetes (T2D), and some of the immune checkpoints may play important roles in the pancreatic islet inflammation. Thus, we aim to explore the immune checkpoint genes (ICGs) associated with T2D, thereby revealing the role of ICGs in the pathogenesis of T2D based on bioinformatic analyses. Methods: Differentially expressed genes (DEGs) and immune checkpoint genes (ICGs) of islets between T2D and control group were screened from datasets of the Gene Expression Omnibus (GEO). A risk model was built based on the coefficients of ICGs calculated by ridge regression. Functional enrichment analysis and immune cell infiltration estimation were conducted. Correlations between ICGs and hub genes, T2D-related disease genes, insulin secretion genes, and beta cell function-related genes were analyzed. Finally, we conducted RT-PCR to verify the expression of these ICGs. Results: In total, pancreatic islets from 19 cases of T2D and 84 healthy subjects were included. We identified 458 DEGs. Six significantly upregulated ICGs (CD44, CD47, HAVCR2, SIRPA, TNFSF9, and VTCN1) in T2D were screened out. These ICGs were significantly correlated with several hub genes and T2D-related genes; furthermore, they were correlated with insulin secretion and beta cell function-related genes. The analysis of immune infiltration showed that the concentrations of eosinophils, T cells CD4 naive, and T cells regulatory (Tregs) were significantly higher, but CD4 memory resting T cells and monocytes were lower in islets of T2D patients. The infiltrated immune cells in T2D pancreatic islet were associated with these six ICGs. Finally, the expression levels of four ICGs were confirmed by RT-PCR, and three ICGs were validated in another independent dataset. Conclusion: In conclusion, the identified ICGs may play an important role in T2D. Identification of these differential genes may provide new clues for the diagnosis and treatment of T2D.

AIMS:Follicle-stimulating hormone (FSH) is associated with higher risks of metabolic syndrome and diabetes in menopausal women. We aimed to investigate whether FSH was associated with the lipid profile in women older than 55 years.DESIGN:The data were obtained from a cross-sectional study.PARTICIPANTS:Our data were from the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (China, including Shanghai and Zhejiang, Jiangxi and Anhui provinces). A total of 1795 women older than 55 years were selected.METHODS:Morning serum sex hormones and lipid profiles were measured. Linear and logistic regression analyses were used to analyse the data.RESULTS:Lower FSH was associated with lower high-density lipoprotein cholesterol (HDL-C) and higher triglycerides (TG), total cholesterol (TC)/HDL-C ratio and low-density lipoprotein cholesterol (LDL-C)/HDL-C ratio (all p for trend <0.05) after adjusting for age and other sex hormones. After further adjustment for body mass index, diabetes and hypertension, the associations of FSH with the lipid profile weakened, but the associations of FSH quartiles with HDL-C and the TC/HDL-C ratio were still significant (both p for trend <0.05). Compared with women in the highest FSH quartile, the odds of low HDL-C (HDL-C<1.04 mmol/L) in women in the lowest FSH quartile were 5.25 (95% CI 1.60 to 17.26) (p for trend <0.05) in the fully adjusted model, and the odds of TC≥6.22 mmol/L, TGs≥2.26 mmol/L and LDL-C≥4.14 mmol/L were not significant. Luteinising hormone did not show a significant association with dyslipidaemia.CONCLUSION:Lower FSH was associated with a worse lipid profile in women older than 55. Diabetes, adiposity and hypertension mostly explained the association of FSH with TGs and the LDL-C/HDL-C ratio but only partially explained the associations of FSH with HDL-C and the TC/HDL-C ratio.

Aim:Previous studies have implicated the uric acid to high-density lipoprotein cholesterol (HDL-C) ratio (UHR) was associated with type 2 diabetes. However, the association between UHR and diabetes-related vascular damages is still unclear. Methods:The total of 4551 patients with type 2 diabetes from the cross-sectional Environmental Pollutant Exposure and Metabolic Diseases in Shanghai study (METAL study) were enrolled. UHR was calculated as uric acid to HDL-C ratio. Cardiovascular disease (CVD) was defined as previously diagnosed with stroke, coronary heart disease, or peripheral arterial disease. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate ≤60 mL/min/1.73 m2 and/or urinary albumin to creatinine ratio ≥30 mg/g. Fundus image was examined by trained individuals and degree of diabetic retinopathy (DR) was evaluated. Results:UHR was positively correlated with CVD (OR = 1.28, 95% CI: 1.02-1.61) and CKD (OR = 1.78, 95% CI: 1.39-2.27) after adjusting for all confounders. No association was found between UHR and DR. In stratified analyses, UHR was predominantly correlated with CVD in diabetic patients with age older than 65 (OR = 1.41, 95% CI: 1.08-1.85), female (OR = 1.43, 95% CI: 1.06-1.94) and BMI≥24kg/m2 (OR = 1.57, 95% CI: 1.17-2.11). A 1-SD increment of UHR was also positively associated with CVD (OR 1.26, 95% CI 1.03, 1.15) and CKD (OR 1.28, 95% CI 1.20,1.39). UHR was positively associated with CKD in all subgroups analysis. No significant interaction effect was observed between UHR and all subgroup variables in CVD and CKD risk. Conclusion:Our study reported a positive association between the UHR and diabetic-related vascular complications in men and postmenopausal women. The relationship between the UHR and DR seems to be uncertain and requires further investigation. And no significant interaction effect was observed between the UHR and all subgroup variables in CVD and CKD risk.

Aims Recent studies have demonstrated the associations of the consumption of different beverages with cardiometabolic diseases, whereas no studies have investigated such associations in heart failure (HF). Thus, this study aimed to explore the associations of the consumption of sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and pure fruit/vegetable juices (PJs) with the risk of incident HF. Methods and results This prospective cohort study included 209 829 participants in the UK Biobank who completed at least one 24-h diet questionnaire and who were free of baseline HF. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 9.9 years, 4328 incident HF cases were recorded. Compared to corresponding non-consumers, individuals who consumed >2 L/week SSBs or ASBs had an increased risk of HF (HR: 1.22, 95% CI: 1.08-1.38 and HR: 1.30, 95% CI: 1.16-1.47, respectively) in the multivariate adjusted model. An inverse association was observed between the consumption of >0-1 L/week PJs and the risk of HF (HR, 0.90; 95% CI, 0.83-0.98). Additionally, a significant interaction was observed between PJ consumption and sleep duration on HF risk (P for interaction = 0.030). Conclusions Increased consumption of SSBs or ASBs may be an independent risk factor for HF, whereas moderate intake of PJs may have a protective effect on HF. Lay Summary High intake of sugar-sweetened or artificially sweetened beverages was associated with an increased risk of heart failure, and moderate intake of pure fruit/vegetable juices was inversely associated with incident heart failure. Consumption of artificially sweetened beverages is a risk factor for heart failure; thus, it may not be a safe alternative to sugar. Moderate consumption of pure fruit/vegetable juices may be a preventive strategy for heart failure.

Objective: Obesity has been identified as a risk factor for chronic kidney disease. However, the impact of obesity, with or without a metabolically healthy condition, on diabetic kidney disease (DKD) remains unclear. We aimed to examine the associations of obesity patterns and metabolic abnormalities with the prevalence of DKD. Methods: This cross-sectional study included 4079 patients with type 2 diabetes from eleven communities in Shanghai, China. General obesity was assessed by body mass index (BMI) and abdominal obesity assessed by waist-to-hip ratio. Metabolic abnormalities were determined according to the Adult Treatment Panel III criteria. DKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m(2) or urinary albumin-creatinine ratio >= 30 mg/g. Poisson regression model with inverse probability of treatment weighting was used to estimate prevalence ratios (PRs) and 95% CIs. Results: Higher BMI and WHR were each associated with a greater prevalence of DKD after mutual adjustment. When considered jointly, patients with both general obesity and abdominal obesity had the highest odds of DKD (PR 1.51, 95% CI 1.29-1.76). The associations of BMI and WHR with prevalent DKD were mainly observed in patients with use of antidiabetic drugs but not in those without drug use. Compared with normal-weight patients with 0-1 metabolic abnormality, patients who were overweight or obese with 0-1 metabolic abnormality showed increased odds of DKD. The PRs (95% CI) of DKD for patients with both overweight/obesity and abdominal obesity who had 0-1, 2, and 3 metabolic abnormalities were 1.59 (1.20-2.10), 1.68 (1.29-2.18), and 2.16 (1.67-2.78), respectively, relative to those with normal BMI and no abdominal obesity who had 0-1 metabolic abnormality. Conclusion: BMI and WHR were positively associated with DKD prevalence. Obesity composite and metabolic abnormalities had an additive effect on the odds of DKD. Further longitudinal studies are warranted to elucidate the role of obesity and metabolic abnormalities in the development of DKD.

Background: Menopause accelerated progression of chronic kidney disease (CKD) in aging women. Our previous research found that macrophage infiltration was observed in follicle stimulating hormone (FSH)-induced tubulointerstitial fibrosis, but the underlying mechanism by which FSH modulated macrophagesremained unclear. Methods: qPCR and transwell assay were performed to evaluate M1 macrophage activation and migration. Transmission electron microscopy, nanoparticle tracking analysis and western blotting were used to characterize the properties of exosomes. miRNAs of FSH-treated HK-2 cells were profiled by small RNA sequencing. Dual-luciferase reporter assays were performed to verify the association between miR-33a-3p and PTEN. Findings: We demonstrated that the number of CD68+CD86+ M1 macrophages and M1 macrophage-related markers were significantly increased in ovariectomized (OVX) and OVX + GnRHa + FSH mice, both of which had high levels of circulating FSH. FSH acted directly on macrophages and induced M1 polarization and migration to activate renal inflammation via AKT and NF-κB pathways, and AKT signaling might function as the upstream of NF-κB pathway. More importantly, exosomal miR-33a-3p from FSH-mediated tubular epithelia cells(TECs) also resulted in proinflammatory phenotype activation and migration by targeting PTEN/AKT signaling axis. High levels of miR-33a-3p were found in plasma and positively associated with the severity of renal function as well as serum FSH levels in postmenopausal women with decreased eGFR.Interpretations：: FSH promoted tubulointerstitial inflammation by modulating M1 macrophage activation and migration via AKT/NF-κB pathways. Our findings revealed a novel effect of FSH on renal injury, which may provide new insights into the mechanisms of postmenopausal CKD.Funding: This study was supported by the National Natural Science Foundation of China (82000750, 82120108008); Postdoctoral Scientific Research Foundation of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (Kun Zhang-2021-startup funding).Declaration of Interest: The authors declare that they have no competing interests.Ethical Approval: All subjects were provided informed consent and the research protocols were approved by Ethics Committee of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. All the experimental procedures were approved by the Animal Research Committee of Shanghai Ninth People's Hospital, School of medicine, Shanghai Jiaotong University.

AIMS:Exposure to lead and cadmium has been associated with type 2 diabetes, but the results are largely inconsistent, and little is known about their joint effect. We aimed to investigate the associations of lead and cadmium co-exposure with fasting plasma glucose (FPG) and type 2 diabetes.MATERIALS AND METHODS:The study included 5732 participants aged ≥18 years from 16 communities in East China. Blood levels of lead and cadmium were determined using graphite furnace atomic absorption spectrometry. Multivariable linear and logistic regression models were performed to evaluate the associations of lead and cadmium alone or in combination with FPG and diabetes.RESULTS:The median (interquartile range) values of blood lead and cadmium were 40.0 (26.8-57.9) and 1.70 (0.56-3.60) μg/L, respectively. After adjustment for potential confounders, blood lead levels were positively associated with FPG (difference comparing extreme lead quartiles = 0.11 [95% CI: 0.03, 0.20] mmol/L) and prevalent diabetes (odds ratio [OR] = 1.35 [95% CI: 1.03, 1.78]). The association between lead and diabetes was observed among participants with high cadmium, but not among those with low cadmium (P for interaction = 0.03). In the joint analysis, compared with participants with low levels of blood lead and cadmium, participants with high levels of two metals had a 0.16 (95% CI: 0.07, 0.25) mmol/L increase in FPG and a 51% (OR = 1.51, 95% CI: 1.15, 1.99) increase in odds of diabetes.CONCLUSIONS:Our findings suggest that lead and cadmium co-exposure is significantly associated with elevated FPG and type 2 diabetes in the general population.