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Aim: We aim to examine the association of plasma leucine-rich-α-2-glycoprotein 1 (LRG1) with diabetic retinopathy (DR) in type 2 diabetes., Methods: At baseline visit, plasma LRG1 levels were assessed using ELISA. Central arterial stiffness was estimated by carotid-femoral pulse wave velocity (PWV). At follow-up visit (median = 3.2 years), digital color fundus photographs were assessed for DR. DR severity was categorized into non-proliferative DR (NPDR) and proliferative DR (PDR)., Results: DR was diagnosed in 396 (32.8%) of 1206 patients. DR has higher LRG1 than non-DR (19.5 ± 11.3vs.16.9 ± 8.9 μg/ml, p ≪ 0.001). After adjustment, LRG1 was not associated with DR (OR = 1.2, [95% CI, 0.96-1.30], p = 0.16). LRG1 was higher in PDR (n = 107) than NPDR (n = 270) (23.2 ± 15.4vs.18.1 ± 8.9 μg/ml, n = 270, p ≪ 0.001). After adjustment, with 1-SD increase in LRG1, the relative risk of NPDR and PDR was 0.99 ([0.83-1.18], p = 0.91) and 1.42 ([95% CI, 1.14-1.76], p = 0.002) (p-trend = 0.01), respectively. We didn't observe significant improvement in AUC after adding LRG1 into the model. Baseline PWV mediated 12.0% of the association between LRG1 and PDR (p = 0.03)., Conclusion: Baseline plasma LRG1 is associated with PDR, suggesting it maybe a promising biomarker for prediction for advanced proliferative stages of DR. The mediation result indicates the potential benefit of ameliorating central arterial stiffness to prevent PDR., (Copyright © 2019. Published by Elsevier Inc.)

Aims: This study evaluated the association of the anti-angiogenic SPARC with known angiogenesis-associated factors and diabetes-related micro- and macro-vascular complications in a Singapore Chinese cohort with type 2 diabetes (T2DM)., Methods: Plasma SPARC was measured by immunoassay in 438 T2DM adults (mean age:58±11years)., Results: Higher SPARC levels in subjects stratified by SPARC tertiles displayed decreased pro-angiogenic adiponectin, osteopontin, vascular cell adhesion molecule (VCAM)-1 and matrix metalloproteinase (MMP)-2 concentrations (all p<0.05). The anti-angiogenic pigment epithelium-derived factor (PEDF) level was not statistically different among the SPARC tertiles. Age-adjusted partial correlation revealed significant associations of SPARC with adiponectin, osteopontin, VCAM-1, MMP-2, and PEDF (all p<0.05). Lower SPARC was accompanied by less favorable estimated glomerular filtration rate (eGFR) and carotid-femoral pulse wave velocity (PWV) readings (all p<0.05). Conversely, ankle-brachial index (ABI) reduced with increasing SPARC (p=0.048). The eGFR (B=0.834, p=0.019), PWV (B=-7.925, p=0.009), and ABI (B=-142.160, p=0.010) remained as determinants of SPARC after confounder adjustment. Moreover, individuals in the lowest SPARC tertile had increased odds of aortic stiffness (OR=1.900, 95% CI=1.103-3.274) but reduced odds of peripheral arterial disease (OR=0.400, 95% CI=0.175-0.919). However, SPARC was not independently associated with chronic kidney disease., Conclusions: The anti-angiogenic SPARC may be associated with the pathophysiology of diabetes-related macrovascular complications., (Copyright © 2016. Published by Elsevier Inc.)

Aim: Albuminuria progression has been associated with renal deterioration in type 2 diabetes (T2DM). Central arterial stiffness can aggravate systemic vasculopathy by propagating elevated systolic and pulse pressures forward, thereby accentuating global vascular injury. We aim to investigate whether central arterial stiffness is an independent predictor for albuminuria progression in a multi-ethnic T2DM Asian cohort in Singapore., Methods: In a prospective cohort, 1012 T2DM patients were assessed at baseline and after a median follow-up of 3.1years. 880 patients with baseline normo- (urinary albumin-to-creatinine ratio (ACR)<30mg/g, n=579) and microalbuminuria (ACR=30-299mg/g, n=301) were divided into progression and non-progression groups according to ACR changes. Progression was defined as transition from normo- to microalbuminuria, micro- to macroalbuminuria, or normo- to macroalbuminuria. Central arterial stiffness was estimated by carotid-femoral pulse wave velocity (PWV) using applanation tonometry method. Stepwise multiple regression analysis was used to determine the predictor(s) for albuminuria progression., Results: Albuminuria progression occurred in 178 patients (20.2%). Baseline PWV was higher in progression (10.1±2.9m/s) than non-progression group (9.2±2.4m/s, p<0.001). 1-SD increase in baseline PWV was associated with albuminuria progression (OR=1.457, 95% CI, 1.236-1.718, p<0.001). Stepwise regression analysis identified that baseline PWV (OR=1.241, 95% CI, 1.033-1.490, p=0.021), BMI (OR=1.046, 95% CI, 1.012-1.080, p=0.008), nature log-transformed estimated glomerular filtration rate (LneGFR) (OR=0.320, 95% CI, 0.192-0.530, p=0.010) and LnACR (OR=1.344, 95% CI, 1.187-1.522, p=0.008) are predictors for albuminuria progression., Conclusion: Increased central arterial stiffness at baseline predicted future progression of albuminuria. Our results suggest the potential benefit of ameliorating central arterial stiffness to retard albuminuria progression in T2DM., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Aims: The association of adhesion molecules ICAM-1 and VCAM-1 with cardiovascular diseases has been well-studied. However, their roles in diabetic kidney disease (DKD) are incompletely understood. We aim to study the association of plasma ICAM-1 and VCAM-1 with DKD in Asians with type 2 diabetes (T2DM)., Subjects and Methods: A total of 1950 Asians with T2DM were included in this cross-sectional study. Plasma ICAM-1 and VCAM-1 were measured by immunoassays., Results: Renal filtration function (eGFR) declined and urinary albumin-to-creatinine ratio (ACR) levels increased progressively with the increase in plasma VCAM-1 levels. In contrast, no significant changes in eGFR and ACR were observed in subjects across different plasma ICAM-1 levels. Both ICAM-1 and VCAM-1 were correlated with ACR (rho = 0.153, p < 0.001 for VCAM-1 and ACR; rho = 0.053, p = 0.020 for ICAM-1 and ACR) in bivariate correlation analysis. However, only VCAM-1 was correlated with eGFR (rho = -0.228, p < 0.001). Multivariable linear regression models revealed that VCAM-1, but not ICAM-1, was independently associated with eGFR and albuminuria. Backward linear regression suggested that plasma VCAM-1 variability was mainly determined by eGFR whereas plasma ICAM-1 level was mainly determined by C-reactive protein in patients with T2DM., Conclusions: Plasma VCAM-1 level, but not ICAM-1 level, was independently associated with prevalent DKD in Asians with T2DM. High level of ICAM-1 may be indicative of systemic inflammation and portends increase risk of incipient DKD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: Chronic kidney disease (CKD) secondary to type 2 diabetes mellitus (T2DM) is associated with multifaceted energy dysmetabolism. We aim to study the relationship between renal function, body composition and irisin, the recently identified myokine which is involved in energy regulation, in T2DM., Methods: Circulating irisin and body composition were measured in 365 T2DM subjects across a wide range of renal function., Results: Circulating irisin was significantly decreased in T2DM with renal insufficiency (77.4 ± 13.7 ng/ml in T2DM with eGFR ≥ 60 ml/min/1.73 m(2) versus 72.5 ± 14.9 ng/ml in those with eGFR<60 ml/min/1.73 m(2), p = 0.001) and the reduction in irisin was most pronounced in stage 5 CKD patients. In T2DM with preserved renal function, irisin was correlated with age (r = -0.242, p = 0.001) and pulse pressure (r = -0.188, p = 0.002). Among those with renal insufficiency, irisin was correlated with BMI (r = 0.171, p = 0.022), fat mass (r = 0.191, p = 0.013), percentage of fat mass (r = 0.210, p = 0.007) and eGFR (r = 0.171, p = 0.020). Multivariate linear regression models revealed that variations in circulating irisin were mainly attributable to eGFR and age in T2DM with and without renal impairment, respectively., Conclusion: Our observations suggest that the level of circulating irisin may be associated with renal function in T2DM. The role of reduced irisin in energy dysmetabolism in diabetic patients with renal insufficiency deserves further investigation., (© 2014.)

Aims: Irisin is a novel myokine secreted in response to PPAR-γ co-activator-1α (PGC-1α) activation. Earlier studies suggested that PGC-1α expression and activity were lower in myocytes in type 2 diabetes mellitus (T2DM). Therefore, we hypothesize that circulating irisin levels are lower in T2DM patients., Methods: In this observational study, we recruited 96 T2DM subjects and 60 non-diabetic control subjects. Among T2DM subjects, 38% were on insulin treatment, 78% were taking statins and 72% were taking renin-angiotensin system antagonists. Circulating irisin was quantified by ELISA and its association with markers of metabolic phenotype was analyzed by Pearson bivariate correlation and multiple linear regression., Results: Circulating irisin was significantly lower in individuals with T2DM compared with non-diabetic controls (T2DM 204 ± 72 ng/ml vs. non-diabetic control 257 ± 24 ng/ml, p < 0.0001). In non-diabetic subjects, circulating irisin was correlated with age (r = 0.398, p < 0.01), BMI (r = 0.387, p < 0.01), total cholesterol (r = 0.341, p < 0.01), total triglycerides (r = 0.299, p < 0.05), fasting blood glucose (r = 0.430, p < 0.01) and diastolic blood pressure (r = 0.306, p < 0.05). Multiple linear regression model revealed that BMI (β = 0.407, p = 0.012) and FBG (β = 0.315, p = 0.034) were associated with irisin in non-diabetic subjects after adjusting for multiple co-variates. However, similar analysis in T2DM subjects didn't reveal significant association between circulating irisin and major markers of metabolic phenotype., Conclusions: Circulating irisin is lower in T2DM compared with non-diabetic controls. Plasma irisin levels appear to be associated with important metabolic factors in non-diabetic subjects but not in individuals with type 2 diabetes., (Copyright © 2013 Elsevier Inc. All rights reserved.)