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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. Graphical abstract

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 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.

Context Elevated levels of plasma leucine-rich α-2-glycoprotein 1 (LRG1), a component of transforming growth factor beta signaling, are associated with development and progression of chronic kidney disease in patients with type 2 diabetes (T2D). However, whether this relationship is causal is uncertain. Objectives To identify genetic variants associated with plasma LRG1 levels and determine whether genetically predicted plasma LRG1 contributes to a rapid decline in kidney function (RDKF) in patients with T2D. Design and participants We performed a genome-wide association study of plasma LRG1 among 3694 T2D individuals [1881 (983 Chinese, 420 Malay, and 478 Indian) discovery from Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes cohort and 1813 (Chinese) validation from Diabetic Nephropathy cohort]. One- sample Mendelian randomization analysis was performed among 1337 T2D Chinese participants with preserved glomerular filtration function [baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2)]. RDKF was defined as an eGFR decline of 3 mL/min/1.73 m2/year or greater. Results We identified rs4806985 variant near LRG1 locus robustly associated with plasma LRG1 levels (meta P = 6.66 × 10−16). Among 1337 participants, 344 (26%) developed RDKF, and the rs4806985 variant was associated with higher odds of RDKF (meta odds ratio = 1.23, P = 0.030 adjusted for age and sex). Mendelian randomization analysis provided evidence for a potential causal effect of plasma LRG1 on kidney function decline in T2D (P Conclusion We demonstrate that genetically influenced plasma LRG1 increases the risk of RDKF in T2D patients, suggesting plasma LRG1 as a potential treatment target. However, further studies are warranted to elucidate underlying pathways to provide insight into diabetic kidney disease prevention.

Background Chronic kidney disease (CKD) is common among people with type 2 diabetes (T2D), and increases the risk of kidney failure and cardiovascular diseases. Shorter leukocyte telomere length (LTL) is associated with CKD in patients with T2D. We previously reported single-nucleotide polymorphisms (SNPs) associated with LTL in an Asian population. In this study, we elucidated the association of these SNPs with CKD in patients with T2D using the Mendelian randomization (MR) approach. Methods The cross-sectional association of 16 LTL SNPs with CKD, defined as an estimated glomerular filtration rate of Results Genetically determined shorter LTL was associated with increased risk of CKD in patients with T2D (meta-IVW adjusted odds ratio = 1.51, 95% confidence interval 1.12–2.12, P = 0.007, Phet = 0.547). Similar results were obtained following sensitivity analysis. MR-Egger analysis (intercept) suggested no evidence of horizontal pleiotropy (β = 0.010, P = 0.751). Conclusions Our findings suggest that genetically determined LTL is associated with CKD in patients with T2D. Further studies are warranted to elucidate the causal role of telomere length in CKD progression.

OBJECTIVE The aim of this study was to determine the relationship between telomere length (TL) in subcutaneous adipose tissue (SAT), visceral adipose tissues (VAT), and leukocytes, as well as to examine the associations of TL in these tissues with postsurgical weight loss in Asians with severe obesity. METHODS Presurgery TL was measured in leukocytes, SAT, and VAT of 91 patients who underwent weight loss surgery. Correlation between TL in multiple tissues was assessed using Pearson correlation. The association of presurgery TL and postsurgical weight loss at 6 or 12 months, expressed as a percentage of weight loss, was determined using linear regression in 70 patients. RESULTS Telomeres were longer in VAT compared with those in leukocytes and SAT (P < 0.001) but were highly correlated between tissues. The strongest correlation was observed between TL in VAT and leukocytes (r = 0.739, P = 6.22 × 10-17 ). Compared with individuals in the highest tertile, those in the lowest tertile of VAT TL showed greater weight loss (β = 6.23, SE = 3.10, P = 0.044) independent of age, sex, ethnicity, types of surgery, diabetes condition, preoperative BMI, and follow-up period. CONCLUSIONS Among patients with severe obesity, TL in leukocytes and adipose tissue was highly correlated. However, there was variability in the association of TL in these tissues with weight loss after surgery.

Although most work has focused on resolution of collagen ECM, fibrosis resolution involves changes to several ECM proteins. The purpose of the current study was two-fold: 1) to examine the role of MMP12 and elastin; and 2) to investigate the changes in degraded proteins in plasma (i.e., the “degradome”) in a preclinical model of fibrosis resolution. Fibrosis was induced by 4 weeks carbon tetrachloride (CCl4) exposure, and recovery was monitored for an additional 4 weeks. Some mice were treated with daily MMP12 inhibitor (MMP408) during the resolution phase. Liver injury and fibrosis was monitored by clinical chemistry, histology and gene expression. The release of degraded ECM peptides in the plasma was analyzed using by 1D-LC-MS/MS, coupled with PEAKS Studio (v10) peptide identification. Hepatic fibrosis and liver injury rapidly resolved in this mouse model. However, some collagen fibrils were still present 28d after cessation of CCl4. Despite this persistent collagen presence, expression of canonical markers of fibrosis were also normalized. The inhibition of MMP12 dramatically delayed fibrosis resolution under these conditions. LC-MS/MS analysis identified that several proteins were being degraded even at late stages of fibrosis resolution. Calpains 1/2 were identified as potential new proteases involved in fibrosis resolution. CONCLUSION. The results of this study indicate that remodeling of the liver during recovery from fibrosis is a complex and highly coordinated process that extends well beyond the degradation of the collagenous scar. These results also indicate that analysis of the plasma degradome may yield new insight into the mechanisms of fibrosis recovery, and by extension, new “theragnostic” targets. Lastly, a novel potential role for calpain activation in the degradation and turnover of proteins was identified.

In recent years, electric mobility devices (EMDs) have become popular in major cities across the globe. Whereas many cities have embraced and integrated this new form of urban green mobility into their public transport systems, in Hong Kong, the growing popularity of EMDs is being met with growing public and government concern about their safety. To address these concerns, the government proposed the EMD regulatory framework to manage their use in such a densely populated and mountainous city. The judicial definition of EMD in the current Hong Kong Road Traffic Ordinance (Cap. 374) considers devices such as unicycles, e-scooters, hoverboards, and electric bicycles as motor vehicles that are prohibited on the roadways, footpaths, and street flex zones. Referring to the transport review of the Hong Kong Legislative Council Panel conducted on June 19, 2020, in this study, we examine the costs and benefits of using EMDs in such a densely populated city. Furthermore, we argue that less populous outlying islands could offer more suitable trial locations to integrate these innovative “first-last mile” micro vehicles. This article contributes to the existing EMD body of knowledge by highlighting the benefits and challenges with specific emphasis on Hong Kong’s EMD proposed framework.

The global importance of English and therefore the teaching of the English language has made the English language curriculum an integral part of all levels of teacher education, including early childhood education. The purpose of this study was to first explore the beliefs about the teaching of English to very young learners held by pre-service pre-primary teachers in Macau and then to see whether these beliefs were reflected in their microteaching. Qualitative content analysis performed on the written reflections and transcriptions of the microteaching videos of 75 pre-service pre-primary teachers found that their beliefs about classroom practices, lesson planning, and English as a foreign language (EFL) learners and learning were the most predominant beliefs exhibited in their reflections and were evidenced in their microteaching. Less predominant, but still salient, were their beliefs about the goals of language learning, assessment, teaching, pedagogical knowledge, and content. No observable practices were found regarding the pre-service teachers’ beliefs about the role of teaching, learning to teach, microteaching, the self, the subject, hearsay, self-assessment, and schooling. The current study found that with only limited exposure to EFL teaching methodology from a single course, the pre-service pre-primary teachers were able to implement some of their beliefs about several important aspects of teaching English to very young learners.

Inadequate access to clean water is detrimental to human health and aquatic industries. Waterborne pathogens can survive prolonged periods in aquatic bodies, infect commercially important seafood, and resist water disinfection, resulting in human infections. Environmental agencies and research laboratories require a relevant, portable, and cost-effective platform to monitor microbial pathogens and assess their risk of infection on a large scale. Advances in microfluidics enable better control and higher precision than traditional culture-based pathogen monitoring approaches. We demonstrated a rapid, high-throughput fish-based teleost (fish)-microbe (TelM) microfluidic-based device that simultaneously monitors waterborne pathogens in contaminated waters and assesses their infection potential under well-defined settings. A chamber-associated port allows direct access to the animal, while the transparency of the TelM platform enables clear observation of sensor readouts. As proof-of-concept, we established a wound infection model using Pseudomonas aeruginosa-contaminated water in the TelM platform, where bacteria formed biofilms on the wound and secreted a biofilm metabolite, pyoverdine. Pyoverdine was used as fluorescent sensor to correlate P. aeruginosa contamination to infection. The TelM platform was validated with environmental waterborne microbes from marine samples. Overall, the TelM platform can be readily applied to assess microbial and chemical risk in aquatic bodies in resource-constrained settings.

The Involvement Load Hypothesis (ILH) has become a widely used framework for predicting second language (L2) vocabulary learning from task completion. The purpose of this systematic review was to analyze the predictive ability of the ILH in the acquisition of aspects of knowing a word, its application in different target populations, the effective vocabulary learning task types designed based on the ILH, and the occurrence rate of the ILH components in vocabulary learning tasks. We searched IEEE, ERIC, WOS, Scopus, and ProQuest databases for empirical studies published between 2001 and 2021, using a vocabulary-focused keyword string combined with an ILH-focused keyword string. A total of 78 studies were selected using a set of inclusion and exclusion criteria. The content analysis of these studies showed that researchers have used the ILH to investigate the acquisition of six aspects of knowing a word. Four types of tasks (i.e., fill-in-the-blanks, reading, composition writing, and meaning-inferring) provided more positive evidence for the validation of the ILH. The search component was least present in the vocabulary learning tasks. Researchers have supported the use of the ILH to predict the vocabulary learning potential of tasks completed mainly by adult learners. This systematic review provides direction for future reviews and empirical studies in L2 vocabulary teaching and learning framed by the ILH.

Language teacher beliefs have received increasing research attention for the past few decades. However, little is known about the beliefs of pre-service teachers in the pre-primary English as a foreign language (EFL) education context. This qualitative case study extends this line of inquiry by investigating the trajectory of student teachers' beliefs about teaching English to pre-primary learners in Macau within a teacher education course. The participants included 60 pre-service teachers taking an English Language Activities course in their third year of a 4-year Bachelor of pre-primary education program. The data comprised written reflections collected at three points in time during the 16-week course: at the beginning of the course, mid-way through the course, and at the end of the course. The findings showed five broad themes, constituted from 15 subthemes, regarding (1) learners and learning, (2) teaching, (3) subject, (4) self, and (5) learning to teach. The major themes have been documented in the literature, but several subthemes were identified for the first time in the context of pre-primary EFL teacher education. More importantly, the findings revealed that some of the subthemes were newly shaped and several subthemes were reshaped as a consequence of taking the course. The findings were interpreted in relation to the content of the course, the experiential learning opportunities, the pre-service teachers' prior experiences of language learning and teaching, and the local language teaching and learning context. Implications for pre-service teacher education programs are discussed.

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.

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. Key words: Glucose-lowering medications, Glycaemic control, High-density lipoprotein

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P, Shortening of leukocyte telomere length (LTL) is associated with age and increased risk for various chronic diseases. Here, the authors report genome-wide association studies for LTL in Singaporean Chinese populations and find that longer LTL associates with less severe outcomes of respiratory disease phenotypes.

Data on specific causes of mortality in South East Asians with type 2 diabetes mellitus (T2DM) remain scarce. We followed 2061 outpatients with T2DM (Chinese 63%, Malays 20%, and Asian Indians 17%) for an average of 5.5 (standard deviation = 2.9) years and identified 365 death events by data linkage with national death registry. Cardiovascular disease was the main cause of mortality (44%), followed by renal disease (17%), infection (17%), cancer (14%), and others causes (8%). Survival analyses revealed that risks for all-cause and cause-specific mortality vary greatly among ethnic groups. Presence of diabetic kidney disease was an independent risk factor for death attributable to cardiovascular disease, renal disease, and infection, while HbA1c level predicted all major causes of deaths even after accounting for multiple other risk factors. These data reinforce the importance of glycemic control and prevention of diabetic kidney disease for mitigation of mortality burden in multiethnic Asians with T2DM.

Objective The outcomes of sepsis and septic shock patients are heterogonous, with avariable response despite standardized care. The aim of this study was toexplore the racial differences in septic shock outcomes, and theirassociation with genetic polymorphisms and cytokine levels in an Asianpopulation. Materials and methods This was an observational cohort study with Intensive Care units of a 500bedded tertiary care hospital in Singapore. 198 patients (73 Chinese, 73Malay and 52 Indian and others) admitted to the Khoo Teck Puat HospitalIntensive Care Unit between August 2016 and June 2017, with a diagnosis ofsevere sepsis (according to) were enrolled. Plasma interlukin-6 (IL-6),interlukin-10 (IL-10) and tumour necrosis factor-a (TNFa) were measuredusing a highly sensitive quantitative sandwich enzyme-linked immunosorbentassay (ELISA) (BioVendor, Modrice, Czech Republic). The gene panel studiedincluded 16 genes. Results The rs7038903 common variant in SVEP1 gene showed significant associationwith sepsis severity independent of other variants in ordinal logistic andlinear regression model (p = 0.001 and p = 0.002 respectively). Moreover, the association between rs7038903 and increased hazard for death remained significant after further adjusting for cytokines level. Interestingly, significant differences were seen in plasma IL6 inindividuals with or without rs7038903 C allele (28pg/ml (IQR 12-86) vs90pg/ml (IQR 49-155); P=0.022) in patients with severe sepsis in the Malayethnic group. Conclusion Our study shows a promising polymorphism in SVEP1 gene (rs7038903) which isassociated with sepsis shock and 28 days mortality, independent of age, gender, and method of diagnosis and SOFA score. Collectively, while our findings so far have shown the additional value or measuring cytokines andgenetic markers in sepsis outcomes in the local population, further largescare studies are needed in a heterogeneous septic population with arigorous analysis to know the significance of our findings. How to cite this article Siddiqui S, Gurung RL et al. Genetic Polymorphisms and Cytokine Profile of Different Ethnicities in Septic Shock Patients, and their Association with Mortality. Indian J Crit Care Med 2019;29(3):135-138.

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10−14–6.94×10−10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers., Xuling Chang et al. study whether low frequency variants are associated with leukocyte telomere length and whether these variants predispose to incident cancers and mortalities among East Asians. They find that three East Asian specific variants at POT1, TERF1 and STN1 loci are associated with leukocyte telomere length and report a mechanistic pathway linking TERF1, leukocyte telomere length and incident colon cancer.

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-naive 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.

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.

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.

Context Metabolites in the tricarboxylic acid (TCA) cycle are not only involved in energy metabolism but also play important roles in non-energy production activities. Objective To study whether baseline urine key TCA cycle metabolites (lactate, pyruvate, citrate, α-ketoglutaric acid, succinate, fumarate, and malate) independently predict risk of chronic kidney disease (CKD) progression [fast estimated glomerular filtration rate (eGFR) decline] in individuals with type 2 diabetes mellitus (T2DM). Design One discovery and one validation nested case-control studies in two independent T2DM cohorts. Setting and participants Subjects with T2DM were recruited and followed in a regional hospital and at a primary care facility. Main outcome measures eGFR trajectory (slope) was estimated by linear regression. Progressive CKD was defined as eGFR decline of ≥5 mL/min/1.73 m2 per year. Results As compared with those with stable renal function (n = 271), participants who experienced progressive CKD (n = 116) had a lower level of urine citrate but significantly higher levels of lactate, fumarate, and malate levels at baseline. Both fumarate and malate predicted progressive CKD independent of traditional cardio-renal risk factors, including eGFR and albuminuria. Fumarate interacted with sex (P for interaction = 0.03) and independently predicted progressive CKD in male but not female participants. All these findings were reproducible in a validation study (case n = 96, control n = 402). Exploratory analysis suggested that fumarate might partially mediate the effect of oxidative stress on CKD progression. Conclusions Key TCA cycle metabolites, especially fumarate, may be involved in the pathophysiologic pathway independent of traditional cardio-renal risk factors, leading to CKD progression in patients with T2DM.

Introduction: Telomere length, a marker for biological aging, is implicated with diabetic kidney disease (DKD); however, the association between telomere length and albuminuria progression among Asian patients with type 2 diabetes (T2D) is not well understood. Here, we aim to study whether leukocyte telomere length (LTL) may independently predict albuminuria progression in patients with T2D with preserved renal filtration function (estimated GFR >60 ml/min per 1.73 m2 and urine albumin-to-creatinine ratio [uACR]

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.

OBJECTIVE Haptoglobin is an acute-phase reactant with pleiotropic functions. We aimed to study whether urine haptoglobin may predict risk of mortality in people with type 2 diabetes. RESEARCH DESIGN AND METHODS We employed a transethnic approach with a cohort of Asian origin (Singapore) (N = 2,061) and a cohort of European origin (France) (N = 1,438) included in the study. We used survival analyses to study the association of urine haptoglobin with risk of all-cause and cause-specific mortality. RESULTS A total of 365 and 525 deaths were registered in the Singapore cohort (median follow-up 7.5 years [interquartile range 3.5–12.8]) and French SURDIAGENE cohort (median follow-up 6.8 years [interquartile range 4.3–10.5], respectively. Singapore participants with urine haptoglobin in quartiles 2 to 4 had higher risk for all-cause mortality compared with quartile 1 (unadjusted hazard ratio [HR] 1.47 [95% CI 1.02–2.11], 2.28 [1.62–3.21], and 4.64 [3.39–6.35], respectively). The association remained significant in quartile 4 after multiple adjustments (1.68 [1.15–2.45]). Similarly, participants in the French cohort with haptoglobin in quartile 4 had significantly higher hazards for all-cause mortality compared with quartile 1 (unadjusted HR 2.67 [2.09–3.42] and adjusted HR 1.49 [1.14–1.96]). In both cohorts, participants in quartile 4 had a higher risk of mortality attributable to cardiovascular disease and infection but not malignant tumor. CONCLUSIONS Urine haptoglobin predicts risk of mortality independent of traditional risk factors, suggesting that it may potentially be a novel biomarker for risk of mortality in patients with type 2 diabetes.

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, Phet = 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, Phet = 0.193) and Hp 2-1 (HR = 1.45 [95% CI 0.98–2.14], P = 0.065, Phet = 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, Phet = 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. Electronic supplementary material The online version of this article (10.1186/s12933-019-0867-4) contains supplementary material, which is available to authorized users.

A recent study suggested that urinary haptoglobin may be a novel biomarker to improve predictive performance of albuminuria in type 2 diabetes mellitus (T2DM). However, the finding has not been externally validated.The objective of the study was to evaluate whether urinary haptoglobin improves predictive performance of albuminuria in Asian T2DM with an estimated glomerular filtration rate (eGFR) of 30 mL/min per 1.73 mThis was a prospective study with 269 T2DM nonprogressors (eGFR changes 0.2 [-0.7 to 1.0] mL/min per 1.73 mThe main outcome was an eGFR decline of 3 mL/min per 1.73 mUrinary haptoglobin level increased 11-fold in progressors as compared with nonprogressors at baseline. In comparison with subjects in the lowest quartile, those with haptoglobin in the third and fourth quartiles had 2.25- (1.11-4.59) and 5.41 (2.63-11.1)-fold increased odds for renal progression, whereas those with an albuminuria level in the third and fourth quartiles had 2.53- (1.17-5.51) and 9.01 (4.00-20.5)-fold increased odds. Notably, urinary haptoglobin predicted renal progression independent of albuminuria. Addition of haptoglobin significantly improved the predictive performance of albuminuria beyond traditional risk factors as reflected by a significant increase in the net reclassification index and integrated discrimination index. In the chronic kidney disease stage 3 subpopulation, urinary haptoglobin outperformed albuminuria for the prediction of rapid renal function decline.Our data confirmed that urinary haptoglobin may improve the predictive performance of albuminuria for renal progression in Asians with T2DM. Moreover, it may potentially outperform albuminuria for the prediction of rapid renal function decline in the T2DM chronic kidney disease stage 3 subpopulation.

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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.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.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.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.摘要: 背景 肥胖与端粒较短会增加糖尿病并发症与死亡的风险。然而，在不同的亚洲2型糖尿病人群中，肥胖与端粒长度之间的关系尚未明确。这项研究在多民族的亚洲2型糖尿病人群中调查基线时的肥胖指数与端粒长度的关系，并且观察这种关系随时间变化的情况。 方法 在SMART2D队列中，使用定量聚合酶链反应测定白细胞的端粒长度(leukocyte telomere length，LTL)(基线时n = 1431，经过中位数为3.2年的随访之后n = 1039)。通过线性回归来分析肥胖指数与LTL之间的关系。 结果 与中国人群相比，马来西亚人群的LTL较长(P0.0001)，而印度人群的LTL则相似。在中国人群中，从横断面来看，体重指数(BMI)-校正后的(残余)内脏脂肪面积(VFA；β = −0.004，P = 0.006)以及腰臀比(β = −1.95，P = 0.030)都与LTL显著相关，但是在马来西亚与印度人群中却无此相关性。只有在中国人群中，BMI(r=−0.080； P =0.053)以及VFA(r = −0.126；P = 0.002)的变化才与LTL的变化呈负相关。此外，在中国人群中BMI(β = −0.070；P = 0.040)以及VFA(β = −0.088，P = 0.028)每1-SD的增量变化都与更大的端粒消耗显著相关，而且这种相关性并不依赖于年龄、性别、糖尿病状况、基线LTL、肥胖以及炎症标志物。 结论 在中国2型糖尿病患者人群中，体重指数以及VFA的3年的变化与端粒的动态变化之间具有相关性，但是在马来西亚与印度人群中却无此相关性。在中国人群中，减少肥胖可能会降低与较短LTL相关的糖尿病并发症风险。.

Aim To study whether plasma fibroblast growth factor 21 independently predicts the risk of end-stage renal disease in Asian people with Type 2 diabetes. Methods In this prospective cohort study, 1700 Asian people with Type 2 diabetes were followed for a mean of 6.3 years in a regional hospital in Singapore. Incident end-stage renal disease was identified by linkage with a national renal registry. The association of baseline fibroblast growth factor 21 levels with risk of progression to end-stage renal disease was studied using survival analyses. Results Participants were aged 60 ± 10 years, with an average diabetes duration of 12 years. Their estimated GFR was 73 ± 28 ml/min/1.73 m2 and 62% had albuminuria at baseline. A total of 179 incident end-stage renal disease cases were identified. Plasma fibroblast growth factor 21 interacted with sex in its association with end-stage renal disease (Pinteraction = 0.003). A 1-sd increment in fibroblast growth factor 21 (natural log-transformed) was associated with a 1.32-fold (95% CI 1.05-1.66, P = 0.02) increased hazard for end-stage renal disease in women, after adjustment for traditional risk factors including estimated GFR and albuminuria. Taking death as a competing risk did not materially change the outcome [sub-distribution hazard ratio 1.35 (95% CI 1.11-1.66, P = 0.003)]. Fibroblast growth factor 21 did not predict end-stage renal disease risk in men after adjustment for baseline estimated GFR and albuminuria [hazard ratio 1.07 (95% CI 0.89-1.28, P = 0.49)]. Conclusions Plasma fibroblast growth factor 21 level independently predicted risk of progression to end-stage renal disease in women with Type 2 diabetes. The pathophysiological relationships among FGF21, sex and renal progression warrant further study.

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

Urine haptoglobin (uHP) level prospectively predicts diabetic kidney disease (DKD) progression. Here, we aim to identify genetic determinants of uHP level and evaluate association with renal function in East Asians (EA) with type 2 diabetes (T2D). Genome-wide association study (GWAS) among 805 [236 Chinese (discovery) and 569 (57 Malay and 512 Chinese) (validation)] found that rs75444904/kgp16506790 variant was robustly associated with uHP level (MetaP = 1.21 × 10−60). rs75444904 correlates well with plasma HP protein levels and multimerization in EA but was not in perfect LD (r2 = 0.911 in Chinese, r2 = 0.536 in Malay) and is monomorphic in Europeans (1000 G data). Conditional probability analysis indicated weakening of effects but residual significant associations between rs75444904 and uHP when adjusted on HP structural variant (MetaP = 8.22 × 10−7). The rs75444904 variant was associated with DKD progression (OR = 1.77, P = 0.014) independent of traditional risk factors. In an additional validation-cohort of EA (410 end-stage renal disease (ESRD) cases and 1308 controls), rs75444904 was associated with ESRD (OR = 1.22, P = 0.036). Furthermore, increased risk of DKD progression (OR = 2.09, P = 0.007) with elevated uHP level through Mendelian randomisation analysis provide support for potential causal role of uHP in DKD progression in EA. However, further replication of our findings in larger study populations is warranted.

Fibroblast growth factor 21 (FGF21) has been well-recognized as a metabolic hormone and a promising target for treatment of metabolic diseases. The level of endogenous FGF21 is elevated in patients with impaired glucose tolerance and progressively increased from patients with overt type 2 diabetes to those with micro- and macro-vascular complications, presumably as a compensation or response to the deterioration of metabolic imbalance. A few exploratory in vivo studies, including a recent clinical trial, showed that exogenous FGF21 mimetics targeting FGF21 signaling can attain beneficial metabolic effects not with-standing the already elevated ambient FGF21 levels. In addition, some clinically available pharmacologic agents such as fenofibrates and metformin may modulate energy and macronutrients metabolism by acting through FGF21. This review mainly focuses on the role of FGF21 in development, progression and treatment of type 2 diabetes from a clinical perspective.

This paper describes a social skills programme implemented to enhance the social competence of Primary-one students in order to ensure a smooth adjustment after transition from kindergarten to a formal school learning environment. The participants were 122 students (64 boys and 58 girls; mean age 6.17 years, SD = 0.29 years) newly enrolled in a Hong Kong primary school. The intervention involved 60 minutes of contact per week for 8 weeks, and focused on playing interactive group games led by trained parent volunteers. Raven’s (1980) Standard Progressive Matrices were used to identify high-ability and average-ability students. In order to assess the programme’s impact on social competence, parents and teachers completed the Early School Behavior Rating Scale. Results indicated that students in the programme made significantly greater progress than a comparison group of Primary-one students who did not go through the intervention. High-ability students showed significant improvements in social competence, sustained over time in both home and school settings. Students of average ability exhibited positive improvements in social competence in school, but this did not always transfer to home. Boys improved their social competence and narrowed the gender difference with girls. Implications for school intervention are discussed.

This exploratory study involved a structured group-games intervention to develop first-grade students’ social competence. The effects were evaluated by assessing possible outcomes for the children's social status. A sample of 119 first-grade, mixed-ability students from a Hong Kong primary school participated in the sessions (63 boys, 56 girls: mean age 74 months). Sessions were led by trained parent-volunteers and involved a 60-minute session each week for 8 weeks in the children's own classrooms. Peer nominations were used before and after intervention to assess participants’ social status under five possible categories ― popular, rejected, controversial, neglected and average. Improvement in children's social awareness and social status was noted following the intervention. Children's competence in playing group games was found to be positively correlated with their social acceptance. The findings support the value of early social intervention in classrooms as a practical way for preparing first-grade students for primary school life.

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

Objectives To study the relationship between plasma soluble klotho (sKlotho) and pro-endothelin-1 (proET-1) in patients with type 2 diabetes (T2DM). Subjects and methods In this cross-sectional study, we recruited 175 T2DM subjects and 56 non-diabetic controls. Plasma sKlotho, proET-1 and extracellular superoxide dismutase (SOD) were measured by ELISA and ILMA, respectively. Results Plasma sKlotho level in patients with T2DM was lower compared to that in non-diabetic controls (416.8 ± 148.1 vs. 494.6 ± 134.3 pg/ml, p = 0.001) and showed significant interaction with diabetes status in its association with proET-1. Plasma sKlotho was inversely correlated with proET-1 in T2DM (Rho = −0.410, p p = 0.505). Multivariable linear regression models revealed that sKlotho was independently associated with proET-1 after adjustment for renal filtration function, albuminuria, diabetes duration, HbA1c, systolic and diastolic blood pressure. Conclusions Plasma sKlotho was associated with proET-1 independent of renal function in patients with T2DM.

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

Altered hepatic lipogenesis is associated with metabolic diseases such as obesity and hepatosteatosis. Insulin resistance and compensatory hyperinsulinaemia are key drivers of these metabolic imbalances. Fas apoptosis inhibitory molecule (FAIM), a ubiquitously expressed antiapoptotic protein, functions as a mediator of Akt signalling. Since Akt acts at a nodal point in insulin signalling, we hypothesize that FAIM may be involved in energy metabolism. In the current study, C57BL/6 wild-type (WT) and FAIM-knockout (FAIM-KO) male mice were fed with normal chow diet and body weight changes were monitored. Energy expenditure, substrate utilization and physical activities were analysed using a metabolic cage. Liver, pancreas and adipose tissue were subjected to histological examination. Serum glucose and insulin levels and lipid profiles were determined by biochemical assays. Changes in components of the insulin signalling pathway in FAIM-KO mice were examined by immunoblots. We found that FAIM-KO mice developed spontaneous non-hyperphagic obesity accompanied by hepatosteatosis, adipocyte hypertrophy, dyslipidaemia, hyperglycaemia and hyperinsulinaemia. In FAIM-KO liver, lipogenesis was elevated as indicated by increased fatty acid synthesis and SREBP-1 and SREBP-2 activation. Notably, protein expression of insulin receptor beta was markedly reduced in insulin target organs of FAIM-KO mice. Akt phosphorylation was also lower in FAIM-KO liver and adipose tissue as compared with WT controls. In addition, phosphorylation of insulin receptor substrate-1 and Akt2 in response to insulin treatment in isolated FAIM-KO hepatocytes was also markedly attenuated. Altogether, our data indicate that FAIM is a novel regulator of insulin signalling and plays an essential role in energy homoeostasis. These findings may shed light on the pathogenesis of obesity and hepatosteatosis.

The association of adhesion molecules ICAM-1 and VCAM-1 with cardiovascular diseases has been well-studied. However, their roles in diabetic kidney disease (DKD) are incompletely understood. We aim to study the association of plasma ICAM-1 and VCAM-1 with DKD in Asians with type 2 diabetes (T2DM).A total of 1950 Asians with T2DM were included in this cross-sectional study. Plasma ICAM-1 and VCAM-1 were measured by immunoassays.Renal filtration function (eGFR) declined and urinary albumin-to-creatinine ratio (ACR) levels increased progressively with the increase in plasma VCAM-1 levels. In contrast, no significant changes in eGFR and ACR were observed in subjects across different plasma ICAM-1 levels. Both ICAM-1 and VCAM-1 were correlated with ACR (rho = 0.153, p0.001 for VCAM-1 and ACR; rho = 0.053, p = 0.020 for ICAM-1 and ACR) in bivariate correlation analysis. However, only VCAM-1 was correlated with eGFR (rho = -0.228, p0.001). Multivariable linear regression models revealed that VCAM-1, but not ICAM-1, was independently associated with eGFR and albuminuria. Backward linear regression suggested that plasma VCAM-1 variability was mainly determined by eGFR whereas plasma ICAM-1 level was mainly determined by C-reactive protein in patients with T2DM.Plasma VCAM-1 level, but not ICAM-1 level, was independently associated with prevalent DKD in Asians with T2DM. High level of ICAM-1 may be indicative of systemic inflammation and portends increase risk of incipient DKD.

Becaplermin (recombinant human platelet-derived growth factor-BB [BB homodimer, rhPDGF-BB]) has demonstrated a favorable safety profile in a series of nonclinical studies designed to assess its systemic toxicity, sensitization, local irritation, and genotoxic potential. No significant local or systemic toxicity directly attributable to becaplermin was observed following single and multiple intravenous or subcutaneous administration at doses up to 3 mg/kg in monkeys. Administration of single large intravenous doses (up to 100 mg/kg) and repeated dosing at 1 or 3 mg/kg in mice resulted in rapidly reversible vasodilation and central nervous system depression. In a bone-toxicity study, becaplermin produced histomorphologic changes suggestive of accelerated bone remodeling, which were judged to be potentially reversible. Similar findings have not been observed in humans. Although becaplermin was not considered a dermal or ocular irritant, some skin-sensitizing effects were observed in animals; this finding was not unexpected for a recombinant human-derived protein. Becaplermin was not genotoxic in a variety of in vitro assays and in one in vivo assay.

Irisin is a novel myokine secreted in response to PPAR-γ co-activator-1α (PGC-1α) activation. Earlier studies suggested that PGC-1α expression and activity were lower in myocytes in type 2 diabetes mellitus (T2DM). Therefore, we hypothesize that circulating irisin levels are lower in T2DM patients.In this observational study, we recruited 96 T2DM subjects and 60 non-diabetic control subjects. Among T2DM subjects, 38% were on insulin treatment, 78% were taking statins and 72% were taking renin-angiotensin system antagonists. Circulating irisin was quantified by ELISA and its association with markers of metabolic phenotype was analyzed by Pearson bivariate correlation and multiple linear regression.Circulating irisin was significantly lower in individuals with T2DM compared with non-diabetic controls (T2DM 204 ± 72 ng/ml vs. non-diabetic control 257 ± 24 ng/ml, p0.0001). In non-diabetic subjects, circulating irisin was correlated with age (r = 0.398, p0.01), BMI (r = 0.387, p0.01), total cholesterol (r = 0.341, p0.01), total triglycerides (r = 0.299, p0.05), fasting blood glucose (r = 0.430, p0.01) and diastolic blood pressure (r = 0.306, p0.05). Multiple linear regression model revealed that BMI (β = 0.407, p = 0.012) and FBG (β = 0.315, p = 0.034) were associated with irisin in non-diabetic subjects after adjusting for multiple co-variates. However, similar analysis in T2DM subjects didn't reveal significant association between circulating irisin and major markers of metabolic phenotype.Circulating irisin is lower in T2DM compared with non-diabetic controls. Plasma irisin levels appear to be associated with important metabolic factors in non-diabetic subjects but not in individuals with type 2 diabetes.

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 mosquitocidal crystal protein, Cry19Aa, from Bacillus thuringiensis ssp. jegathesan, has high toxicity to Anopheles stephensi and Culex pipiens but is less toxic to Aedes aegypti. To study the functional role of putative domain II and surface residues in mosquito toxicity, 16 alanine substitution mutations were introduced into Cry19Aa. All mutant constructs were expressed as 65-kDa protoxins and subsequently digested by trypsin to produce further fragmented polypeptides of 40 and 25 kDa. With chymotrypsin, however, most protoxins were digested to 60 kDa and minor bands. The circular dichroism spectra of the chymotrypsin-activated toxins of Cry19Aa and muteins, Y324A, W357A, Y412A, Y414A, W416A, D418A and F485A indicated that there was no significant variation in their structure. In mosquito bioassays, Y324A, W357A, Y410A, W416A, D418A and F485A muteins showed substantial reductions in mosquitocidal activity toward A. aegypti and C. pipiens. These muteins also showed reduced competition with wild-type fluorescein 5-isothiocyanate-labeled Cry19Aa for binding to C. pipiens brush border membrane vesicles. These data suggest that the reduction of toxicity was a result of the reduced binding affinity. From these studies we have identified loop residues of domain II that are important in toxicity and receptor binding to Culex larval midgut.