Clinical variable-based cluster analysis identifies novel subgroups with a distinct genetic signature, lipidomic pattern and cardio-renal risks in Asian patients with recent-onset type 2 diabetes.

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.

Association of Plasma Leucine-Rich Alpha-2 Glycoprotein 1 (LRG1) with All-Cause and Cause-Specific Mortality in Individuals with Type 2 Diabetes.

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.

Factors predicting one-year post-surgical mortality amongst older Asian patients undergoing moderate to major non-cardiac surgery - a retrospective cohort study.

BACKGROUND: While short-term perioperative outcomes have been well studied in Western surgical populations, the aim of this study is to look at the one-year perioperative mortality and its associated factors in an Asian surgical population after non-cardiac surgery. METHODS: A retrospective cohort study of 2163 patients aged above 45 undergoing non-cardiac surgery in a university-affiliated tertiary hospital from January to July 2015 was performed. Relevant demographic, clinical and surgical data were analysed to elicit their relationship to mortality at one year after surgery. A univariate analysis was first performed to identify significant variables with p-values ≤ 0.2, which were then analysed using Firth multiple logistic regression to calculate the adjusted odds ratio. RESULTS: The one-year mortality in our surgical population was 5.9%. The significant factors that increased one-year mortality include smoking (adjusted OR 2.17 (1.02-4.45), p = 0.044), anaemia (adjusted OR 1.32 (1.16-1.47), p < 0.001, for every 1 g/dL drop in haemoglobin level), lower BMI (adjusted OR 0.93 (0.87-0.98), p = 0.005, for every 1 point increase in BMI), Malay and Indian ethnicity (adjusted OR 2.68 (1.53-4.65), p = 0.001), peripheral vascular disease (adjusted OR 4.21 (1.62-10.38), p = 0.004), advanced age (adjusted OR 1.04 (1.01-1.06), p = 0.004, for every one year increase in age), emergency surgery (adjusted OR 2.26 (1.29-3.15), p = 0.005) and malignancy (adjusted OR 3.20 (1.85-5.52), p < 0.001). CONCLUSIONS: Our study shows that modifiable risk factors such as malnutrition, anaemia and smoking which affect short term mortality extend beyond the immediate perioperative period into longer term outcomes. Identification and optimization of this subset of patients are therefore vital. Further similar large studies should be done to develop a risk scoring system for post-operative long-term outcomes. This would aid clinicians in risk stratification, counselling and surgical planning, which will help in patients' decision making and care planning.

The neglected perioperative population of undiagnosed diabetics - a retrospective cohort study.

BACKGROUND: Diabetes is known to increase morbidity and 30-day mortality in adults undergoing non-cardiac surgery, but longer term outcomes are less studied. This study was done to explore how undiagnosed and known diabetes affect 30-day and one-year morbidity and mortality outcomes. The secondary aim was to study the prevalence of undiagnosed diabetics in our perioperative Asian surgical population. METHODS: A retrospective cohort study of 2106 patients aged > 45 years undergoing non-cardiac surgery in a single tertiary hospital was performed. Undiagnosed diabetics were identified (HbA1c ≥6.5% or fasting blood glucose ≥126 mg/dL) and relevant demographic, clinical and surgical data were analyzed to elicit the relationship to adverse outcomes. Univariate analysis was first performed to identify significant variables with p-values ≤0.1, which were then analyzed using multiple logistic regression to calculate the adjusted odds ratio. RESULTS: The prevalence of undiagnosed diabetes was 7.4%. The mean and median HbA1c of known diabetics were 7.9 and 7.5%, while the mean and median HbA1c for undiagnosed diabetics were 7.2 and 6.8% respectively. 36.4% of known diabetics and 20.5% of undiagnosed diabetics respectively had a random blood glucose > 200 mg/dL. Undiagnosed diabetics had a three-fold increase in 1-year mortality compared to non-diabetics (adjusted OR 3.46(1.80-6.49) p < 0.001) but this relationship was not significant between known and non-diabetics. Compared to non-diabetics, known diabetics were at increased risks of new-onset atrial fibrillation (aOR 2.48(1.01-6.25) p = 0.047), infection (aOR 1.49(1.07-2.07) p = 0.017), 30-day readmission (aOR 1.62(1.17-2.25) p = 0.004) and 30-day mortality (aOR 3.11(1.16-8.56) p = 0.025). CONCLUSIONS: Although undiagnosed diabetics have biochemically less severe disease compared to known diabetics at the point of testing, they are at a one-year mortality disadvantage which is not seen among known diabetics. This worrying trend highlights the importance of identifying and treating diabetes. Congruent to previous studies, known diabetics have higher morbidity and 30-day mortality compared to non-diabetics.

Impact of haemoglobin A1c trajectories on chronic kidney disease progression in type 2 diabetes.

AIM: To characterize haemoglobin A1c (HbA1c) trajectories and examine their associations with chronic kidney disease (CKD) progression. METHODS: This was a prospective cohort study on 770 patients with type 2 diabetes mellitus (T2DM) attending a diabetes centre in 2002-2017. Group-based trajectory modelling was used to identify HbA1c trajectories. Cox proportional hazards models were used to examine association between the trajectories and CKD progression which was defined as deterioration across the Kidney Disease: Improving Global Outcomes estimated glomerular filtration rate categories with ≥25% drop from baseline. RESULTS: We identified four HbA1c trajectories: 'near-optimal stable' (49.1%), 'moderate stable' (37.9%), 'moderate-increasing' (6.0%) and 'high-decreasing' (7.0%). Over a median follow-up period of 4.6 years (interquartile range 2.5-5.6), CKD progression occurred in 35.6% of patients. The risk of CKD progression was significantly higher in the moderate-increasing with adjusted hazard ratios (HR) 2.23 (95% confidence interval (CI) 1.09-4.57). After additional adjustment for mean HbA1c, the association between the moderate-increasing subgroup and CKD progression remained significant at HR 3.07 (95% CI 1.08-8.77). CONCLUSION: Moderate-increasing HbA1c trajectory is associated with renal disease progression in patients with T2DM, independent of mean HbA1c. The deleterious effects of deteriorating HbA1c trajectory highlight the importance of achieving sustained good glycaemic control in diabetes management.

Medical costs associated with chronic kidney disease progression in an Asian population with type 2 diabetes mellitus.

AIM: We aim to examine difference in incremental direct medical costs between non-progressive and progressive chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) in Singapore. METHODS: This was a prospective study on 676 patients with T2DM attending a diabetes centre in a regional hospital. Annual direct medical costs were extracted from the administrative database. Ordinary least squares regression was used to estimate contribution of CKD progression to annual costs, adjusting for demographics and baseline clinical covariates. RESULTS: Over mean follow-up period of 2.8 ± 0.4 years, 266 (39.3%) had CKD progression. The excess total follow-up medical costs from baseline was S$4243 higher in progressors compared to non-progressors (P = 0.002). The mean cost differential between the two groups increased from S$2799 in Stages G1-G2 to S$11180 in Stage G4. Inpatient cost accounted for 63.4% of total cost of progression. When stratified by glomerular filtration rate stages, the respective total mean annual costs at stages glomerular filtration rate Stages G3a-G3b and G4 were S$3290 (132%; P = 0.001) and S$4416 (135%; P = 0.011) higher post-progression. CONCLUSION: Chronic kidney disease progression in T2DM is associated with high medical costs. The cost of progression is higher with higher severity of CKD stage at baseline and could be largely driven by inpatient admission.

Efficacy of an enhanced recovery nursing plan as a rooming-in practice for women with preeclampsia post-cesarean section.

Our purpose was to develop and evaluate the clinical outcomes of a nursing plan as a rooming-in practice for enhanced recovery of women with preeclampsia following a cesarean section. The authors developed a postoperative enhanced recovery nursing plan as a rooming-in practice for women with preeclampsia based on summarizing evidence-based best practices. The authors used convenience sampling to select women with preeclampsia after a cesarean section from the obstetrics department of a Class A tertiary hospital in Nanjing, China, as the participants in our study. There were 30 women in the experimental group. The postoperative enhanced recovery nursing care plan was formulated for five postoperative time points and incorporated management of blood pressure, temperature, and fluids, as well as monitoring of complications, pain management, activity and rest, diet management, and breastfeeding. The control group consisted of 30 women who received routine nursing care and health education. The authors compared levels of maternal self-efficacy, breastfeeding efficacy, anxiety, pain scores, and deep vein thrombosis (DVT) prevention compliance before and after the intervention. Women in the experimental group had a self-efficacy score of 7.5 ± 0.63, which was higher than that in the control group (5.4 ± 0.85); they had a higher breastfeeding efficacy score of 7.13 ± 0.68 when compared to the control group (4.23 ± 0.86); the anxiety score was 6.7 ± 1.62, which was lower than that in the control group (10.03 ± 1.87); and the pain score was lower at 3.26 ± 0.52 when compared to the control group (3.83 ± 0.83). All the differences were statistically significant (P < 0.05). Postoperative blood pressure was controlled within the target range, and the rate of DVT prevention compliance increased in the experimental group. The implementation of a postoperative enhanced recovery nursing intervention for women with preeclampsia as part of the rooming-in practice was effective in helping manage the blood pressure, pain, and fluids of women with preeclampsia, improved their postoperative self-management ability and breastfeeding efficacy, reduced their anxiety levels, improved their compliance with the prevention of related complications, and ultimately promoted enhanced postoperative recovery, thereby guaranteeing the safety of mothers and newborns.

Glycolytic lactate in diabetic kidney disease.

Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.

A generalized sequential Bonferroni procedure using smoothed weights for genome-wide association studies incorporating information on Hardy-Weinberg disequilibrium among cases.

BACKGROUND/OBJECTIVES: For genome-wide association studies (GWAS) with case-control designs, one of the most widely used association tests is the Cochran-Armitage (CA) trend test assuming an additive mode of inheritance. The CA trend test often has higher power than other association tests under additive and multiplicative disease models. However, it can have very low power under a recessive disease model in GWAS. Although tests (such as MAX3) robust to different genetic models have been developed, they often have relatively lower power than the CA trend test under additive and multiplicative models. The goal of this study is to propose an efficient method that not only has higher power than the CA trend test under dominant and recessive models but also maintains the power of the CA trend test under additive and multiplicative models. METHODS: We employed the generalized sequential Bonferroni (GSB) procedure of Holm to incorporate information from a Hardy-Weinberg disequilibrium (HWD) test into the CA trend test based on estimating weights from the p values of the HWD test. We proposed to smooth the weights to reduce possible noise. RESULTS AND CONCLUSIONS: Results from extensive simulation studies showed that the proposed GSB procedure can achieve the goal described above.

Urine Leucine-Rich α-2 Glycoprotein 1 (LRG1) Predicts the Risk of Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes.

OBJECTIVE: Leucine-rich α-2 glycoprotein 1 (LRG1) was recently identified as an amplifier of transforming growth factor-ß (TGF-ß)-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-ß 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.

Association Between Use of Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors and Cognitive Function in a Longitudinal Study of Patients with Type 2 Diabetes.

BACKGROUND: The association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) use and cognitive function in type 2 diabetes remains unclear. OBJECTIVE: Explore the association between SGLT2i and longitudinal changes in cognitive function in adults with type 2 diabetes (T2DM) and assessed the cognitive domains which were impacted by SGLT2i. METHODS: We conducted a prospective cohort study of 476 patients aged 60.6±7.4 years with follow-up period up to 6.4 years. Data on SGLT2i use was derived from questionnaire and verified with clinical database. We used Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to assess cognition. The association between SGLT2i use and rate of RBANS score change was examined using multiple linear regression. RESULTS: There were 138 patients (29.0%) on SGLT2i, including 84 (17.7%) for < 3 years and 54 (11.3%) for ≥3 years. SGLT2i use was positively associated with RBANS total score increase in language (coefficient 0.60; 95% CI 0.10-1.11; p = 0.019) in unadjusted analysis. This positive association persisted in fully adjusted model (coefficient 0.74; 95% CI 0.12 to 1.36; p = 0.019). SGLT2i use for ≥3 years was positively associated with RBANS score increase globally and in language domain in fully adjusted analysis with coefficients 0.54 (95% CI 0.13 to 0.95; p = 0.010) and 1.12 (95% CI 0.27 to 1.97; p = 0.010) respectively. CONCLUSION: Our findings revealed a previously unobserved association between ≥3 years SGLT2i use and improved cognitive scores globally and in language domain and executive function. Future studies should investigate the role of SGLT2i in ameliorating cognitive decline.

Risk of Incident Heart Failure in Individuals With Early-Onset Type 2 Diabetes.

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.

Genetic Risk Score for Plasma Uric Acid Levels Is Associated With Early Rapid Kidney Function Decline in Type 2 Diabetes.

CONTEXT: Observational studies have shown that elevated uric acid (UA) is associated with chronic kidney disease (CKD). However, whether the relationship is causal remains unclear. OBJECTIVE: To determine the association of plasma UA and incident CKD and the causal relationship between plasma UA and rapid decline in kidney function (RDKF) in patients with type 2 diabetes (T2D). METHODS: Multivariable Cox regression was conducted to evaluate the hazard ratio (HR) between plasma UA and incident CKD among 1300 normoalbuminuric patients in 2 T2D study cohorts (DN, n = 402; SMART2D, n = 898). A weighted genetic risk score (wGRS) was calculated based on 10 single nucleotide polymorphism (SNPs) identified in genome-wide association studies of UA in East Asians. Mendelian randomization (MR) analysis was performed among 1146 Chinese T2D patients without CKD (estimated glomerular filtration rate [eGFR] > 60 mL/min/1.73m2) at baseline (DN, 478; SMART2D, 668). The wGRS and individual SNPs were used as genetic instruments and RDKF was defined as eGFR decline of 5 mL/min/1.73m2/year or greater. RESULTS: During mean follow-up of 5.2 and 5.4 years, 81 (9%) and 46 (11%) participants in SMART2D and DN developed CKD, respectively. A 1-SD increment in plasma UA conferred higher risk of incident CKD (DN, adjusted-HR = 1.40 [95% CI, 1.02-1.91], P = 0.036; SMART2D, adjusted-HR = 1.31 [95% CI, 1.04-1.64], P = 0.018). Higher wGRS was associated with increased odds for RDKF (meta-adjusted odds ratio = 1.12 [95% CI, 1.01-1.24], P = 0.030, Phet = 0.606). CONCLUSION: Elevated plasma UA is an independent risk factor for incident CKD. Furthermore, plasma UA potentially has a causal role in early eGFR loss in T2D patients.

Amino acid profile of skeletal muscle loss in type 2 diabetes: Results from a 7-year longitudinal study in asians.

AIMS: Little is known about pathophysiology of sarcopenia in diabetes. We aimed to study amino acid profile associated with skeletal muscle mass loss longitudinally in Type 2 Diabetes Mellitus (T2DM). METHODS: This is a prospective study of 1140 patients aged 56.6 ± 10.6 years from the SMART2D cohort. Skeletal muscle mass was measured using bio-impedance analysis at baseline and follow-up. Amino acids were measured by mass spectrometry. RESULTS: Over a period of up to 7.9 years, 43.9% experienced skeletal muscle mass loss. Lower baseline valine, leucine and isoleucine levels were associated with decreased skeletal muscle mass index (SMI) with corresponding coefficient 0.251(95 %CI 0.009 to 0.493), 0.298(95 %CI 0.051 to 0.544)) and 0.366(95 %CI 0.131 to 0.600). Higher baseline valine, leucine, isoleucine, alanine and tryptophan levels were associated with reduced odds of muscle mass loss with corresponding odds ratio (OR)0.797 (95 %CI 0.690 to 0.921), 0.825 (95 %CI 0.713 to 0.955), 0.826 (95 %CI 0.718-0.950), 0.847 (95 %CI 0.739-0.969) and 0.835 (95 %CI 0.720-0.979). CONCLUSION: The branched-chain amino acids valine, leucine and isoleucine were positively associated with change in SMI and reduced odds of muscle mass loss longitudinally. Further studies should be conducted to elucidate the pathophysiological mechanisms underlying the relationship between these amino acids and muscle mass loss in T2DM.

Association of Plasma Leucine-Rich α-2 Glycoprotein 1, a Modulator of Transforming Growth Factor-ß Signaling Pathway, With Incident Heart Failure 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.

Low muscle mass is associated with progression of chronic kidney disease and albuminuria - An 8-year longitudinal study in Asians with Type 2 Diabetes.

AIMS: We examined the longitudinal relationship between baseline skeletal muscle mass and its change over time with eGFR decline and albuminuria progression among Asians with type 2 diabetes(T2D). METHODS: This was a prospective cohort study of 1272 T2D patients. Skeletal muscle mass was estimated using tetra-polar multi-frequency bio-impedance analysis and Skeletal Muscle Mass Index(SMI) was defined as skeletal muscle mass/weight * 100. RESULTS: After up to 8 years of follow-up, 33.3% of participants had CKD progression and 28.3% albuminuria progression. Every 1-SD above baseline SMI was associated with 18% lower risk of CKD progression[Hazards Ratio(HR)0.82; 95%CI 0.70-0.97; p = 0.018] and 17% lower risk of albuminuria progression [HR 0.83 (95%CI 0.71-0.97; p = 0.017)]. The largest decrease in SMI over time was associated with 67% higher risk of CKD progression, compared to those with the smallest change from baseline SMI tertile 2[HR 1.67 (95%CI 1.10-2.55); p = 0.016]. Pigment epithelium-derived factor(PEDF) and plasma leucine-rich α-2-glycoprotein (LRG1) accounted for 40.1% of the association between SMI and CKD progression. CONCLUSIONS: Low baseline skeletal muscle mass and its reduction over time is associated with increased risk of progression of CKD among Asians with T2D. PEDF and LRG1 mediated the inverse relationship between SMI and CKD progression.

The role of pulse pressure in navigating the paradigm of chronic kidney disease progression in type 2 diabetes mellitus.

BACKGROUND AND AIMS: Arterial stiffness is a risk factor for chronic kidney disease progression (CKD). Pulse pressure is a surrogate marker of arterial stiffness. It is unclear if pulse pressure predicts CKD progression in type 2 diabetes mellitus. METHODS: This was prospective study involving 1494 patients with estimated glomerular filtration rate (eGFR) ≥ 15 ml/min/1.73 m2. Carotid-femoral pulse wave velocity was measured using applanation tonometry. Pulse pressure was calculated as difference between systolic and diastolic blood pressures. CKD progression was defined as worsening of eGFR categories (stage 1, ≥ 90 ml/min/1.73 m2; stage 2, 60-89 ml/min/1.73 m2; stage 3a, 45-59 ml/min/1.73 m2; stage 3b, 30-44 ml/min/1.73 m2; stage 4; 15-29 ml/min/1.73 m2; and stage 5, < 15 ml/min/1.73 m2) with ≥ 25% decrease in eGFR from baseline. RESULTS: After follow-up of up to 6 years, CKD progression occurred in 33.5% of subjects. Subjects in 2nd, 3rd and 4th quartiles of peripheral pulse pressure experienced higher risk of CKD progression with unadjusted hazard ratios (HRs) 1.55 [95% confidence interval (CI) 1.13-2.11; p = 0.006], 2.58 (1.93-3.45; p < 0.001) and 3.41 (2.58-4.52; p < 0.001). In the fully adjusted model, the association for 2nd, 3rd and 4th quartiles remained with HRs 1.40 (1.02-1.93; p = 0.038), 1.87 (1.37-2.56; p < 0.001) and 1.75 (1.25-2.44; p = 0.001) respectively. Similarly, 2nd, 3rd and 4th quartiles of aortic pulse pressure were associated with higher hazards of CKD progression with HRs 1.73 (1.25-2.40; p = 0.001), 1.65 (1.18-2.29; p = 0.003) and 1.81 (1.26-2.60; p = 0.001). Increasing urinary albumin-to-creatinine ratio accounted for 44.0% of the association between peripheral pulse pressure and CKD progression. CONCLUSIONS: Individuals with high pulse pressure were more susceptible to deterioration of renal function. Pulse pressure could potentially be incorporated in clinical practice as an inexpensive and readily available biomarker of renal decline in type 2 diabetes mellitus. Graphic abstract.

Association of Genetic Variants for Plasma LRG1 With Rapid Decline in Kidney Function in Patients With Type 2 Diabetes.

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 < 0.05). 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.

Higher ratio of extracellular water to total body water was associated with reduced cognitive function in type 2 diabetes.

BACKGROUND: Fluid imbalance is associated with various clinical conditions, but the association between elevated extracellular-water to total-body-water (ECW/TBW) ratio, an indicator of fluid balance, and cognitive impairment is unknown. We aimed to investigate relationship between ECW/TBW ratio and cognitive function in type 2 diabetes mellitus. METHODS: This study was a cross-sectional design, comparing 1233 patients aged 61.4 ± 8.0 years from the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D) cohort. ECW/TBW was measured using bioelectrical impedance method. Cognitive function was assessed with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Multiple linear regression was used to examine association between ECW/TBW and RBANS scores, adjusting for demographics, education, clinical covariates, and apolipoprotein E allele. RESULTS: In unadjusted analyses, there was an inverse dose-dependent association between ECW/TBW and RBANS total score. The associations persisted in fully adjusted model with ß = -1.18 (95% confidence interval [CI] -2.19 to -0.17; P = 0.022) for slight edema and -2.33 (-3.99 to -0.67; P = 0.006) for edema. Slight edema and edema were significantly associated with reduced cognitive function in delayed memory and attention. There was significant association between edema but not slight edema, with reduced cognitive function in language. Pulse pressure accounted for 16.8% of association between ECW/TBW and RBANS total score. CONCLUSIONS: Our novel finding of an independent association between higher ECW/TBW and poorer cognitive function highlights the potential importance of maintaining body fluid balance in the management of cognitive impairment.