Lee Ying Yeoh

High normal albuminuria is independently associated with aortic stiffness in patients with Type 2 diabetes

High normal albuminuria is associated with higher cardiovascular risk in patients with diabetes. Increased aortic stiffness is an established risk factor of vascular events. However, the relationship between albuminuria within the normal range (0–30 mg/g) and aortic stiffness in patients with Type 2 diabetes is unknown.

Adipocytokine zinc α2 glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathy.

Diabet. Med. 29, 945–949 (2012)

Ethnic disparities in risk of cardiovascular disease, end-stage renal disease and all-cause mortality: a prospective study among Asian people with Type 2 diabetes.

To study prospectively the ethnic‐specific risks of cardiovascular disease, end‐stage renal disease and all‐cause mortality in patients with Type 2 diabetes mellitus among native Asian subpopulations.

Osteoprotegerin is independently associated with metabolic syndrome and microvascular complications in type 2 diabetes mellitus

Aims: Osteoprotegerin (OPG) is a glycoprotein from tumour necrosis factor receptor superfamily, responsible for osteoclastogenesis inhibition and associated with arterial calcification and stiffness. We describe the association between metabolic syndrome (MS) and OPG in type 2 diabetes mellitus patients. Methodology: We consecutively enrolled 1220 patients from our institution’s Diabetes Centre from August 2011. Anthropometric data such as fasting blood/urine were obtained, and OPG was measured by enzyme-linked immunosorbent assay (ELISA). Results: Mean (standard deviation (SD)) of age and diabetes duration was 57.4 (10.9) years and 11.2 (8.9) years, respectively. Prevalence of MS was 64.3% (95% confidence interval (CI): 61.3%–67.2%) and associated with significantly higher OPG (5.44 vs 4.47 pmol/L) and microvascular complications. The presence of microvascular complications was associated with higher OPG: nephropathy (5.54 (2.20) vs 4.65 (1.70) pmol/L, p < 0.0001), neuropathy (6.33 (2.64) vs 5.06 (1.91) pmol/L, p < 0.0001) and retinopathy (6.08 (2.47) vs 5.00 (1.95) pmol/L, p < 0.0001). After adjusting for age, gender, ethnicity, glucose and microvascular complications, OPG remained an independent predictor of MS: (odds ratio (OR) = 1.102 (95% CI: 1.015–1.196), p = 0.021). Conclusion: Higher OPG levels were associated with risk of MS and microvascular complications. Studies are needed to test whether OPG could be a useful biomarker identifying patients at risk of vascular complications and whether further exploration of this pathway may lead novel therapeutic options.

Elevation of a Novel Angiogenic Factor, Leucine-Rich-α2-Glycoprotein (LRG1), Is Associated With Arterial Stiffness, Endothelial Dysfunction, and Peripheral Arterial Disease in Patients With Type 2 Diabetes

CONTEXT Increased arterial stiffness and endothelial dysfunction are associated with peripheral arterial disease (PAD). Leucine-rich-α2-glycoprotein (LRG1) is a proangiogenic factor involved in regulation of the TGFβ signaling pathway. OBJECTIVE This study in patients with type 2 diabetes mellitus explored the associations of plasma LRG1 with arterial stiffness, endothelial function, and PAD. DESIGN Based on the ankle brachial index (ABI), patients were classified as having PAD (ABI ≤ 0.9) or as being borderline abnormal (ABI, 0.91-0.99) or normal (ABI, 1.00-1.40). LRG1 was measured by immunoassay; arterial stiffness, by carotid-femoral pulse-wave velocity and augmentation index; and endothelial function, by laser Doppler flowmetry. RESULTS A total of 2058 patients with type 2 diabetes mellitus were recruited. Mean age (1 SD) was 57.4 (0.2) years. Patients with PAD (n = 258) had significantly higher LRG1 compared to patients with borderline ABI and patients without PAD (19.00 [13.50] vs 17.35 [13.30] and 15.28 [10.40] μg/mL, respectively; P < .0001). Multiple regression analysis revealed that female gender (P < .0001), non-Chinese ethnicity (P < .0001), higher waist circumference (P = .017), lower estimated glomerular filtration rate (P < .0001), higher urine albumin-creatinine ratio (P = .009), lower ABI (P < .0001), higher pulse wave velocity (P = .040), and poorer endothelium-dependent vasodilation (P = .007) were independent significant predictors of higher plasma LRG1 levels. A generalized linear model showed that a 1-SD increase in log LRG1 was associated with an odds ratio of 4.072 (95% confidence interval, 1.889-8.777; P < .0001) for prevalence of PAD, after adjustment for traditional risk factors. CONCLUSIONS Higher LRG1 is a significant predictor for arterial stiffness, endothelial function, and PAD. The pathobiological basis and the temporal relationships of these associations need to be explored by further mechanistic and prospective studies to understand the clinical significance of these findings.

Vascular cell adhesion molecule-1, but not intercellular adhesion molecule-1, is associated with diabetic kidney disease in Asians with type 2 diabetes

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.

The effect of long‐term glycemic variability on estimated glomerular filtration rate decline among patients with type 2 diabetes mellitus – insights from the Diabetic Nephropathy Cohort in Singapore

In the present study, we examined the association between HbA1c variability and renal disease progression based on estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes mellitus (T2DM) in Singapore.

Genetic variants in the receptor for advanced glycation end products (RAGE) gene were associated with circulating soluble RAGE level but not with renal function among Asians with type 2 diabetes: a genome-wide association study.

Background The soluble receptor for advanced glycation end products (sRAGE) has been shown to play an important role in diabetic complications. We conducted genome-wide association study (GWAS) of sRAGE in Asian type 2 diabetes mellitus (T2DM) patient and validated the association in an independent cohort of T2DM. Methods GWAS for sRAGE was performed in 2058 T2DM patients. Associations between single-nucleotide polymorphisms (SNPs) and plasma sRAGE level were analyzed in an additive model using a linear mixed model. To validate the associations, we performed de novo genotyping in an independent cohort (n = 1984). We selected the top SNP for assessment with diabetic kidney disease (DKD). Results The strongest SNP, rs2070600C>T (P = 1.21 × 10-52), was a genotyped, missense SNP located on chromosome 6, corresponding to the RAGE (AGER) gene locus, the gene encoding RAGE. Conditioning analysis on rs2070600 revealed that rs2071288C>T was the top genotyped independent SNP (P = 8.36 × 10-10). Both SNPs were strongly and dose-dependently correlated with sRAGE level (TT = 399.6 pg/mL, CT = 737.0 pg/mL and CC = 967.0 pg/mL, P < 0.001 for rs2070600; TT = 687.9 pg/mL, CT = 737.6 pg/mL and CC = 904.7 pg/mL, P < 0.001 for rs2072188). Both SNPs were robustly replicated in the independent cohort, especially among Chinese patients (P = 9.02 × 10-72 for rs2070600; P = 1.13 × 10-9 for rs2071288). Log-transformed sRAGE was associated with DKD after adjustment for age, gender and ethnicity in pooled cohorts [odds ratio 2.536 (95% confidence interval 1.864-3.450), P < 0.001]. However, we did not observe any significant association between rs2070600 and DKD. Conclusions Common variants in RAGE are strongly associated with plasma sRAGE level, which is associated with DKD. However, we did not find a causal link between sRAGE and renal function by Mendelian randomization.

Arterial stiffness is an independent predictor for albuminuria progression among Asians with type 2 diabetes—A prospective cohort study

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.

Evaluation of body adiposity index as a predictor of aortic stiffness in multi-ethnic Asian population with type 2 diabetes

Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes mellitus. We evaluated the predictive ability of the recently developed body adiposity index for aortic stiffness, an intermediate endpoint of cardiovascular disease, in a cross-sectional multi-ethnic Asian type 2 diabetes mellitus cohort (N = 1408). AS was estimated using carotid–femoral pulse wave velocity measured by applanation tonometry. Body adiposity index was computed as hip circumference/(height)1.5 – 18. Compared to body mass index, waist circumference and visceral fat area, body adiposity index displayed the weakest association with pulse wave velocity (r = 0.077, 0.096, 0.134 and 0.058, respectively; all p < 0.05). Interestingly, the relationship between measurements of obesity and pulse wave velocity was ethnic dependent − body mass index, body adiposity index, waist circumference and visceral fat area consistently predicted pulse wave velocity only in Indians but not others. In multi-variable analysis, body mass index was a significant determinant of pulse wave velocity in all ethnicities. In conclusion, body adiposity index is a weak predictor of aortic stiffness (when compared with body mass index) in Asians with type 2 diabetes mellitus.