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Context Patients with younger onset of type 2 diabetes (YT2D) have increased risk for kidney failure compared to those with late onset. However, the mechanism of diabetic kidney disease (DKD) progression in this high-risk group is poorly understood. Objective This work aimed to identify novel biomarkers and potential causal proteins associated with DKD progression in patients with YT2D. Methods Among YT2D (T2D onset age <40 years), 144 DKD progressors (cases) were matched for T2D onset age, sex, and ethnicity with 292 nonprogressors (controls) and divided into discovery and validation sets. DKD progression was defined as decline of estimated glomerular filtration rate (eGFR) of 3 mL/min/1.73 m2 or greater or 40% decline in eGFR from baseline. A total of 1472 plasma proteins were measured through a multiplex immunoassay that uses a proximity extension assay technology. Multivariable logistic regression was used to identify proteins associated with DKD progression. Mendelian randomization (MR) was used to evaluate causal relationship between plasma proteins and DKD progression. Results Forty-two plasma proteins were associated with DKD progression, independent of traditional cardiorenal risk factors, baseline eGFR, and urine albumin-to-creatinine ratio. The proteins identified were related to inflammatory and remodeling biological processes. Our findings suggest angiogenin as one of the top signals (odds ratio = 5.29; 95% CI, 2.39-11.73; P = 4.03 × 10−5). Furthermore, genetically determined plasma angiogenin level was associated with increased odds of DKD progression. Conclusion Large-scale proteomic analysis identified novel proteomic biomarkers for DKD progression in YT2D. Genetic evidence suggest a causal role of plasma angiogenin in DKD progression. [ABSTRACT FROM AUTHOR]

Context Metabolites in the tricarboxylic acid (TCA) pathway have pleiotropic functions. Objective To study the association between urine TCA cycle metabolites and the risk for chronic kidney disease progression in individuals with type 2 diabetes. Design, setting and participants A prospective study in a discovery (n = 1826) and a validation (n = 1235) cohort of people with type 2 diabetes in a regional hospital and a primary care facility Exposure and Outcome Urine lactate, pyruvate, citrate, alpha-ketoglutarate, succinate, fumarate, and malate were measured by mass spectrometry. Chronic kidney disease progression was defined as a composite of sustained estimated glomerular filtration rate below 15 mL/min/1.73 m2, dialysis, renal death, or doubling of serum creatinine. Results During a median of 9.2 (interquartile range 8.1-9.7) and 4.0 (3.2-5.1) years of follow-up, 213 and 107 renal events were identified. Cox regression suggested that urine lactate, fumarate, and malate were associated with an increased risk (adjusted hazard ratio, [95% CI] 1.63 [1.16-2.28], 1.82 [1.17-2.82], and 1.49 [1.05-2.11], per SD), whereas citrate was associated with a low risk (aHR 0.83 [0.72-0.96] per SD) for the renal outcome after adjustment for cardiorenal risk factors. These findings were reproducible in the validation cohort. Noteworthy, fumarate and citrate were independently associated with the renal outcome after additional adjustment for other metabolites. Conclusion Urine fumarate and citrate predict the risk for progression to end-stage kidney disease independent of clinical risk factors and other urine metabolites. These 2 metabolites in TCA cycle pathway may play important roles in the pathophysiological network, underpinning progressive loss of kidney function in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Introduction : Osteoprotegerin (OPG) inhibits vascular calcification which is central to pathogenesis of arterial stiffness. However, it promotes inflammation by upregulating expression of vascular cell adhesion molecule-1(VCAM-1), thereby contributing to arterial stiffness. We investigated longitudinal association between OPG and arterial stiffness in type 2 diabetes (T2D), causality of the association and mediation by VCAM-1. Methods : This was a prospective cohort study of T2D patients (N = 1877, mean age 57.0 ± 10.8) with 10 years' follow-up. Baseline plasma OPG was measured using immunoassay. Pulse wave velocity (PWV) was assessed using applanation tonometry. We examined association between OPG and follow-up PWV using linear mixed model. One-sample Mendelian Randomization (MR) was conducted with rs1385492 as OPG-associated single nucleotide polymorphism (SNP). Results : Baseline natural log (Ln)-transformed OPG was positively associated with baseline and follow-up PWV with adjusted coefficients 0.43 (95%CI 0.05, 0.80; p =.026) and 0.51 (95%CI 0.06 to 0.97; p =.028) respectively. Genetically-predicted higher levels of plasma OPG was associated with higher last follow-up PWV with coefficient 10.81 (95%CI 2.97, 18.65; p =.007) per unit increase in LnOPG. Higher VCAM-1 accounted for 10.2% of association between LnOPG and follow-up PWV. Discussion : Baseline plasma OPG was associated with higher follow-up PWV in patients with T2D, with genetic evidence from MR. This association may be mediated, at least in part, by VCAM-1. [ABSTRACT FROM AUTHOR]

Context Leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in the pathogenesis of diabetic complications, but its association with cognitive function remains unclear. Objective Our primary objective is to investigate the longitudinal association between LRG1 and cognitive function in patients with type 2 diabetes mellitus (T2DM). Secondarily, we determine the causal relationship using Mendelian randomization (MR) and the role of arterial stiffness as a potential mediator. Methods T2DM patients (n = 1039; age = 64.1 ± 6.4 years) were followed-up for 5.3 ± 1.2 years. Plasma LRG1 was measured at baseline using enzyme-linked immunosorbent assay. Baseline and follow-up cognitive function was assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). One-sample MR was performed with rs4806985 as plasma LRG1-associated single-nucleotide polymorphism. Mediation analysis was performed to examine if pulse wave velocity (PWV), an arterial stiffness index, mediated the association between plasma LRG1 and follow-up cognitive function. Results Elevated baseline natural log (Ln)-transformed LRG1 was inversely associated with baseline and follow-up RBANS total score with adjusted coefficients −1.38 (95% CI −2.55 to −.21; P =.021) and −1.38 (95% CI −2.70 to −.07; P =.039), respectively. Genetically predicted higher levels of plasma LRG1 was associated with lower follow-up RBANS total score with coefficient −7.44 (95% CI −14.14 to −.74; P =.030) per unit increase in LnLRG1. Higher PWV accounted for 27.7% of the association between LnLRG1 and follow-up RBANS total score. Conclusion Baseline plasma LRG1 was associated with lower cognitive function at follow-up in patients with T2DM, mediated by PWV. MR analysis provided evidence of an association between genetically influenced plasma LRG1 and lower cognitive function at follow-up. [ABSTRACT FROM AUTHOR]

Introduction The leading cause of morbidity and mortality in type 2 diabetes (T2D) is cardiovascular disease. Mounting evidence supports increased arterial stiffness as a powerful risk factor for cardiovascular disease. [...], Background: Studies investigating the association between depression and aortic stiffness in older patients with type 2 diabetes are lacking. We postulated an association between depressive symptoms and aortic stiffness, and this relationship may be mediated by increased adiposity. Methods: We analyzed participants with type 2 diabetes aged 55 years or older (n = 958). We measured aortic stiffness using carotid-femoral pulse wave velocity (cut-off [greater than or equal to] 12 m/s) using the tonometry method. We defined depressive symptoms as a score of greater than 5 on the Geriatric Depression Scale-15 (GDS-15). Adiposity indices we assessed were body mass index, waist- circumference, waist-to-height ratio, visceral fat area and fat mass. Results: Among the participants, 27.2% had aortic stiffness, of whom 6.5% had depressive symptoms. Score on the GDS-15 was correlated with pulse wave velocity, and both variables were correlated with the adiposity markers we analyzed (all p < 0.05). Depressive symptoms were associated with pulse wave velocity (B = 1.79, 95% confidence interval [CI] 0.83-2.75) or aortic stiffness (risk ratio 1.60, 95% CI 1.10-2.33) in the unadjusted model. The association persisted after controlling for demographics, duration of diabetes, glycated hemoglobin, comorbidities and medications. Further adjustment for visceral fat area and fat mass in separate models reduced the association between depressive symptoms and pulse wave velocity or aortic stiffness. Mediation models revealed that the mediation proportions of fat mass and visceral fat area on the association between depressive symptoms and pulse wave velocity were 11.8% and 9.7%, respectively. A preliminary analysis of longitudinal data (n = 184) showed similar findings. Limitations: Causality cannot be inferred from the associations we observed. Conclusion: Depressive symptoms are associated with elevated pulse wave velocity in older people with type 2 diabetes, and this relationship may be partially mediated by increased adiposity.

The War on Diabetes campaign was launched in 2016, encouraging Singapore residents to engage in regular exercise, adopt healthy dietary habits and screen for early detection of diabetes. This study aims to examine campaign awareness and its associations with sedentary behaviour, dietary habits and identifying diabetes. Data were obtained from the nationwide Knowledge, Attitudes and Practices study on diabetes in Singapore. A total of 2895 participants responded to a single question assessing campaign awareness. The Dietary Approaches to Stop Hypertension (DASH) diet screener assessed dietary habits, and the Global Physical Activity Questionnaire (GPAQ) measured sedentary behaviour. Recognition of diabetes was established using a vignette depicting a person with diabetes mellitus. Logistic and linear regression models were used to measure the associations. Most participants were 18- to 34-years old (29.9%) and females (51.6%). About 57.4% identified the campaign. Campaign awareness exhibited positive associations with identifying diabetes based on the vignette [odds ratio (OR): 1.5; 95% confidence interval (CI): 1.1–2.2; P  = 0.022], lower odds of sedentary behaviour ≥7 h/day (OR: 0.7; CI: 0.5–0.9; P  = 0.018) and higher DASH scores (β  = 1.3; P  < 0.001). The study recognized early significant associations between the behavioural outcomes and the campaign, emphasizing the need for ongoing campaign sustainability and evaluation of its long-term impact on population health. [ABSTRACT FROM AUTHOR]

Introduction This study aims to establish the Knowledge, Attitudes and Practices (KAP) of the general population (people with and without diabetes) towards diabetes. The study will examine (a) recognition and understanding of causes, prevention and treatment strategies of diabetes; (b) identify the knowledge gaps and behavioural patterns that may hamper diabetes prevention and control; (c) stigma towards and stigma perceived by people with diabetes and (d) awareness of anti-diabetes campaigns.Methods and analysis The study is a nationwide, cross-sectional study of Singapore’s general population aged 18 years and above (n=3000), comprising Chinese, Malay, Indian and other ethnic groups, who can understand English, Chinese, Malay or Tamil language. The sample was derived using a disproportionate stratified sampling using age and ethnicity. The proportion of respondents in each ethnic group (Chinese, Malay and Indian) was set to approximately 30%, while the proportion of respondents in each age group was set around 20% in order to ensure a sufficient sample size. The respondents will be administered questionnaires on diabetes KAP, stigma towards diabetes, lifestyle, diet and awareness of local anti-diabetes campaigns. The analysis will include descriptive statistics and multiple logistic and linear regression analyses to determine the socio-demographic correlates of correct recognition of diabetes, help-seeking preferences, as well as overall knowledge and attitudes among those with and without diabetes. We will consider a p value ≤0.05 as significant.Ethics and dissemination This study protocol has been reviewed by the Institutional Research Review Committee and the National Healthcare Group Domain Specific Review Board (NHG DSRB Ref 2018/00430). The results of the study will be shared with policymakers and other stakeholders. There will be a local mass media briefing to disseminate the findings online, in print and on television and radio. The results will be published in peer-reviewed journals and presented in scientific meetings.