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Context: The CERT1 (Cardiovascular Event Risk Test) score derived from plasma ceramides has been applied clinically for cardiovascular risk assessment., Objective: To study whether plasma ceramides predict risk of mortality in patients with type 2 diabetes., Design, Setting and Participants: A prospective study which included 1903 outpatients with type 2 diabetes in a regional hospital and a primary care facility in Singapore., Exposure and Outcome: Plasma ceramides (d18:1/16:0, d18:1/18:0, d18:1/24:0, d18:1/24:1) were measured by mass spectrometry and CERT1 score was calculated accordingly. Main outcomes were all-cause and cause-specific mortality., Results: 252 death events were identified during median of 9.3 years of follow-up. Compared to those with low score (≤ 2), participants with a high CERT1 score (≥ 7) had 1.86 (95% CI 1.30-3.65) fold increased risk for all-cause death after adjustment for cardio-renal risk factors including eGFR and albuminuria. As continuous variable, one- unit increment in CERT1 was associated with 8% increased risk for all-cause death (adjusted HR 1.08 [1.04-1.13]). Adding CERT1 onto RECODe (Risk Equations for Complications Of type 2 Diabetes) mortality risk engine significantly improved prediction of 10- year risk of all-cause death (AUC 0.810 to 0.823, delta 0.013 [0.005-0.022]). The association between CERT1 and non-cardiovascular death remained significant (adjusted HR 2.12 [1.32-3.42]), whereas its association with cardiovascular death became non-significant after adjustment for kidney measurements (adjusted HR 1.41 [0.78-2.56])., Conclusion: CERT1 score predicts mortality risk independent of clinical cardio-renal risk factors. Further studies are warranted to elucidate the mechanistic linkage between ceramide and mortality, especially non-cardiovascular mortality., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Context: Metabolites in tricarboxylic acid (TCA) pathway have pleiotropic functions., Objective: To study the association between urine TCA cycle metabolites and the risk for chronic kidney disease (CKD) 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 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. CKD progression was defined as a composite of sustained eGFR below 15 ml/min/1.73 m2 , dialysis, renal death or doubling of serum creatinine., Results: During a median of 9.2 (IQR 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, aHR [95% CI] 1.63 [1.16-2.28], 1.82 [1.17-2.82] and 1.49 [1.05-2.11], per SD), while citrate was associated with a low risk (aHR 0.83 [0.72-0.96] per SD) for the renal outcome after adjustment for cardio-renal 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 ESKD independent of clinical risk factors and other urine metabolites. These two 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Triglyceride-rich remnant lipoproteins (TRLs) are considered atherogenic due to the presence of remnant cholesterol, which is transported by apolipoprotein B. In clinical practice, the concentration of TRLs can be estimated by calculating remnant cholesterol or non-HDL cholesterol levels., Aim: This study aims to investigate the proportion of patients who have low LDL cholesterol (LDL-C) concentration but elevated remnant cholesterol concentration, stratified by the presence of hypertriglyceridaemia and ethnicity, using real-world hospital data. Our secondary aim is to investigate the proportion of patients with elevated non-HDL cholesterol levels using guideline-recommended goals., Methods: A 2-year retrospective study was conducted at a single centre, analyzing lipid blood tests of all patients, including directly measured LDL-C. Fasting for blood tests was not mandatory., Results: The study included a total of 21,605 consecutive patients with plasma lipid profiles analyzed in our hospital laboratory. The median age was 61 years. In patients with ASCVD ( n  = 14,704), 23.7% had an LDL-C level of <1.8 mmol/L, 11.3% had elevated remnant cholesterol concentrations at ≥0.65 mmol/L, and 48.8% were at the non-high-density lipoprotein cholesterol (non-HDL-C) goal (<2.6 mmol/L). Among patients diagnosed with atherosclerotic cardiovascular disease (ASCVD) with LDL-C levels of <1.8 mmol/L ( n  = 3,484), only 11.9% had high levels of remnant cholesterol, but 96% of the ASCVD patients also achieved the recommended non-HDL-C target of <2.6 mmol/L. When the LDL-C level was <1.8 mmol/L, the mean concentration of remnant cholesterol was 0.214 mmol/L when the triglyceride level was <1.7 mmol/L ( n  = 3,380), vs. 0.70 mmol/L when the triglyceride level was elevated ( n  = 724), p  < 0.001. Among patients with a triglyceride level of ≥1.7 mmol/L and an LDL-C level of <.8 mmol/L, there were 254 patients with elevated remnant cholesterol concentration and 71 patients with suboptimal non-HDL levels. Malays had a higher mean remnant cholesterol concentration compared with both Chinese and Indians across all LDL-C levels, particularly in the presence of hypertriglyceridaemia., Conclusions: An elevated remnant cholesterol concentration of >0.65 mmol/L was present in 11% of all patients. The current guideline-recommended non-HDL-C goal, which uses a 0.8 mmol/L estimate of remnant cholesterol concentration, was achieved in >92% of patients, suggesting that it is unlikely to be clinically useful for the majority of our patient population except where there is concomitant hypertriglyceridaemia. Further studies are needed to establish the appropriate non-HDL-C goal or calculated remnant cholesterol concentration, paired with the LDL-C goal or otherwise, in a Southeast Asian population., Competing Interests: WL has received honoraria from Medtronic, Abbott, DKSH, and Novartis, and a research grant from Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Loh, Soh, Tun, Tan, Lau, Tavintharan, Watts and Aw.)

Diabetic Foot in Primary and Tertiary (DEFINITE) Care is an inter-institutional and multi-disciplinary team (MDT) health systems innovation programme at a healthcare cluster in Singapore. We aim to achieve coordinated MDT care across primary and tertiary care for patients with diabetic foot ulcers (DFU), within our public healthcare cluster - an integrated network of seven primary care polyclinics and two acute care tertiary hospitals (1700-bed and 800-bed) with a total catchment population of 2.2 million residents. Results from prospective DEFINITE Care is referenced against a retrospective 2013-2017 cohort, which was previously published. Cardiovascular profile of the study population is compared against the same population's profile in the preceding 12 months. Between June 2020 and December 2021, there were 3475 unique patients with DFU with mean age at 65.9 years, 61.2% male, mean baseline HbA1c at 8.3% with mean diabetes duration at 13.3 years, mean diabetes complication severity index (DCSI) at 5.6 and mean Charlson Comorbidity Index (CCI) at 6.8. In the 12-months preceding enrolment to DEFINITE Care, 35.5% had surgical foot debridement, 21.2% had minor lower extremity amputation (LEA), 7.5% had major LEA whilst 16.8% had revascularisation procedures. At 18-months after the implementation of DEFINITE Care programme, the absolute minor and major amputation rates were 8.7% (n = 302) and 5.1% (n = 176), respectively, equating to a minor and major LEA per 100000 population at 13.7 and 8.0, respectively. This represents an 80% reduction in minor amputation rates (P < .001) and a 35% reduction in major amputation rates (P = .005) when referenced against a retrospective 2013-2017 cohort, which had minor and major LEA per 100000 population at 68.9 and 12.4, respectively. As compared to the preceding 12 months, there was also a significant improvement in cardiovascular profile (glycemic and lipid control) within the DEFINITE population, with improved mean HbAc1 (7.9% from 8.4%, P < .001), low-density lipoprotein (LDL) levels (2.1 mmol/L from 2.2, P < .001), total cholesterol (3.9 mmol/L from 4.1, P < .001) and triglycerides levels (1.6 mmol/L from 1.8, P = .002). Multivariate analysis revealed a history of minor amputation in the preceding 12 months to be an independent predictor for major and minor amputation within the study period of 18 months (Hazard Ratio 3.4 and 1.8, respectively, P < .001). In conclusion, within DEFINITE care, 18-month data showed a significant reduction of minor and major LEA rates, with improved medical optimisation and cardiovascular profile within the study population., (© 2022 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Objective: To examine the association of triglyceride glucose (TyG) index (product of fasting triglyceride and glucose) with prevalence and incidence of diabetic retinopathy (DR) in type 2 diabetes., Methods: 1339 patients from an ongoing Singapore Study of Macro-angiopathy and Micro-Vascular Reactivity in Type 2 Diabetes (SMART2D) were included in this study. Fasting triglyceride and glucose levels were quantified and color fundus photographs were assessed for DR presence and severity. Logistic regression models were used to evaluate associations of TyG index with DR prevalence and incidence (median follow-up period = 3.2 years)., Results: Mean TyG index was higher in patients with DR than no DR (9.24±0.7 versus 9.04± 0.6, p<0.001). TyG index was significantly associated with DR prevalence (OR=1.4, CI 1.1-1.7, p=0.002) and incidence (OR=1.8, CI 1.04-2.9, p=0.03), after adjusting for confounders. In a stratified analysis, the association between TyG index and DR prevalence reached significance only in the subgroup with HbA1c levels < 7.0% (OR=2, CI 1.1-3.8, p=0.03). TyG index significantly predicted DR prevalence and incidence with area under receiver operating curve as 0.77 (CI 0.74-0.80, p <0.001) and 0.66 (CI 0.57-0.76, p value <0.01), respectively., Conclusion: TyG index is a good predictor for DR prevalence and incidence. It can also be a secondary treatment target for patients with optimally controlled levels of HbA1c., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Neelam et al.)

Objective: Leucine-rich α-2 glycoprotein 1 (LRG1) was recently identified as an amplifier of transforming growth factor-β (TGF-β)-induced kidney fibrosis in animal models. We aimed to study whether urine LRG1 is associated with risk of progression to end-stage kidney disease (ESKD) in individuals with type 2 diabetes., Research Design and Methods: A total of 1,837 participants with type 2 diabetes and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 were recruited from a regional hospital and a primary care facility. Association of urine LRG1 with risk of ESKD (progression to sustained eGFR <15 mL/min/1.73 m2, dialysis, or death resulting from renal causes) was assessed by survival analyses., Results: During a median follow-up of 8.6 (interquartile range 5.8-9.6) years, 134 incident ESKD events were identified. Compared with those in the lowest tertile, participants with baseline urine LRG1 in the highest tertile had a 1.91-fold (95% CI 1.04-3.50) increased risk of progression to ESKD, after adjustment for cardiorenal risk factors, including eGFR and albuminuria. As a continuous variable, 1 SD increment in urine LRG1 was associated with a 1.53-fold (95% CI 1.19-1.98) adjusted risk of ESKD. Of note, the association of urine LRG1 with ESKD was independent of plasma LRG1. Moreover, urine LRG1 was associated with rapid kidney function decline and progression to macroalbuminuria, two common pathways leading to ESKD., Conclusions: Urine LRG1, a TGF-β signaling modulator, predicts risk of progression to ESKD independently of clinical risk factors in patients with type 2 diabetes, suggesting that it may be a novel factor involved in the pathophysiological pathway leading to kidney disease progression., (© 2023 by the American Diabetes Association.)

Aims/hypothesis: We sought to subtype South East Asian patients with type 2 diabetes by de novo cluster analysis on clinical variables, and to determine whether the novel subgroups carry distinct genetic and lipidomic features as well as differential cardio-renal risks., Methods: Analysis by k-means algorithm was performed in 687 participants with recent-onset diabetes in Singapore. Genetic risk for beta cell dysfunction was assessed by polygenic risk score. We used a discovery-validation approach for the lipidomics study. Risks for cardio-renal complications were studied by survival analysis., Results: Cluster analysis identified three novel diabetic subgroups, i.e. mild obesity-related diabetes (MOD, 45%), mild age-related diabetes with insulin insufficiency (MARD-II, 36%) and severe insulin-resistant diabetes with relative insulin insufficiency (SIRD-RII, 19%). Compared with the MOD subgroup, MARD-II had a higher polygenic risk score for beta cell dysfunction. The SIRD-RII subgroup had higher levels of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (phosphatidylethanolamine and phosphatidylcholine), whereas the MARD-II subgroup had lower levels of sphingolipids and glycerophospholipids but higher levels of lysophosphatidylcholines. Over a median of 7.3 years follow-up, the SIRD-RII subgroup had the highest risks for incident heart failure and progressive kidney disease, while the MARD-II subgroup had moderately elevated risk for kidney disease progression., Conclusions/interpretation: Cluster analysis on clinical variables identified novel subgroups with distinct genetic, lipidomic signatures and varying cardio-renal risks in South East Asian participants with type 2 diabetes. Our study suggests that this easily actionable approach may be adapted in other ethnic populations to stratify the heterogeneous type 2 diabetes population for precision medicine., (© 2022. The Author(s).)

Context: Early-onset diabetes has been associated with unfavorable cardiovascular risk but data on heart failure (HF) in this subpopulation are scarce., Objective: We aimed to study the risk of, and risk factors for, incident HF in individuals with early-onset type 2 diabetes., Methods: We studied 606 individuals with type 2 diabetes diagnosed before 40 years of age (early-onset) and 1258 counterparts with diabetes diagnosed from 41 to 65 years of age (usual-onset) with no HF history, at a regional hospital, over a median follow-up period of 7.1 years. Incident HF by European Cardiology Society criteria was determined., Results: A total of 62 and 108 HF events were identified in the early- and usual-onset groups (1.55 and 1.29 per 100 patient-years), respectively. Compared with usual-onset counterparts, individuals with early-onset diabetes had a 1.20-fold unadjusted (95% CI, 0.88-1.63; P = 0.26) and 1.91-fold age-adjusted (95% CI, 1.37-2.66; P < 0.001) hazard ratio (HR) for incident HF. Adjustment for traditional cardiometabolic risk factors only moderately mitigated the hazards (adjusted HR 1.69; 95% CI, 1.19-2.40; P = 0.003). However, additional adjustment for estimated glomerular filtration rate and albuminuria markedly attenuated the association of early-onset age with incident HF (adjusted HR 1.24; 95% CI, 0.87-1.77; P = 0.24). Notably, a long diabetes duration was not significantly associated with HF risk after accounting for kidney measures., Conclusion: Individuals with early-onset diabetes have at least the same absolute risk and a 2-fold age-adjusted relative risk for incident HF. Excess cardiorenal risk factors but not a long diabetes duration are main drivers for HF development in this diabetic population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Leucine-rich alpha-2 glycoprotein 1 (LRG1) is a circulating protein in the transforming growth factor-beta superfamily. We sought to study whether LRG1 might predict risk for all-cause and cause-specific mortality in individuals with type 2 diabetes., Methods: 2012 outpatients with type 2 diabetes were followed for a median of 7.2 years and 188 death events were identified. Association of LRG1 with risk for mortality was assessed by multivariable Cox regression models., Results: Participants with a higher concentration of LRG1 had an increased risk for all-cause mortality [HR (95% CI), 1.76 (1.03-3.01), 1.75 (1.03-2.98), and 4.37 (2.72-7.02) for quartiles 2, 3, and 4, respectively, compared to quartile 1]. The association remained significant after adjustment for known cardio-renal risk factors including estimated glomerular filtration rate and albuminuria [adjusted HR 2.76 (1.66-4.59), quartile 4 versus 1]. As a continuous variable, a 1-SD increment in LRG1 was associated with 1.34 (1.14-1.57)-fold adjusted risk for all-cause mortality. High plasma LRG1 was independently associated with mortality attributable to cardiovascular disease, infection, and renal diseases. Adding LRG1 into a clinical variable-based model improved discrimination (c statistics from 0.828 to 0.842, P = 0.006) and reclassification (net reclassification improvement 0.47, 95% CI 0.28-0.67) for prediction of 5-year all-cause mortality., Conclusion: Plasma LRG1 predicts risk for all-cause mortality and mortality attributable to cardiovascular disease, infection, and renal disease independent of known cardio-renal risk factors. It may be a potential novel biomarker to improve risk stratification in individuals with type 2 diabetes., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: To study the relationship between genetic risk of beta cell dysfunction, young onset age and glycaemic progression in individuals with type 2 diabetes (T2D)., Materials and Methods: 1385 T2D outpatients were included in cross-sectional sub-study and 730 insulin-naïve outpatients were followed for 3 years in prospective sub-study. Genetic risk score (GRS) was derived from 24 beta cell dysfunction-related single nucleotide polymorphisms, with lower and upper 25 percentiles defined as low and high genetic risk. Glycaemic progression was defined as requirement for sustained insulin therapy., Results: 388 participants in cross-sectional and 128 in prospective sub-study experienced glycaemic progression. Young onset age (T2D diagnosis below 40 year-old) was associated with high risk of glycaemic progression as compared to usual-onset counterparts (adjusted OR 1.64 [95% CI 1.14-2.36], and 2.92 [95% CI 1.76-4.87] in cross-sectional and prospective sub-study, respectively). As compared to those with intermediate risk, a low GRS was associated with lower risk for glycaemic progression (adjusted OR 0.72 [95% CI 0.49-1.06], and 0.51 [95% CI 0.29-0.90]) whereas a high GRS was not significantly associated with glycaemic progression. Notably, the association of young-onset T2D with high risk of glycaemic progression was independent of known clinical risk factors and beta cell dysfunction GRS (P interaction > 0.10)., Conclusion: Young onset age and low genetic risk of beta cell dysfunction are independently associated with risk of glycaemic progression. Our data do not support that genetic risk modulates the risk of glycaemic progression in individuals with young-onset T2D., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: The impact of lockdown measures can be widespread, affecting both clinical and psychosocial aspects of health. This study aims to assess changes in health services access, self-care, behavioural, and psychological impact of COVID-19 and partial lockdown amongst diabetes patients in Singapore., Methods: We conducted a cross-sectional online survey amongst people with diabetes with the Diabetes Health Profile-18 (DHP-18). Hierarchical regression analyses were performed for each DHP-18 subscale (Psychological Distress, Disinhibited Eating and Barriers to Activity) as dependent variables in separate models., Results: Among 301 respondents, 45.2% were women, 67.1% of Chinese ethnicity, 24.2% were aged 40 to 49 years, 68.4% have Type 2 diabetes and 42.2% on oral medications alone. During the pandemic and the lockdown, nearly all respondents were able to receive care safely from the clinics they attend (94%) and obtain their medications and diabetes equipment and supplies (97%) when needed. Respondents reported less frequent engagement in physical activity (38%), checking of blood pressure (29%) and blood glucose (22%). Previous diagnosis of mental health conditions (β = 9.33, P = .043), Type 1 diabetes (β = 12.92, P = .023), number of diabetes-related comorbidities (β = 3.16, P = .007) and Indian ethnicity (β = 6.65, P = .034) were associated with higher psychological distress. Comorbidities were associated with higher disinhibited eating (β = 2.49, P = .014) while ability to reach their doctor despite not going to the clinic is negatively associated with psychological distress (β = -9.50 P = .002) and barriers to activity (β = -7.53, P = .007)., Conclusion: Health services access were minimally affected, but COVID-19 and lockdown had mixed impacts on self-care and management behaviours. Greater clinical care and attention should be provided to people with diabetes with multiple comorbidities and previous mental health disorders during the pandemic and lockdown., (© 2021 John Wiley & Sons Ltd.)

Autosomal recessive hypercholesterolemia (ARH) is a rare form of genetic hypercholesterolemia caused by mutations in low density lipoprotein receptor adaptor protein 1 (LDLRAP1). The proband first presented with linear eruptive xanthomas over her ankles, knees and elbows, with low density lipoprotein cholesterol (LDL-C) of 16.0 mmol/L (618.7 mg/dL), at 2.5 years old. Next generation sequencing revealed a novel homozygous mutation in LDLRAP1 exon 5 (c.466delG). In the first year, drug regimens of either cholestyramine or simvastatin, reduced her LDL-C to 10.5 mmol/L (406 mg/dL) and 11.7 mmol/L (452.4 mg/dL), respectively. Combination simvastatin and ezetimibe was the mainstay of therapy from age 5 - 10 years. Her lowest achieved LDL-C was 6.3 mmol/L (243.6 mg/dL). Switching to atorvastatin did not lead to further reduction. Carotid intima-media thickness was 0.47 mm (> 97 th percentile) and 0.32 mm (75 - 95 th percentile) at ages 8 years and 11 years, respectively. Addition of monthly injections of evolocumab for 3 months, led to an increase in LDL-C, from 7.0 mmol/L (270.7 mg/dL) to a range of [(8.4 - 9.1) mmol/L or (324.8 - 351.9) mg/dL]. In this report, a decade-long lipid management is described in a patient with ARH. Residual activity of LDLRAP1 is a likely determinant of her response. Clinical management remains sub-optimal and options for the paediatric population are limited. Novel classes of cholesterol-lowering medications are needed for this ultra-rare and severe hypercholesterolemia., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Leucine-rich α-2 glycoprotein 1 (LRG1) is a circulating protein potentially involved in several pathways related to pathogenesis of heart failure (HF). We aimed to study whether plasma LRG1 is associated with risks of incident HF and hospitalization attributable to HF (HHF) in individuals with type 2 diabetes., Research Design and Methods: A total of 1,978 individuals with type 2 diabetes were followed for a median of 7.1 years (interquartile range 6.1-7.6). Association of LRG1 with HF was studied using cause-specific Cox regression models., Results: In follow-up, 191 incident HF and 119 HHF events were identified. As compared with quartile 1, participants with LRG1 in quartiles 3 and 4 had 3.60-fold (95% CI 1.63-7.99) and 5.99-fold (95% CI 2.21-16.20) increased risk of incident HF and 5.88-fold (95% CI 1.83-18.85) and 10.44-fold (95% CI 2.37-45.98) increased risk of HHF, respectively, after adjustment for multiple known cardiorenal risk factors. As a continuous variable, 1 SD increment in natural log-transformed LRG1 was associated with 1.78-fold (95% CI 1.33-2.38) adjusted risk of incident HF and 1.92-fold (95% CI 1.27-2.92) adjusted risk of HHF. Adding LRG1 to the clinical variable-based model improved risk discrimination for incident HF (area under the curve [AUC] 0.79-0.81; P = 0.02) and HHF (AUC 0.81-0.84; P = 0.02)., Conclusions: Plasma LRG1 is associated with risks of incident HF and HHF, suggesting that it may potentially be involved in pathogenesis of HF in individuals with type 2 diabetes. Additional studies are warranted to determine whether LRG1 is a novel biomarker for HF risk stratification., (© 2020 by the American Diabetes Association.)

Delayed wound healing is commonly associated with diabetes. It may lead to amputation and death if not treated in a timely fashion. Limited treatments are available partially due to the poor understanding of the complex disease pathophysiology. Here, we investigated the role of leucine-rich α-2-glycoprotein 1 (LRG1) in normal and diabetic wound healing. First, our data showed that LRG1 was significantly increased at the inflammation stage of murine wound healing, and bone marrow-derived cells served as a major source of LRG1. LRG1 deletion causes impaired immune cell infiltration, reepithelialization, and angiogenesis. As a consequence, there is a significant delay in wound closure. On the other hand, LRG1 was markedly induced in diabetic wounds in both humans and mice. LRG1-deficient mice were resistant to diabetes-induced delay in wound repair. We further demonstrated that this could be explained by the mitigation of increased neutrophil extracellular traps (NETs) in diabetic wounds. Mechanistically, LRG1 mediates NETosis in an Akt-dependent manner through TGFβ type I receptor kinase ALK5. Taken together, our studies demonstrated that LRG1 derived from bone marrow cells is required for normal wound healing, revealing a physiological role for this glycoprotein, but that excess LRG1 expression in diabetes is pathogenic and contributes to chronic wound formation., (© 2020 by the American Diabetes Association.)

Objective: Individuals with diabetic peripheral neuropathy (DPN) have functional deficits that increase their risk of falling. However, psychological aspects such as loss of confidence in undertaking activities could also contribute to this risk. We examined correlations between balance confidence and fall risk among individuals with DPN., Methods: This was a cross-sectional study of 146 individuals with DPN. Elevated fall risk was determined by timed up-and-go test with standard cut-off time of 13.5 seconds, and balance confidence was measured by 16-item Activities Specific Balance Confidence scale. Functional parameters assessed included functional reach, body sway velocity during quiet standing and muscle strength at ankle and toe., Results: Twenty percent of the DPN patients were at increased risk of falls. Every unit increase in balance confidence was associated with 9% (95% confidence interval: 0.88, 0.95; p<0.001) reduced odds of falling, after adjusting for socio-demographic, health and functional characteristics. No other functional parameters had significant associations with fall risk in adjusted analyses., Conclusions: Psychological factors like balance confidence appear to be more important for fall risk among DPN patients, compared to objective functional performance. Interventions targeting balance confidence may be beneficial in reducing the risk of falls in this population., (Copyright © 2020 Riandini, Khoo, Tai, Tavintharan, Phua, Chandran, Hwang and Venkataraman.)

Introduction: This was a retrospective cross-sectional study to assess the impact of chronic kidney disease (CKD) and its severity in Type 2 diabetes mellitus (T2DM) on direct medical costs, and the effects of economic burden on CKD related complications in T2DM in Singapore., Methods: A total of 1,275 T2DM patients were recruited by the diabetes centre at Khoo Teck Puat Hospital from 2011-2014. CKD stages were classified based on improving global outcome (KDIGO) categories, namely the estimated glomerular filtration rate (eGFR) and albuminuria kidney disease. Medical costs were extracted from the hospital administrative database., Results: CKD occurred in 57.3% of patients. The total mean cost ratio for CKD relative to non-CKD was 2.2 ( P <0.001). Mean (median) baseline annual unadjusted costs were significantly higher with increasing CKD severity-S$1,523 (S$949), S$2,065 (S$1,198), S$3,502 (S$1,613), and S$5,328 (S$2,556) for low, moderate, high, and very high risk respectively ( P <0.001). CKD ( P <0.001), age at study entry ( P =0.001), Malay ethnicity ( P =0.035), duration of diabetes mellitus (DM; P <0.001), use of statins/fibrates ( P =0.021), and modified Diabetes Complications Severity Index (DCSI) ( P <0.001) were positively associated with mean annual direct medical costs in the univariate analysis. In the fully adjusted model, association with mean annual total costs persisted for CKD, CKD severity and modified DCSI., Conclusion: The presence and increased severity of CKD is significantly associated with higher direct medical costs in T2DM patients. Actively preventing the occurrence and progression in DM-induced CKD may significantly reduce healthcare resource consumption and healthcare costs.

Severe familial hypercholesterolemia (SFH) is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) and severe early-onset cardiovascular disease if left untreated. We report on the decade-long therapeutic journey of a 15-year-old boy with SFH due to a severe compound heterozygous genotype. He presented at the age of 5 years with widespread xanthomas and LDL-C of 17.4 mmol/L. He was diagnosed with SFH, initially treated with colestyramine that was subsequently combined with simvastatin. At the age of 12 years, he was diagnosed to have supravalvular aortic stenosis and ezetimibe/atorvastatin was introduced in place of colestyramine/simvastatin. At the age of 14 years, he received triple therapy with evolocumab, initially at the recommended dose of 420 mg monthly and then reduced to 140 mg biweekly. Currently at the age of 15 years, he is on atorvastatin 40 mg ON, ezetimibe 10 mg OM, and evolocumab 140 mg biweekly, achieving LDL-C levels of 2.4 mmol/L. Genetic testing identified compound heterozygous mutations in the LDL receptor genes [c.(940 + 1&#95;941-1) (1845 + 1&#95;1846-1)dup] and exon 12, nucleotide c.1747 C > T, amino acid p.(His583Tyr). Medical management without lipoprotein apheresis can achieve target LDL-C in children with SFH. Our patient, who developed supravalvular aortic stenosis at the age of 12 years, needed early aggressive treatment when SFH guidelines and newer drugs for young children were unavailable. Our patient demonstrated that 140 mg biweekly of evolocumab has the same cholesterol-lowering effect as the recommended 420 mg monthly dose., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Pulse wave velocity (PWV), central pulse pressure and augmentation index are arterial stiffness- related hemodynamic parameters but their associations with renal outcome are still controversial. We hereby aim to study, 1) which hemodynamic parameter is independently associated with progressive chronic kidney disease (CKD), 2) the association of 3-year change in PWV with CKD progression and, 3) the additive predictive value of PWV for progressive CKD., Methods: Carotid- femoral PWV, central pulse pressure and augmentation index were measured in 1444 participants with type 2 diabetes at baseline and 3 years apart. Progressive CKD was defined as confirmed eGFR decline 40% or greater., Results: In the follow-up, 102 participants experienced progressive CKD. All 3 hemodynamic parameters were significantly associated with progressive CKD In univariable analysis. However, only PWV remained statistically significant after adjustment for known clinical risk factors and the other 2 hemodynamic parameters (OR 1.14 [95% CI 1.01-1.29] per m/s increment). One m/s regression (decrement) in PWV in the 3-year follow-up was associated with 26% lower adjusted- risk of progressive CKD (OR 0.74, 95% CI 0.56-0.97). Adding PWV onto traditional risk factor- based model significantly improved classification (net reclassification improvement 0.25, 95% CI 0.05-0.45, P = 0.01) and positive prediction rate (24.5 to 32.3%)., Conclusions: Of 3 arterial stiffness- related hemodynamic parameters, only PWV is independently associated with progressive CKD. PWV may be a potential intervention target to mitigate risk of CKD progression and also a biomarker to improve risk-stratification of adverse renal outcome in individuals with type 2 diabetes.

Introduction: Diabetic peripheral neuropathy (DPN) is a common microvascular complication in patients with type 2 diabetes (T2D). Apart from hyperglycemia, few modifiable risk factors have been identified. Endothelin-1 is a potent vasoconstrictor peptide, implicated in the causal pathway of microangiopathy. We investigated whether baseline plasma endothelin-1 and other metabolic and vascular risk factors predicted the incidence of DPN., Design: This is a 3-year observational, cohort study., Methods: In patients with T2D (n = 2057), anthropometric data, fasting blood, and urine were collected for biochemistry and urine albumin/creatinine measurements. Forearm cutaneous endothelial reactivity was assessed by iontophoresis and laser Doppler flowmetry/imaging. Measurements were repeated on follow-up. Incident DPN was considered present if an abnormal finding in monofilament (<8 of 10 points) or neurothesiometer testing was ≥25 volts on either foot at 3-year follow-up, but normal at baseline. Plasma endothelin-1 was assessed by ELISA., Results: At baseline, mean age of patients was 57.4 ± 10.8 years old and prevalence of DPN was 10.8%. Of the 1767 patients without DPN, 1250 patients returned for follow-up assessment ((2.9 ± 0.7) years), with a 10.7% incidence of DPN. Patients with incident DPN had significantly higher baseline endothelin-1 (1.43 (1.19-1.73) vs 1.30 (1.06-1.63)) pg/mL, P < 0.0001. Multivariable Cox proportional hazards ratio showed a 1-s.d. increase in log endothelin-1 (adjusted HR: 4.345 (1.451-13.009), P = 0.009), systolic blood pressure (per 10-unit) (adjusted HR: 1.107 (1.001-1.223), P = 0.047) and diabetes duration (adjusted HR: 1.025 (1.004-1.047), P = 0.017) predicted incident DPN, after adjustment for glycemic control, eGFR, albuminuria, peripheral arterial disease and retinopathy status., Conclusion: Higher baseline endothelin-1, blood pressure and diabetes duration were significant and independent predictors for incident DPN. Validation of our findings in independent cohorts and molecular mechanistic studies will help better our understanding on the role of endothelin-1 in DPN.

Literature evaluating the relationship between central obesity and cognitive deficits in type 2 diabetes (T2DM) remains scarce. This cross-sectional analysis explored the association of novel and traditional central obesity measures with cognitive performance in older (aged ≥60 years) non-demented multi-ethnic Asians with T2DM, including a stratified analysis by body mass index (BMI). Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status. Central obesity measures including visceral fat area (VFA), waist circumference, waist:hip ratio, waist:height ratio, abdominal volume index, body roundness index and conicity index were measured and/or computed. In our cohort (N = 677; mean age = 67 ± 5 years, 51.7% men), VFA emerged as an associate of overall cognitive performance after covariate adjustment and Bonferroni correction (β = -.10, 95% CI = -0.18, -0.03), outperforming the other adiposity indices. Specifically, VFA was inversely associated with delayed memory and language scores. Additionally, compared with normal-weight individuals, excess visceral obesity (VFA ≥100 cm 2 ) was independently associated with lower cognitive scores to a greater extent in normal BMI (<23 kg/m 2 ) adults than in those with high BMI (≥23 kg/m 2 ). Assessment and management of visceral adiposity may help to prevent cognitive decline in older people with T2DM, and reduce the global burden of dementia in ageing populations., (© 2020 World Obesity Federation.)

Background: The progression trajectory of renal filtration function has not been well characterized in patients with early-onset type 2 diabetes mellitus (T2DM) although albuminuria is often reported in this population. We aim to study the risk of progressive chronic kidney disease (CKD) in individuals with early-onset T2DM., Methods: In total, 1189 T2DM participants were followed for 3.9 (interquartile range 3.2-4.7) years. Progressive CKD was defined as estimated glomerular filtration rate (eGFR) decline of ≥5 mL/min/1.73 m2 per year. Early-onset T2DM was defined as age at T2DM diagnosis between 18 and 30 years., Results: Compared with later-onset counterparts (N = 1032), participants with early-onset T2DM (N = 157) were more obese and had poorer glycaemic control at baseline. In the follow-up, 24.2% and 15.6% experienced progressive CKD in early-onset and later-onset participants, respectively (P = 0.007). Logistic regression suggested that participants with early-onset T2DM had 2.63-fold [95% confidence interval (CI) 1.46-4.75] higher risk of progressive CKD after accounting for multiple traditional risk factors. Furthermore, the excess risk of progressive CKD associated with early-onset T2DM mainly occurred in participants with preserved renal function [eGFR ≥60 mL/min/1.73 m2, odds ratio (OR) 2.85, 95% CI 1.50-5.42] and was more pronounced in those with diabetes duration <10 years (OR 3.67, 95% CI 1.51-8.90)., Conclusions: Individuals with early-onset T2DM have a higher risk of progressive CKD. The excess risk mainly exhibits in early stage of CKD and cannot be solely attributed to traditional risk factors and a longer diabetes duration., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Aims/hypothesis: The aim of this study was to test the effectiveness of a structured strength and balance training intervention in improving health-related quality of life (HRQoL) and functional status in individuals with diabetic peripheral neuropathy (DPN)., Methods: The study was a single-blind parallel-group randomised controlled trial comparing 2 months of once-weekly home-based strength and balance training against standard medical therapy. Participants were patients with physician-diagnosed type 2 diabetes and neuropathy recruited from five public sector institutions in Singapore between July 2014 and October 2017. Participants were block-randomised to intervention or control arms. Outcomes were assessed at baseline, 2 months and 6 months by a trained assessor blinded to group assignment. Primary outcomes were change in physical component summary (PCS) score of SF-36v2 (a 36-item generic HRQoL instrument that has been validated for use in Singapore) and EQ-5D-5L index score (derived from a five-item generic HRQoL instrument [EQ-5D-5L]) over 6 months. Secondary outcomes were change in functional status (timed up-and-go [TUG], five times sit-to-stand [FTSTS], functional reach, static balance, ankle muscle strength and knee range of motion) and balance confidence over 6 months. Mean differences in scores between groups were compared using mixed models., Results: Of the 143 participants randomised (intervention, n = 70; control, n = 73), 67 participants were included in each arm for the final intention-to-treat analysis. The two groups were similar, except in terms of sex. There were no significant differences between groups on the primary outcomes of PCS score (mean difference [MD] 1.56 [95% CI -1.75, 4.87]; p = 0.355) and EQ-5D-5L index score (MD 0.02 [95% CI -0.01, 0.06]; p = 0.175). There were significant improvements in TUG test performance (MD -1.14 [95% CI -2.18, -0.1] s; p = 0.032), FTSTS test performance (MD -1.31 [95% CI -2.12, -0.51] s; p = 0.001), ankle muscle strength (MD 4.18 [95% CI 0.4, 7.92] N; p = 0.031), knee range of motion (MD 6.82 [95% CI 2.87, 10.78]°; p = 0.001) and balance confidence score (MD 6.17 [95% CI 1.89, 10.44]; p = 0.005). No adverse events due to study participation or study intervention were reported., Conclusions/interpretation: Short-term structured strength and balance training did not influence HRQoL but produced sustained improvements in functional status and balance confidence at 6 months. More intensive interventions may be needed to influence HRQoL in these individuals. However, this intervention may be a useful treatment option for individuals with DPN to reduce the risk of falls and injuries., Trial Registration: ClinicalTrials.gov NCT02115932 FUNDING: This work was supported by the National Medical Research Council, Singapore.

Objective: Arterial stiffness has been associated with diabetic retinopathy; however, the information is limited in Asians. We aim to examine the association of central arterial stiffness with the presence and severity of diabetic retinopathy in type 2 diabetes mellitus patients in Singapore., Methods: Arterial stiffness was estimated by carotid-femoral pulse wave velocity and augmentation index using applanation tonometry method. Digital colour fundus photographs from 1,203 patients were assessed for diabetic retinopathy. Diabetic retinopathy severity was categorized into non-proliferative diabetic retinopathy and proliferative diabetic retinopathy. Logistic regression model was used to evaluate the associations of diabetic retinopathy with pulse wave velocity and augmentation index., Results: Diabetic retinopathy was diagnosed in 391 (32.5%) patients, including 271 non-proliferative diabetic retinopathy and 108 proliferative diabetic retinopathy. Diabetic retinopathy have higher pulse wave velocity (11.2 ± 3.3 vs 9.5 ± 2.6 m/s, p  < 0.001) and augmentation index (28.4 ± 9.4 vs 26.1 ± 10.6%, p  < 0.001) than non-diabetic retinopathy. After multivariable adjustment, pulse wave velocity [odds ratio = 1.11 (95% confidence interval = 1.05-1.17), p  < 0.001] and augmentation index [odds ratio = 1.03 (95% confidence interval = 1.01-1.04), p  = 0.009] was associated with diabetic retinopathy. In severity analyses, pulse wave velocity was associated with non-proliferative diabetic retinopathy [odds ratio = 1.10 (95% confidence interval = 1.03-1.17), p  = 0.002] and proliferative diabetic retinopathy [odds ratio = 1.15 (95% confidence interval = 1.06-1.25), p  = 0.001] ( p -trend < 0.001). Augmentation index showed significant associations with non-proliferative diabetic retinopathy [odds ratio = 1.02 (95% confidence interval = 1.01-1.04), p  = 0.008], but not with proliferative diabetic retinopathy [odds ratio = 1.01 (95% confidence interval = 0.98-1.04), p  = 0.36] ( p -trend = 0.03)., Conclusion: Central arterial stiffness was associated with the presence and severity of diabetic retinopathy in type 2 diabetes mellitus patients, suggesting its etiologic implication in diabetic retinopathy.

Objective: Resting heart rate (RHR) has been associated with cardiovascular risk, but data on renal outcomes are still scarce. We aimed to study the association of RHR with rapid renal function decline (RRFD) and to explore whether the association of RHR with RRFD is modulated by arterial stiffness in individuals with type 2 diabetes mellitus. Approach and Results: One thousand one hundred forty-two Asian people with type 2 diabetes mellitus were followed for 3.9±0.9 years in a regional hospital and a primary care facility. RRFD was defined as eGFR decline of 5 mL/min per 1.73 m2 or greater per year. Arterial stiffness was assessed by carotid-femoral pulse wave velocity. One hundred sixty-eight participants (15%) were classified as having RRFD. Participants with elevated RHR were younger, had higher levels of HbA1c, albuminuria, C-reactive protein, and pulse wave velocity. Compared with the lowest quartile, participants in quartile 4 had a higher risk for RRFD after adjustment for known risk factors (adjusted odds ratio 1.91 [1.11-3.28]). RHR improved discrimination and net reclassification for prediction of RRFD above traditional risk factors. Remarkably, arterial stiffness modulated the association of RHR with RRFD ( P for interaction =0.03). RHR was significantly associated with risk of RRFD only in those with increased arterial stiffness (pulse wave velocity above age-reference value 7.7 m/s)., Conclusions: RHR independently predicts RRFD, and the association is modulated by arterial stiffness. An elevated heart rate may be one factor in the spectrum of cardiovascular risk factors associated with renal functional impairment, especially in those with type 2 diabetes mellitus and an increased arterial stiffness.

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.)

Introduction: The risk for diabetes progression varies greatly in individuals with type 2 diabetes mellitus (T2DM). We aimed to study the clinical determinants of diabetes progression in multiethnic Asians with T2DM., Materials and Methods: A total of 2057 outpatients with T2DM from a secondary-level Singapore hospital were recruited for the study. Diabetes progression was defined as transition from non-insulin use to requiring sustained insulin treatment or glycated haemoglobin (HbA1c) ≥8.5% when treated with 2 or more oral hypoglycaemic medications. Multivariable logistic regression (LR) was used to study the clinical and biochemical variables that were independently associated with diabetes progression. Forward LR was then used to select variables for a parsimonious model., Results: A total of 940 participants with no insulin use or indication for insulin treatment were analysed. In 3.2 ± 0.4 (mean ± SD) years' follow-up, 163 (17%) participants experienced diabetes progression. Multivariable LR revealed that age at T2DM diagnosis (odds ratio [95% confidence interval], 0.96 [0.94-0.98]), Malay ethnicity (1.94 [1.19-3.19]), baseline HbA1c (2.22 [1.80-2.72]), body mass index (0.96 [0.92-1.00]) and number of oral glucose-lowering medications (1.87 [1.39-2.51]) were independently associated with diabetes progression. Area under receiver operating characteristic curve of the parsimonious model selected by forward LR (age at T2DM diagnosis, Malay ethnicity, HbA1c and number of glucose-lowering medication) was 0.76 (95% CI, 0.72-0.80)., Conclusion: Young age at T2DM diagnosis, high baseline HbA1c and Malay ethnicity are independent determinants of diabetes progression in Asians with T2DM. Further mechanistic studies are needed to elucidate the pathophysiology underpinning progressive loss of glycaemic control in patients with T2DM.

Background: Haptoglobin (Hp) is an abundant plasma protein with anti-oxidant properties. Hp polymorphism is associated with cardio-metabolic dysfunction but the allele conferring risk of developing acute myocardial infarction (AMI) in type 2 diabetes (T2D) patients is unclear. This study aimed to investigate the association of Hp phenotype (Hp 1-1, 2-1 and 2-2) with incident AMI in Chinese T2D patients., Methods: This prospective study included Chinese T2D participants from the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D) and Diabetic Nephropathy (DN) cohorts. Information on incidence of non-fatal AMI was collected by data linkage with the Singapore Myocardial Infarction Registry. Hp phenotype was determined using enzyme-linked immunosorbent assay. Cox proportional hazards regression models were used to evaluate the association of Hp phenotype with incident AMI, adjusted for traditional risk factors separately in two cohorts, then meta-analysed., Results: In total, 2324 Chinese participants (SMART2D; N = 1034, mean age [SD] of 59 [11]) and (DN: N = 1290, mean age [SD] of 58 [12]) were included in this study. There were total of 30 (56 events per 10,000 patient-years) and 99 (128 events per 10,000 patient-years) AMI events in SMART2D and DN cohorts respectively. In meta-analysis, presence of Hp 1 allele conferred 43% (hazard ratio [HR] = 1.43 [95% CI 1.10-1.87], P = 0.008, P het  = 0.413) increased risk of incident AMI, independent of age, sex, smoking, body mass index, HbA1c, diabetes duration, lipids, hypertension, renal function and usage of insulin and RAS antagonist. In adjusted model, compared to Hp 2-2 groups, individuals with Hp 1-1 (HR = 2.18 [95% CI 1.19-3.76], P = 0.010, P het  = 0.193) and Hp 2-1 (HR = 1.45 [95% CI 0.98-2.14], P = 0.065, P het  = 0.576) were at a higher risk of incident AMI. Moreover, compared to Hp 2-2 groups, non-Hp 2-2 groups (Hp 1-1 and Hp 2-1) were at 55% increased risk of incident AMI (HR = 1.55 [95% CI 1.07-2.24], P = 0.021, P het  = 0.940)., Conclusions: Hp 1-1 phenotype was associated with increased risk of incident AMI, independent of traditional risk factors, in Chinese patients with T2D. Hp phenotyping may allow for identification of T2D individuals at higher risk for onset of AMI. However, further studies are needed to understand the underlying mechanism between Hp alleles and risk for AMI.

Background: Obesity and shorter telomeres increase the risk for diabetes complications and mortality. However, the relationship between obesity and telomere length in diverse Asian populations with type 2 diabetes (T2D) is not well understood. This study examined the association of baseline and changes in obesity indices with telomere length in multiethnic Asian populations with T2D., Methods: Leukocyte telomere length (LTL) was measured by quantitative polymerase chain reaction in the SMART2D cohort (n = 1431 at baseline, n = 1039 after 3.2 years median follow-up). Associations between obesity indices and LTL were assessed by linear regression., Results: Compared with Chinese, LTL was longer in Malays (P < 0.0001) and similar in Indians. Cross-sectionally, body mass index (BMI)-adjusted (residual) visceral fat area (VFA; β = -0.004, P = 0.006), and waist-to-hip ratio (β = -1.95, P = 0.030) were significantly associated with LTL in Chinese but not in Malays and Indians. Changes in BMI (r = -0.080; P = 0.053) and VFA (r = -0.126; P = 0.002) were inversely correlated with changes in LTL only in Chinese. Furthermore, in Chinese, 1-SD incremental changes in BMI (β = -0.070; P = 0.040) and VFA (β = -0.088, P = 0.028) were significantly associated with larger telomere attrition, independent of age, sex, diabetes condition, baseline LTL, obesity, and inflammation markers., Conclusions: Three-year changes in BMI and VFA were associated with telomere dynamics in Chinese but not in Malays and Indians with T2D. Reducing obesity may reduce the risk of diabetes complications associated with shorter LTL in the Chinese population., (© 2018 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: This study evaluated the association between gain in adiposity and renal decline in a large prospective multiethnic South-east Asian cohort with type 2 diabetes mellitus (T2DM)., Methods: Three years after the baseline visit, 2057 T2DM subjects were recalled for reassessment. The final cohort comprised 1014 subjects and was categorized into tertiles based on changes in body weight (ΔWt), body mass index (ΔBMI), visceral fat area (ΔVFA), and BMI-adjusted VFA (ΔVFA BMI ). Outcomes included annual and rapid (≥3 mL/min per 1.73 m 2 per year) decline in estimated glomerular filtration rate (eGFR) and progression of albuminuria., Results: Participants (mean [±SD] age 57 ± 11 years, 48.8% women, BMI 27.7 ± 5.4 kg/m 2 ) exhibited a median annual decline in eGFR of 1.0 mL/min per 1.73 m 2 . Compared with the lower tertiles, Tertile 3 of ΔWt, ΔBMI, ΔVFA, and ΔVFA BMI had the highest anthropometric increase, albeit of modest magnitude, and this was accompanied by the worst renal outcomes (all P < 0.05). The relationship between annual eGFR decline and Tertile 3 of ΔWt, ΔBMI, and ΔVFA BMI persisted after multivariate adjustment in men but not in women. In addition, Tertile 3 of ΔWt, ΔBMI, ΔVFA, and ΔVFA BMI predicted rapid eGFR decline. Anthropometric gains were also associated with progression of albuminuria., Conclusions: Modest longitudinal gain in adiposity was associated with progressive renal decline in T2DM patients, suggesting that increased adiposity over time adversely affects renal outcomes. Therefore, a carefully designed weight-neutral or -loss antidiabetic treatment regimen is important when managing T2DM in the clinic., (© 2018 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background and Aim: The kidney is the main site for glucagon clearance. However, a recent study showed that hyperglucagonemia in patients with end-stage renal disease might not be caused by full-length intact glucagon. Additionally, the relationship between glucagon and renal function in early-stage chronic kidney disease (CKD) has not yet been characterized. We studied the association of fasting glucagon with renal function across a wide range of glomerular filtration rates (GFRs) in participants with type 2 diabetes., Participants and Methods: 326 participants with type 2 diabetes and renal function spanning CKD stage 1 to 5 were included in the present cross-sectional study. Fasting full-length plasma glucagon was quantified using a newly developed ELISA (Mercodia AB, Uppsala, Sweden)., Results: The fasting plasma glucagon level was elevated linearly from CKD stage 1 to 5 [from a median of 2.5 pM (interquartile range, 1.4 to 4.7) in CKD 1 to a median of 8.3 pM (interquartile range, 5.9 to 12.8) in CKD 5; P for trend < 0.0001], from as early as CKD stage 2 compared with that in stage 1 (Bonferroni-corrected P < 0.0001). The estimated GFR and homeostatic model of assessment-insulin resistance were the main determinants of the fasting glucagon level. These explained 14.3% and 10.3% of the glucagon variance, respectively. Albuminuria was not associated with fasting glucagon after adjustment for estimated GFR., Conclusions: Fasting full-length glucagon was elevated linearly with the deterioration in renal function in individuals with type 2 diabetes, even in those with early CKD. In addition to renal function, insulin sensitivity was also a main determinant of glucagon variance.

Background: Fluctuation of kidney function may signify intra-glomerular microvascular hemodynamic instability. We aim to examine the association of long-term serum creatinine and estimated glomerular filtration rate variability with diabetic retinopathy., Methods: We included type 2 diabetes mellitus patients who attended the Diabetes Centre in 2011-2014 and were followed up (median = 3.2 years). Digital colour fundus photographs were assessed for diabetic retinopathy at follow-up. Diabetic retinopathy severity was categorized into non-proliferative diabetic retinopathy and proliferative diabetic retinopathy. We conducted a nested case-control study involving 177 diabetic retinopathy (118 non-proliferative diabetic retinopathy, 50 proliferative diabetic retinopathy) and 327 age- and gender-matched non-diabetic retinopathy. Serum creatinine measured before follow-up visit was obtained (⩾3 readings/patient). Variability was calculated as intra-individual standard deviation/√ n/( n - 1)., Results: Diabetic retinopathy have higher adjusted-serum creatinine-standard deviation than non-diabetic retinopathy [9.1 (4.9-21.6) vs 5.4 (3.4-10.1) µM, p < 0.001]. After multivariable adjustment, adjusted-serum creatinine-standard deviation was associated with diabetic retinopathy [odds ratio = 1.47, 95% confidence interval (1.02-2.10), p = 0.04]. The area under the curve increased significantly after adding adjusted-serum creatinine-standard deviation [0.70 (0.65-0.75) vs 0.72 (0.68-0.77), p < 0.03]. Proliferative diabetic retinopathy have higher adjusted-serum creatinine-standard deviation than non-proliferative diabetic retinopathy [15.5 (6.6-39.7) vs 7.47 (4.52-17.8) µM, p < 0.001]. After adjustment, adjusted-serum creatinine-standard deviation remained associated with non-proliferative diabetic retinopathy [1.48 (1.04-2.12), p = 0.03] and proliferative diabetic retinopathy [2.43 (1.34-4.39), p = 0.003; p-trend = 0.002]. Similar findings were observed for estimated glomerular filtration rate variability., Conclusion: Serum creatinine and estimated glomerular filtration rate variability is associated with the presence and severity of diabetic retinopathy independent of intra-individual means. This may inform novel therapeutic strategies aiming to achieve stable renal function in type 2 diabetes mellitus.

Background: Obesity confers substantial excess risk for morbidity and mortality, especially for type 2 diabetes (T2D). Leucine-rich-α2-glycoprotein 1 (LRG1), a novel proinflammatory factor, was recently reported to be higher in patients with T2D with complications of peripheral arterial disease. Association of LRG1, obesity, and weight loss is unknown. We examined whether plasma LRG1 is associated with obesity in health screening participants and if it predicts future weight loss in morbidly obese patients after metabolic/bariatric surgery., Methods: Cohort 1 was a cross-sectional study from a Health Screening program (n = 616) in a tertiary hospital. Cohort 2 was a prospective study of morbidly obese patients (n = 231) who underwent metabolic/bariatric surgery with follow-up weight measurements. Anthropometric data, baseline fasting glucose, plasma adiponectin, high sensitivity C-reactive protein (HsCRP), and LRG1 were measured. Postsurgery blood, after metabolic/bariatric surgery, were available for LRG1and HsCRP measurements in 57 patients., Results: In the group with highest tertile of LRG1, body mass index (BMI), waist circumference, and HsCRP were significantly higher, while total cholesterol, high-density lipoprotein, low-density lipoprotein, and adiponectin were lower than tertiles 1 and 2. Generalized linear model analysis showed that female gender (P < .0001), non-Chinese ethnicity (P < .019), and higher HsCRP (P < .0001) levels were independent and significant determinants of higher plasma LRG1 levels. After adjustment for age, gender, ethnicity, and baseline BMI, female gender (P = .020), higher presurgery BMI (P = .001), and lower presurgery LRG1 (P = .002) remained statistically significant predictors for greater weight loss. Plasma LRG1 increased significantly [from 28.2 (21.9-36.8) to 34.9 (22.6-49.5)] μg/mL (P = .003) within 1.5 months, after metabolic/bariatric surgery., Conclusions: Our study demonstrates that LRG1 level is positively associated with obesity and a lower level of plasma LRG1 predicts weight loss in metabolic/bariatric surgery. Our novel findings suggest LRG1, itself or in combination with other known factors, is a potential biomarker of inflammation and obesity., (© 2018 John Wiley & Sons, Ltd.)

Aim: Glomerular hyperfiltration usually occurs early in development of kidney complications in diabetes. To understand hyperfiltration as a marker of renal disease progression in type 2 diabetes mellitus, we aimed to examine association between glomerular hyperfiltration (estimated glomerular filtration rate ⩾ 120 mL/min/1.73 m 2 ) and rapid renal decline (annual estimated glomerular filtration rate loss ⩾ 3 mL/min/1.73 m 2 )., Methods: This was a prospective cohort comprising 1014 patients with type 2 diabetes mellitus attending a Diabetes Centre of a regional hospital in 2002-2014. A separate prospective cohort, comprising 491 patients who attended Diabetes Centre or primary-care polyclinics, was used for validation. We performed binary mediation analysis to examine role of hyperfiltration on relationship between baseline haemoglobin A1c and rapid renal decline., Results: Among patients in discovery cohort, 5.2% had baseline hyperfiltration. Over mean follow-up of 6 years, 22.9% had rapid glomerular filtration rate decline. Baseline hyperfiltration was significantly associated with greater odds of rapid renal decline after adjusting for demographics, diabetes duration and clinical covariates (odds ratio: 2.57; 95% confidence interval: 1.21-5.46; p = 0.014). Similar finding was found in validation cohort (odds ratio: 2.98; 95% confidence interval: 1.06-8.42; p = 0.034). Hyperfiltration significantly accounted for 35.3% of association between increasing baseline haemoglobin A1c and rapid renal decline., Conclusion: Glomerular hyperfiltration is an independent risk factor of rapid renal decline. It mediates the association between increasing haemoglobin A1c and rapid renal decline.

Purpose/Aim: Diabetic retinopathy (DR) is the most common diabetic microvascular complication, and it typically develops after 10 years of diabetes diagnosis. The primary aim of this study was to evaluate the association between adiposity and DR susceptibility among individuals with longstanding type 2 diabetes mellitus (T2D)., Materials and Methods: In this cross-sectional study, DR was assessed by fundus photography in 953 T2D subjects. DR prevalence by categories of T2D duration was evaluated. In a sub-cohort analysis, subjects having T2D for ≥10 years were divided into DR (N = 241) and non-DR (N = 377) groups. Measures of adiposity including body mass index (BMI), waist circumference (WC), and visceral fat area (VFA) were analyzed. Urinary albumin:creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were measured., Results: DR prevalence markedly increased 10 years after T2D diagnosis (p < 0.001). Among subjects with T2D duration ≥10 years, BMI, WC, and VFA were elevated in DR compared with non-DR (all p < 0.05). Contrasting with BMI and WC, the association between VFA and DR sustained adjustment for demographics, metabolic factors, and insulin treatment (OR: 1.060, 95% CI: 1.004-1.119, p = 0.035). However, the association became insignificant after controlling for ACR and eGFR. Mediation analysis revealed that ACR and eGFR explained 47.3% of the relationship between VFA and DR., Conclusions: The findings suggest that visceral adiposity is associated with DR in individuals with longstanding T2D. This relationship may be attributable to generalized vascular injury as reflected by coexisting renal burden. Therefore, effective management of visceral adiposity and ameliorating renal burden may ameliorate susceptibility to DR.

Objective: We aim to investigate whether microvascular endothelial dysfunction is an independent predictor for future albuminuria progression in T2DM cohort., Methods: A total of 1098 patients with T2DM were clinically assessed at baseline and 3.2-year follow-up. Progression was defined as transition from normoalbuminuria (ACR <30 mg/g) to microalbuminuria (ACR = 30-299 mg/g) or macroalbuminuria (ACR >300 mg/g), or microalbuminuria to macroalbuminuria. Microvascular endothelial vasodilation at baseline was quantified using LDF. The increase in perfusion in response to ACh and NaNP was calculated. Logistic regression model was used to estimate the OR for albuminuria progression., Results: Albuminuria progression occurred in 226 (20.6%) patients. Baseline ACh was significantly higher in nonprogression than progression group (80.0 ± 53.2% vs 72.0 ± 49.7%, P = .04). There is no significant difference in NaNP between the two groups (111.1 ± 80.3% vs 121.1 ± 87.4%, P = .12). After multivariable adjustment, 1-SD increase in ACh was marginally associated with albuminuria progression (OR = 0.87, 95% CI, 0.72-1.02, P = .08) in all patients. When stratified by baseline albuminuria, 1-SD increase in ACh was significantly associated with albuminuria progression in normoalbuminuria (OR = 0.76, 95% CI, 0.59-0.97, P = .03), but not in microalbuminuria patients (OR = 1.18, 95% CI, 0.81-1.70, P = .39)., Conclusions: Impaired endothelial-dependent microvascular reactivity predicts the onset of albuminuria progression among T2DM patients with normoalbuminuria., (© 2018 John Wiley & Sons Ltd.)

The anticipated increase in the prevalence and incidence of type 2 diabetes in Asia, and its associated cardiovascular-renal complications, will place a significant burden on patients, caregivers, and society. Despite the proven effectiveness of lipid management in reducing these complications, there are major treatment gaps, especially in Asian patients with young-onset diabetes and chronic kidney disease (CKD). Recent international guidelines recommended the adoption of absolute risk estimation of atherosclerosis and cardiovascular disease to guide treatment intensity. These recommendations replaced the previous strategy of using low-density lipoprotein cholesterol targets to guide initiation and intensification of lipid lowering, albeit still widely practiced in Asia. The latest guidelines also highlight the high risk of atherosclerosis and cardiovascular disease (ASCVD) for people with diabetes, who should be protected with statins, except for young patients without other risk factors, who will need yearly monitoring of blood lipid levels. Given the propensity of Asian patients with diabetes to develop CKD and the amplifying effect of CKD on ASCVD, the use of statins in Asian patients is particularly important. Due to interethnic differences in drug metabolism, rosuvastatin, which is largely cleared by the kidney, should be prescribed in low dosages (5-10 mg daily) in Asian populations. Conversely, epidemiological and experimental data confirm pleotropic and organ-protective effects of atorvastatin, with proven safety in Asian populations within a daily dose range of 10-40 mg. Thus, there is a need for Asian countries to review and align their lipid-lowering treatment guidelines to reduce the substantial burden of diabetes in the Asian region., (© 2017 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.)

Purpose: Osteopontin (OPN) is a proinflammatory cytokine with diverse functions. Increased levels of OPN in vitreous fluid have been reported in patients with diabetic retinopathy (DR); however, studies on circulating OPN levels in DR are limited. We aim to examine the association of plasma OPN levels with the presence and severity of DR in a multiethnic cohort with type 2 diabetes mellitus (type 2 diabetes) in Singapore., Methods: Plasma levels of OPN were measured using enzyme-linked immunosorbent assay. Digital color fundus photographs were assessed for DR. DR severity was categorized into non-proliferative DR (NPDR) and proliferative DR (PDR). Gradable fundus photographs and OPN measurements for 443 patients were used for analysis. A logistic regression model was used to evaluate the association of OPN with DR., Results: DR was diagnosed in 174 (39.3%) patients, including 132 (75.9%) with NPDR and 42 (24.1%) with PDR. The median of OPN was higher in the patients with DR (64.7 [49.7-89.5] ng/ml) than in the patients without DR (51.7 [38.9-66.9] ng/ml; p<0.001). After adjustment for clinical and biochemical factors, a 1-unit increase in nature logarithm (ln)-transformed OPN was associated with the presence of DR (2.770 [1.599-3.800], p<0.001). The area under the curve (AUC) increased statistically significantly after the addition of OPN (0.805[0.763-0.846] versus 0.825 [0.785-0.865], p=0.011). In the severity analyses, the median of OPN was statistically significantly higher in the patients with PDR (76.8 [55.0-103.6] ng/ml) than in the patients with NPDR (61.7 [47.7-87.3] ng/ml; p=0.017). After adjustment, the 1-unit increase in lnOPN remained associated with NPDR (2.673 [1.519-4.704], p=0.001) and PDR (3.389 [1.254-9.226], p=0.017), respectively (p-trend=0.001)., Conclusions: Plasma OPN levels were associated with the presence and severity of DR in patients with type 2 diabetes, suggesting OPN may be useful as a potential biomarker for DR.

Aims: To examine differences in health-related quality of life (HRQoL) between patients with and without diabetic peripheral neuropathy (DPN), and whether these differences can be explained by functional deficits., Methods: This was a cross-sectional study of 160 patients with type 2 diabetes mellitus, 80 with DPN and 80 without. Assessments included HRQoL (health utility score derived from EQ-5D-5L), functional status measurements [muscle strength, timed up and go (TUG), five times sit-to-stand (FTSTS), functional reach, body sway velocity] and self-reported balance confidence [Activities-specific Balance Confidence (ABC) scale]., Results: Mean utility scores were 0.67 ± 0.14 and 0.77 ± 0.16 in patients with and without DPN, respectively (p < 0.001). Patients with DPN had lower great toe extensor strength (6.4 ± 1.8 vs 7.6 ± 2.8 lbs, p = 0.001), greater body sway velocity (2.40 ± 1.31 vs 1.90 ± 0.52 mm/s, p = 0.002), slower TUG (12.1 ± 4.6 vs 10.1 ± 2.3 s, p < 0.001) and FTSTS (15.8 ± 5.8 vs 13.9 ± 5.4 s, p = 0.03) scores, and lower ABC score (73.4 ± 21.3 vs 82.6 ± 16.9, p = 0.003), compared to those without DPN. On stepwise multiple regression, DPN status, FTSTS, body sway velocity, BMI, diabetes duration, pain, and gender explained 38% of HRQoL variance. Addition of ABC score into the model explained 45% of variance. Results from structural equation modelling showed that DPN had direct effects on HRQoL and indirect effects through FTSTS, body sway velocity, and ABC score, with χ 2  = 8.075 (p = 0.044), root mean square error of approximation = 0.103 (lower bound 0.015, upper bound 0.191), Comparative Fit Index = 0.966, Tucker-Lewis Index = 0.887, and Standardized Root Mean Square Residual = 0.053., Conclusions: Patients with DPN have worse HRQoL compared to patients without DPN, partly mediated by functional status parameters. Effective interventions targeting functional status may be beneficial in improving HRQoL in these patients.

Background and Aims: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by the presence of high plasma low density lipoproteins cholesterol (LDL-c). Patients with FH, with mutation detected, are at increased risk of premature cardiovascular disease compared to those without mutations. The aim of the study was to assess the type of mutations in patients, clinically diagnosed with FH in Singapore., Methods: Patients (probands) with untreated/highest on-treatment LDL-c>4.9 mmol/l were recruited (June 2015 to April 2017). Anthropometric, biochemical indices, blood and family history were collected. DNA was extracted and Next Generation Sequencing (NGS) was performed in 26 lipid-related genes, including LDLR, APOB and PCSK9, and validated using Sanger. Multiplex-ligation probe analyses for LDLR were performed to identify large mutation derangements. Based on HGVS nomenclature, LDLR mutations were classified as "Null"(nonsense, frameshift, large rearrangements) and "Defective"(point mutations which are pathogenic)., Results: Ninety-six probands were recruited: mean age: (33.5 ± 13.6) years. 52.1% (n = 50) of patients had LDLR mutations, with 15 novel mutations, and 4.2% (n = 4) had APOB mutations. Total cholesterol (TC) and LDL-c were significantly higher in those with LDLR mutations compared to APOB and no mutations [(8.53 ± 1.52) vs. (6.93 ± 0.47) vs. (7.80 ± 1.32)] mmol/l, p = 0.012 and [(6.74 ± 0.35) vs. (5.29 ± 0.76) vs. (5.98 ± 1.23)] mmol/l, p=0.005, respectively. Patients with "null LDLR" mutations (n = 13) had higher TC and LDL-c than "defective LDLR" mutations (n = 35): [(9.21 ± 1.60) vs. (8.33 ± 1.41)]mmol/l, p = 0.034 and [(7.43 ± 1.47) vs. (6.53 ± 1.21)]mmol/l, p=0.017, respectively., Conclusions: To our knowledge, this is the first report of mutation detection in patients with clinically suspected FH by NGS in Singapore. While percentage of mutations is similar to other countries, the spectrum locally differs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Context: We previously reported an association between lysophosphatidylinositol (LPI) (16:1) and risk for type 2 diabetes in a Chinese population using an untargeted analysis., Objective: To examine the overall associations of LPIs and their related metabolites, such as nonesterified fatty acids (NEFAs) and acylcarnitines, with incident and prevalent type 2 diabetes using a targeted approach., Design and Setting: A case-control study was nested within the Singapore Chinese Health Study. Cases and controls were individually matched by age, sex, and date of blood collection. We used both liquid and gas chromatography tandem mass spectrometry to measure serum metabolite levels at baseline, including 8 LPIs, 19 NEFAs, and 34 acylcarnitines. Conditional logistic regression models were used to estimate the associations between metabolites and diabetes risk., Participants: Participants included 160 incident and 144 prevalent cases with type 2 diabetes and 304 controls., Main Outcome Measure: Incident and prevalent type 2 diabetes., Results: On the basis of a false discovery rate <0.1, we identified 37 metabolites associated with prevalent type 2 diabetes, including 7 LPIs, 18 NEFAs, and 12 acylcarnitines, and 11 metabolites associated with incident type 2 diabetes, including 2 LPIs and 9 NEFAs. Two metabolites, LPI (16:1) and dihomo-γ-linolenic acid, showed independent associations with incident type 2 diabetes and significantly enhanced the risk prediction., Conclusions: We found several LPIs and NEFAs that were associated with risk for type 2 diabetes and may improve our understanding of the pathogenesis. The findings suggest that lipid profiles could aid in diabetes risk assessment in Chinese populations., (Copyright © 2017 Endocrine Society)

Context: Abnormal angiogenesis plays an important role in pathogenesis of diabetic kidney disease (DKD). Leucine-rich α-2 glycoprotein 1 (LRG1) is a newly identified angiogenic factor., Objective: To study whether plasma LRG1 may independently predict progression of DKD in individuals with type 2 diabetes mellitus (T2DM)., Design and Setting: Prospective cohort study in a regional hospital., Patients: In total, 1226 T2DM participants were followed for a mean ± standard deviation (SD) of 3.1 ± 0.4 years., Main Outcomes: Albuminuria progression was defined as elevation in albuminuria level to a higher category. Chronic kidney disease (CKD) progression [rapid estimated glomerular filtration rate (eGFR) decline] was defined as a 40% or greater deterioration in eGFR in 3 years., Results: Both participants with albuminuria progression and those with CKD progression had higher plasma LRG1 levels at baseline. LRG1 independently predicted albuminuria progression above traditional risk factors, including baseline eGFR and urine albumin to creatinine ratio. A 1-SD increment in LRG1 was associated with a 1.26-fold [95% confidence interval (CI), 1.04 to 1.53, P = 0.018] higher adjusted risk for albuminuria progression. The association of LRG1 with microalbuminuria to macroalbuminuria progression was stronger than its association with normoalbuminuria to microalbuminuria progression [odds ratio (OR), 1.51; 95% CI, 1.04 to 2.18, P = 0.029 vs OR, 1.09; 95% CI, 0.86 to 1.37, P = 0.486, per 1-SD LRG1 increment]. Also, LRG1 independently predicted CKD progression above traditional risk factors. A 1-SD increment in LRG1 was associated with a 1.48-fold (95% CI, 1.04 to 2.11, P = 0.032) higher adjusted risk for CKD progression., Conclusions: Plasma LRG1 predicts both albuminuria and CKD progression beyond traditional risk factors. It may play a role in the pathologic pathway leading to progression of DKD in T2DM., (Copyright © 2017 Endocrine Society)

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., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Diabetic retinopathy (DR) is a leading cause of vision-loss globally among type 2 diabetes (T2DM) patients. Information on the economic burden of DR in Singapore is limited. We aim to identify the total annual direct medical costs of DR at different stages, and to examine factors influencing the costs. Four hundreds and seventy T2DM patients who attended the Diabetes Centre in a secondary hospital in Singapore in 2011-2014 were included. Digital color fundus photographs were assessed for DR in a masked fashion. Retinopathy severity was further categorized into non-proliferative DR (NPDR), including mild, moderate and severe NPDR, and proliferative DR (PDR). Medical costs were assessed using hospital administrative data. DR was diagnosed in 172 (39.5%) patients, including 51 mild, 62 moderate and 18 severe NPDR, and 41 PDR. The median cost in DR [2012.0 (1111.2-4192.3)] was significantly higher than that in non-DR patients [1158.1 (724.1-1838.9)] (p<0.001). The corresponding costs for mild, moderate, severe NPDR and PDR were [1167.1 (895.4-2012.0)], [2212.0 (1215.5-3825.5)], [2717.5 (1444.0-6310.7)], and [3594.8.1 (1978.4-8427.7)], respectively. After adjustment, the corresponding cost ratios for mild, moderate, severe NPDR, and PDR relative to non-DR were 1.1 (p = 0.827), 1.8 (p = 0.003), 2.0 (p = 0.031) and 2.3 (p<0.001), respectively. The other factors affecting the total cost include smoking (ratio = 1.7, p = 0.019), neuropathy (ratio = 1.9, p = 0.001) and chronic kidney disease (CKD) (ratio = 1.4, p = 0.019). The presence and severity of DR was associated with increased direct medical costs in T2DM. Our results suggest that preventing progression of DR may reduce the economic burden of DR.

Background: Diabetic peripheral neuropathy (DPN) is a common complication of Type 2 diabetes (T2D). Apart from hyperglycemia, its pathogenesis is poorly understood. Apolipoprotein-CIII (apoC-III) associated with triglyceride metabolism, is a risk factor for cardiovascular disease. Its role in DPN is not well-established. We studied the associations of apoC-III, endothelial function and DPN., Methods: In patients with T2D, anthropometric data, fasting blood, and urine were collected for biochemistry and urine albumin/creatinine measurements (uACR). Endothelial function assessments were performed by laser Doppler flowmetry/imaging. DPN was considered present if there was an abnormal finding in monofilament (≤8 of 10 points) or neurothesiometer testing≥25V on either foot. Plasma apoC-III was assessed by ELISA., Results: Monofilament and neurothesiometer readings were measured in 1981 patients, mean age 57.4±10.8 years old. DPN prevalence was 10.8% (n=214). Patients with DPN compared to those without, were significantly older (p<0.0001), with longer duration of T2D (p<0.0001), had higher BMI (p=0.006), higher glucose (p=0.015) and HbA1c (p<0.0001), Systolic blood pressure (SBP) (p<0.0001), lower eGFR (p<0.0001), higher urine ACR (p<0.0001), poorer endothelium-dependent and endothelium-independent vasodilation (both p<0.0001), higher VCAM-1 (p<0.0001) and higher apoC-III [285.3 (195.2-405.6) vs 242.9(165.0-344.0) μg/ml]. After adjustment, log transformed apoC-III, remained independently associated with the presence of DPN (B=0.965, SE=0.397, p=0.015)., Conclusion: Plasma apoC-III is higher in patients with DPN. Apart from its known association with lipids and macrovascular complications, this study suggests its association with DPN. Whether regulating apoC-III metabolism may be an important new therapeutic approach to managing dyslipidemia and microvascular complications in T2D remains to be proven in future mechanistic and clinical studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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: This 3-year prospective study aimed to identify baseline parameters that predicted the progression of carotid-femoral pulse wave velocity (cf-PWV), which was used to evaluate aortic stiffness, among Singapore's multi-ethnic Asians with type 2 diabetes (T2DM)., Methods: The cf-PWV was measured by the gold-standard tonometry method in 994 T2DM subjects at baseline and follow-up. The annual rate of cf-PWV change was calculated, and individuals above the 90 th percentile with rate≥1.42 m/s per year were regarded as rapid progressors (n = 104). In a subgroup analysis of subjects with normal cf-PWV at 1 st visit (n = 611), incident aortic stiffness was defined as follow-up cf-PWV≥10 m/s (n = 188)., Results: The total cohort (mean age:57 ± 10 years; 53.4% Chinese, 20.4% Malay, 22.9% Indian, 3.2% 'Others') displayed a median annual cf-PWV progression rate of 0.2 m/s. Adjusted multivariate regression analyses showed that baseline age, cf-PWV and body mass index (BMI) constantly predicted follow-up cf-PWV, annual cf-PWV progression rate, rapid cf-PWV progression, and incident aortic stiffness. Paradoxically, lower baseline cf-PWV was associated with elevated annual cf-PWV progression rate and rapid progressors. This inverse relationship remained significant across ethnicities after ethnic stratification. Higher BMI independently predicted cf-PWV progression in Chinese and Indians, but not in Malay and 'Others' ethnic groups. Increased age was a significant predictor in Chinese and 'Others' ethnicities., Conclusions: We demonstrated that baseline BMI is a modifiable independent risk factor of cf-PWV progression and incident aortic stiffness. Therefore, better obesity management may impede aortic stiffness in Singapore's T2DM patients, especially in the Chinese and Indians., (Copyright © 2017. Published by Elsevier B.V.)

Aims: This study aims to develop and validate a predictive model for Chronic Kidney Disease (CKD) progression in Type 2 Diabetes Mellitus (T2DM)., Methods: We conducted a prospective study on 1582 patients with T2DM from a Diabetes Centre in regional hospital in 2002-2014. CKD progression was defined as deterioration across eGFR categories with ⩾25% drop from baseline. The dataset was randomly split into development (70%) and validation (30%) datasets. Stepwise multivariable logistic regression was used to identify baseline predictors for model development. Model performance in the two datasets was assessed., Results: During median follow-up of 5.5years, 679 (42.9%) had CKD progression. Progression occurred in 467 (42.2%) and 212 patients (44.6%) in development and validation datasets respectively. Systolic blood pressure, HbA1c, estimated glomerular filtration rate and urinary albumin-to-creatinine ratio were associated with progression. Areas under receiving-operating-characteristics curve for the training and test datasets were 0.80 (95%CI, 0.77-0.83) and 0.83 (95%CI, 0.79-0.87). Observed and predicted probabilities by quintiles were not statistically different with Hosmer-Lemeshow χ 2 0.65 (p=0.986) and 1.36 (p=0.928) in the two datasets. Sensitivity and specificity were 71.4% and 72.2% in development dataset, and 75.6% and 72.3% in the validation dataset., Conclusions: A model using routinely available clinical measurements can accurately predict CKD progression in T2DM., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Pathophysiology of diabetic kidney disease (DKD) is incompletely understood. We aim to elucidate metabolic abnormalities associated with DKD in type 2 diabetes mellitus (T2DM) by targeted plasma metabolomics., Methods: A total of 126 T2DM participants with early DKD (urinary albumin-to-creatinine ratio [ACR] 30-299 mg/g and eGFR ≥ 60 ml/min/1.73 m 2 ), 154 overt DKD (ACR ≥ 300 mg/g or eGFR < 60 ml/min/1.73 m 2 ), and 129 non-DKD T2DM controls (ACR < 30 mg/g and eGFR ≥ 60 ml/min/1.73 m 2 ) were included in discovery study. Findings were subsequently validated in 149 T2DM with macroalbuminuria (ACR ≥ 300 mg/g) and 149 matched non-DKD T2DM controls. Plasma amino acid, acylcarnitine, Krebs cycle organic acid, and sphingolipids/ceramide levels were quantified by liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry., Results: Of 123 metabolites included in the data analysis, 24 differed significantly between DKD and controls in the same direction in both discovery and validation subpopulations. A number of short acylcarnitines including their dicarboxylic derivatives (C2-C6) were elevated in DKD, suggesting abnormalities in fatty acids and amino acids metabolic pathways. Five phosphatidylcholines were lower whereas 4 metabolites in the sphingomyelin-ceramide subfamily were higher in DKD. Principal component regression revealed that long-chain ceramides were independently associated with ACR but not eGFR. Conversely, essential amino acids catabolism and short dicarboxylacylcarnitine accumulation were associated with eGFR but not ACR., Discussion: DKD is associated with altered fuel substrate use and remodeling of sphingolipid metabolism in T2DM with DKD. Associations of albuminuria and impaired filtration function with distinct metabolomic signatures suggest different pathophysiology underlying these 2 manifestations of DKD.