A head-to-head comparison between Guardian Connect and FreeStyle Libre systems and an evaluation of user acceptability of sensors in patients with type 1 diabetes.

AIMS: A user-calibrated real-time continuous glucose monitoring (rt-CGM) system is compared to a factory-calibrated flash glucose monitoring (FGM) system and assessed in terms of accuracy and acceptability in patients with type 1 diabetes (T1D). METHODS: Ten participants with T1D were enroled from a specialist diabetes centre in Singapore and provided with the Guardian Connect with Enlite Sensor (Medtronic, Northridge, CA, USA) and first-generation Freestyle Libre System (Abbott Diabetes Care, Witney, UK), worn simultaneously. Participants had to check capillary blood glucose four times per day. At the end of week 1 and week 2, participants returned for data download and were given a user evaluation survey. RESULTS: Accuracy evaluation between Guardian Connect and Freestyle Libre includes the overall mean absolute relative difference value (9.7 ± 11.0% vs. 17.5 ± 10.9%), Clarke Error Grid zones A + B (98.6% vs. 98.1%), sensitivity (78.9% vs. 63.4%), and specificity (93.4% vs. 81.0%). Notably, time below range (<3.9 mmol/L) was 10.5% for FGM versus 2% for rt-CGM. From the evaluation survey, 90% of participants perceived rt-CGM to be accurate versus 40% for FGM, although the majority found both devices to be easy to use, educational, and useful in improving glycaemic control. However, due to the cost of sensors, only 30% were keen to use either device for continuous monitoring. CONCLUSIONS: Although rt-CGM was superior to FGM in terms of accuracy, the value of glucose trends in both devices is still useful in diabetes self-management. Patients and clinicians may consider either technology depending on their requirements.

Diabetes predicts severity of COVID-19 infection in a retrospective cohort: A mediatory role of the inflammatory biomarker C-reactive protein.

Diabetes is a risk factor for developing severe COVID-19, but the pathogenesis remains unclear. We investigated if the association of diabetes and COVID-19 severity may be mediated by inflammation. We also hypothesized that this increased risk may extend to prediabetes. Hospitalized patients in Singapore with COVID-19 were subdivided into three groups in a retrospective cohort: normoglycemia (HbA1c: ≤5.6%), prediabetes (HbA1c: 5.7%-6.4%) and diabetes (HbA1c: ≥6.5%). The primary outcome of severe COVID-19 was defined by respiratory rate ≥30, SpO2 ≤93% or intensive care unit admission. The association between clinical factors on severe COVID-19 outcome was analyzed by cox regression. Adjusted mediation analysis of C-reactive protein (CRP) on the relationship between diabetes and severe COVID-19 was performed. Of 1042 hospitalized patients, mean age 39 ± 11 years, 13% had diabetes, 9% prediabetes and 78% normoglycemia. Severe COVID-19 occurred in 4.9% of subjects. Compared to normoglycemia, diabetes was significantly associated with severe COVID-19 on both univariate (hazard ratio [HR]: 9.94; 95% confidence interval [CI]: 5.54-17.84; p < .001) and multivariate analysis (HR: 3.99; 95% CI: 1.92-8.31; p < .001), while prediabetes was not a risk factor (HR: 0.94; 95% CI: 0.22-4.03; p = .929). CRP, a biomarker of inflammation, mediated 32.7% of the total association between diabetes and severe COVID-19 outcome. In conclusion, CRP is a partial mediator of the association between diabetes and severe COVID-19 infection, confirming that inflammation is important in the pathogenesis of severe COVID-19 in diabetes.

Association between depressive symptoms and pulse wave velocity is mediated by increased adiposity in older adults with type 2 diabetes.

Background: Studies investigating the association between depression and aortic stiffness in older patients with type 2 diabetes are lacking. We postulated an association between depressive symptoms and aortic stiffness, and this relationship may be mediated by increased adiposity. Methods: We analyzed participants with type 2 diabetes aged 55 years or older (n = 958). We measured aortic stiffness using carotid-femoral pulse wave velocity (cut-off ≥ 12 m/s) using the tonometry method. We defined depressive symptoms as a score of greater than 5 on the Geriatric Depression Scale-15 (GDS-15). Adiposity indices we assessed were body mass index, waist circumference, waistto-height ratio, visceral fat area and fat mass. Results: Among the participants, 27.2% had aortic stiffness, of whom 6.5% had depressive symptoms. Score on the GDS-15 was correlated with pulse wave velocity, and both variables were correlated with the adiposity markers we analyzed (all p < 0.05). Depressive symptoms were associated with pulse wave velocity (B = 1.79, 95% confidence interval [CI] 0.83-2.75) or aortic stiffness (risk ratio 1.60, 95% CI 1.10-2.33) in the unadjusted model. The association persisted after controlling for demographics, duration of diabetes, glycated hemoglobin, comorbidities and medications. Further adjustment for visceral fat area and fat mass in separate models reduced the association between depressive symptoms and pulse wave velocity or aortic stiffness. Mediation models revealed that the mediation proportions of fat mass and visceral fat area on the association between depressive symptoms and pulse wave velocity were 11.8% and 9.7%, respectively. A preliminary analysis of longitudinal data (n = 184) showed similar findings. Limitations: Causality cannot be inferred from the associations we observed. Conclusion: Depressive symptoms are associated with elevated pulse wave velocity in older people with type 2 diabetes, and this relationship may be partially mediated by increased adiposity.

Role of endothelium-independent vasodilation in the relationship between visceral adiposity and reduced cognitive performance in older adults with type 2 diabetes.

OBJECTIVE: In this cross-sectional analysis, we sought to assess the relationship of adiposity and forearm microvascular reactivity with cognitive dysfunction among older Asians with type 2 diabetes (T2D). METHODS: Subjects with T2D aged ≥ 55 years were analyzed (N = 907). Cognitive performance was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Mini-Mental State Exam (MMSE). Visceral fat area (VFA) was estimated by tetrapolar multi-frequency bioimpedance. Forearm microvascular endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIV) were assessed by laser Doppler imaging with iontophoresis. RESULTS: RBANS total score was correlated with VFA, EDV, and EIV (all P < .05). However, VFA was correlated with EIV, but not with EDV. Multivariable linear regression showed significant association between VFA and RBANS total score (B = -0.02, 95% CI= -0.03 to -0.01) or memory (immediate and delayed) index scores. These associations were attenuated after adjustment for EIV. Mediation analysis showed that EIV partially mediated the relationship between visceral adiposity and RBANS scores (all Sobel tests P < .05). EIV also mediated the relationship between VFA and MMSE score. CONCLUSIONS: Impaired endothelium-independent vascular smooth muscle reactivity may exert a mediatory effect on the association between increased visceral adiposity and decreased cognitive performance in older adults with T2D.

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.

Microvascular endothelial function is an independent predictor for albuminuria progression among Asians with type 2 diabetes-A prospective cohort study.

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

Association Between Kidney Disease Index and Decline in Cognitive Function with Mediation by Arterial Stiffness in Asians with Type 2 Diabetes.

Background: Decline in renal function impairs systemic clearance of amyloid-ß which characterizes Alzheimer's disease while albuminuria is associated with blood-brain barrier disruption due to endothelial damage. Arterial stiffness adversely affects the brain with high pulsatile flow damaging cerebral micro-vessels. Objective: To examine association between a novel kidney disease index (KDI), which is a composite index of estimated glomerular filtration (eGFR) and urinary albumin-to-creatinine ratio (uACR), and cognitive function with potential mediation by arterial stiffness. Methods: This was a longitudinal multi-center study of participants with type 2 diabetes (T2D) aged 45 years and above. We assessed cognitive function with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Pulse wave velocity (PWV), an index of arterial stiffness, was measured using applanation tonometry method. KDI was calculated as geometric mean of 1/eGFR and natural logarithmically-transformed (ln)(ACR*100). Results: There were 1,303 participants with mean age 61.3±8.0 years. LnKDI was associated with lower baseline RBANS total score with adjusted coefficient -2.83 (95% CI -4.30 to -1.35; p < 0.001). 590 participants were followed over up to 8.6 years. LnKDI was associated with lower follow-up RBANS score in total, immediate memory, visuo-spatial/construction and attention domains with corresponding adjusted coefficients -2.35 (95% CI -4.50 to -0.20; p = 0.032), -2.93 (95% CI -5.84 to -0.02; p = 0.049), -3.26 (95% CI -6.25 to -0.27; p = 0.033) and -4.88 (95% CI -7.95 to -1.82; p = 0.002). PWV accounted for 19.5% of association between and follow-up RBANS total score. Conclusions: KDI was associated with lower cognitive function globally, and in immediate memory, visuo-spatial/construction and attention domains. Arterial stiffness mediated the association between KDI and cognitive decline in patients with T2D.

Association Between Plasma LRG1 and Lower Cognitive Function in Asians With Type 2 Diabetes Mellitus.

CONTEXT: Leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in the pathogenesis of diabetic complications, but its association with cognitive function remains unclear. OBJECTIVE: Our primary objective is to investigate the longitudinal association between LRG1 and cognitive function in patients with type 2 diabetes mellitus (T2DM). Secondarily, we determine the causal relationship using Mendelian randomization (MR) and the role of arterial stiffness as a potential mediator. METHODS: T2DM patients (n = 1039; age = 64.1 ± 6.4 years) were followed-up for 5.3 ± 1.2 years. Plasma LRG1 was measured at baseline using enzyme-linked immunosorbent assay. Baseline and follow-up cognitive function was assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). One-sample MR was performed with rs4806985 as plasma LRG1-associated single-nucleotide polymorphism. Mediation analysis was performed to examine if pulse wave velocity (PWV), an arterial stiffness index, mediated the association between plasma LRG1 and follow-up cognitive function. RESULTS: Elevated baseline natural log (Ln)-transformed LRG1 was inversely associated with baseline and follow-up RBANS total score with adjusted coefficients -1.38 (95% CI -2.55 to -.21; P = .021) and -1.38 (95% CI -2.70 to -.07; P = .039), respectively. Genetically predicted higher levels of plasma LRG1 was associated with lower follow-up RBANS total score with coefficient -7.44 (95% CI -14.14 to -.74; P = .030) per unit increase in LnLRG1. Higher PWV accounted for 27.7% of the association between LnLRG1 and follow-up RBANS total score. CONCLUSION: Baseline plasma LRG1 was associated with lower cognitive function at follow-up in patients with T2DM, mediated by PWV. MR analysis provided evidence of an association between genetically influenced plasma LRG1 and lower cognitive function at follow-up.

Reduced skeletal muscle mass to visceral fat area ratio is independently associated with reduced cognitive function in type 2 diabetes mellitus.

AIM: Skeletal muscle mass to visceral fat area ratio (SVR) has been recognised as an index of sarcopenic obesity. SVR is associated with type 2 diabetes mellitus (T2DM), metabolic syndrome and arterial stiffness which are known risk factors for cognitive dysfunction. We aimed to investigate association between SVR and cognitive function in patients with T2DM. METHODS: This was a cross-sectional study of 1326 patients with T2DM and mean age 61.3 ± 8.0 years. SVR was assessed based on bioelectrical impedance measurements of muscle mass and visceral fat area (VFA). Cognitive function was assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Linear regression was used to examine the association between SVR in quartiles and RBANS score, adjusting for demographics, education, presence of depressive symptoms, clinical covariates and medications. RESULTS: The lower SVR quartiles were negatively associated with RBANS total score in the unadjusted analysis. The corresponding coefficients for Quartiles 1 and 2 SVR were -3.79 (95 % CI -5.39 to -2.19; p < 0.001) and -1.47 (95 % CI -2.86 to -0.07; p = 0.039) in fully adjusted analysis. The negative association between Quartile 1 SVR and RBANS score was evident in immediate memory, delayed memory, visuo-spatial construction, language and attention domains. Muscle mass and VFA alone had weaker associations with RBANS scores. CONCLUSION: Our study demonstrated, for the first time, an independent association between reduced SVR and lower cognitive function. This is evident in global and multiple cognitive domains. The synergistic effects of reduced muscle mass and visceral obesity may be more pronounced than their independent effects on cognitive function.

Association between neutrophil/lymphocyte ratio and kidney impairment in type 2 diabetes mellitus: A role of extracellular water/total body water ratio.

AIMS: We explored the predictive utility of baseline neutrophil/lymphocyte ratio (NLR), which reflects a systemic inflammatory tone, in kidney impairment in type 2 diabetes mellitus (T2DM); and investigated the effect of extracellular water/total body water (ECW/TBW) ratio on the relationship. METHODS: This longitudinal study included 1,224 T2DM adults recruited from a single centre. Cox regression analyses examined the association between NLR and progressive kidney function decline or albuminuria progression. Improvements in risk discrimination were assessed using Harrell's concordance-statistics. The mediatory role of ECW/TBW ratio estimated by bioelectrical impedance was evaluated. RESULTS: Higher baseline NLR levels were observed in cases with kidney function decline or albuminuria progression over a median 2-year follow-up. NLR independently predicted progressive kidney function decline (hazard ratio:1.39, 95% CI:1.21-1.60, P < 0.001) or albuminuria progression (hazard ratio:1.34, 95% CI:1.08-1.68, P = 0.009). Addition of NLR to a base model comprising demographics, T2DM duration, metabolic and renal parameters, and medications significantly improved the risk discrimination of kidney function decline (P = 0.022) but not albuminuria progression. ECW/TBW ratio accounted for 19.7% of the total effect between NLR and kidney function loss. CONCLUSIONS: Increased NLR reflecting systemic inflammation is associated with progressive kidney function decline in T2DM, partially explained by dysregulated body fluid balance.

The Role of Triglyceride-Glucose Index in the Prediction of the Development of Hypertension - Findings from a Community Cohort in Singapore.

Objectives: Triglyceride-glucose index (TyGI) is an emerging surrogate marker of insulin resistance. We aim to explore the role of triglyceride-glucose index in the prediction of the development of hypertension. Methodology: We conducted a retrospective cohort study that included 3,183 study participants identified from a community health screening programme who had no baseline hypertension and were then followed up after an average of 1.7 years. Cox proportional-hazard model was used to assess the association between risk of incident hypertension and TyGI in quartiles, while adjusting for demographics and clinical characteristics. Results: Hypertension occurred in 363 study participants (11.4%). Those who developed hypertension had higher TyGI [8.6 (IQR 8.2-9.0)] than those who did not [8.2 (IQR 8.0-8.7)] (p<0.001). Significant association between TyGI and hypertension was observed in both the unadjusted and proportional hazard model [Quartile (Q)2, p=0.010; Q3, p<0.001 and Q4, p<0.001] and the model that adjusted for demographics (Q2, p=0.016; Q3, p=0.003; Q4, p<0.001). In the model adjusted for clinical covariates, the hazard of developing hypertension remained higher in TyGI Q4 compared to TyGI Q1(Hazard Ratio=2.57; 95% Confidence Interval: 1.71, 3.87). Increasing triglyceride-glucose index accounted for 16.4% of the association between increasing BMI and incident hypertension, after adjusting for age, gender, ethnicity and baseline HDL cholesterol (p<0.001). Conclusion: Triglyceride-glucose index was an independent predictor of the development of hypertension. It may potentially be used as an inexpensive indicator to predict the development of hypertension and risk-stratify individuals to aid management in clinical practice.

Longitudinal profiling and tracking stability in the Singapore study of macro-angiopathy and microvascular reactivity in type 2 diabetes cohort.

INTRODUCTION: The Singapore Study of Macro-Angiopathy and microvascular Reactivity in Type 2 Diabetes (SMART2D) is a prospective cohort study which was started in 2011 to investigate the effect of risk factors on vascular function and diabetes-related complications in Asians. We aimed to compare the longitudinal change in risk factors by accounting for batch effect and assess the tracking stability of risk factors over time in patients recruited for SMART2D. In this study, we (1) described batch effect and its extent across a heterogenous range of longitudinal data parameters; (2) mitigated batch effect through statistical approach; and (3) assessed the tracking stability of the risk factors over time. METHODS: A total of 2258 patients with type 2 diabetes mellitus (T2DM) were recruited at baseline. The study adopted a three-wave longitudinal design with intervals of 3 years between consecutive waves. The changes in a few selected risk factors were assessed after calibration, assuming patients with similar demographic and anthropometry profile had similar physiology. The tracking pattern of the risk factors was determined with stability coefficients derived from generalised estimating equations. RESULTS: The medians of the longitudinal differences in risk factors between the waves were mostly modest at <10%. Larger increases in augmentation index (AI), aortic systolic blood pressure (BP) and aortic mean BP were consistently observed after calibration. The medians of the longitudinal differences in AI, aortic systolic BP and aortic mean BP between the waves were <2% before calibration, but increased slightly to <5% after calibration. Most of the risk factors had moderate to high tracking stability. Muscle mass and serum creatinine were among those with relatively high tracking stability. CONCLUSIONS: The longitudinal differences in parameters between the waves were overall modest after calibration, suggesting that calibration may attenuate longitudinal differences inflated by non-biological factors such as systematic drift due to batch effect. Changes of the hemodynamic parameters are robust over time and not entirely attributable to age. Our study also demonstrated moderate to high tracking stability for most of the parameters.

Association of Baseline Triglyceride-Glucose Index with Poor Glycemic Control and Diabetes Remission After Metabolic Surgery.

PURPOSE: The utility of insulin resistance (IR) as a predictor of diabetes remission after metabolic surgery is not well-defined. We assessed the association of baseline surrogate IR indices including triglyceride-glucose (TyG) index and homeostatic model assessment for IR (HOMA-IR) with glycemic control and diabetes remission after metabolic surgery. MATERIALS AND METHODS: Patients with type 2 diabetes scheduled for metabolic surgery were recruited at a single-center (n = 149; age: 44 ± 10 years, 47.7% men, body mass index: 41.5 ± 7.5 kg/m2), and followed-up for 12 months postoperatively. The relationships between the IR indices and poor glycemic control (HbA1c ≥ 7%) at baseline or complete diabetes remission (HbA1c < 6% without glucose-lowering medications at 12 months) post-surgery were examined. RESULTS: Elevated TyG index was associated with poor glycemic control cross-sectionally. Compared with non-remitters, lower baseline TyG index levels were observed in individuals with complete diabetes remission after surgery (P = 0.012); whereas HOMA-IR was not significantly different. Consistently, the proportion of diabetes non-remitters (compared to remitters) increased with increasing TyG tertiles from 1 to 3 (P = 0.015). Both TyG index (relative risk = 0.62, 95% CI = 0.42-0.91, P = 0.014) and TyG tertile 1 (relative risk = 1.99, 95% CI = 1.25-3.24, P = 0.003) independently predicted diabetes remission. The TyG index identified diabetes remission with an area under the curve of 0.68. The optimal TyG threshold was 9.41, yielding a sensitivity of 69.6%, specificity of 60.9%, positive predictive value of 64.0%, and negative predictive value of 66.7%. CONCLUSION: TyG index, previously suggested to predominantly reflect muscle IR, outperforms HOMA-IR as an IR indicator associated with glycemic control and diabetes remission after metabolic surgery.

Associations of non-invasive indices of liver steatosis and fibrosis with progressive kidney impairment in adults with type 2 diabetes.

AIMS: Longitudinal data linking non-alcoholic fatty liver disease to kidney dysfunction in type 2 diabetes (T2D) are limited. This study evaluated the associations of non-invasive indices of liver steatosis and liver fibrosis with kidney impairment, and the mediatory role of the pro-angiogenic factor leucine-rich α-2 glycoprotein 1 (LRG1). METHODS: T2D adults (n = 2057) were followed for a mean period of 6.1 ± 1.6 years. Baseline liver steatosis [(hepatic steatosis index (HSI) and Zhejiang University index (ZJU)] and liver fibrosis [aspartate transaminase/alanine transaminase ratio (AAR) and BARD] indices derived from composite scoring systems were calculated. Plasma LRG1 levels were quantified using immunoassay. The study outcomes were progressive kidney function decline defined as estimated glomerular filtration rate (eGFR) decline of ≥ 40% and albuminuria progression defined as an increase in albuminuria category. RESULTS: Cross-sectionally, liver steatosis and liver fibrosis indices were associated with increased albuminuria (urinary albumin/creatinine ratio ≥ 30 µg/mg) and reduced renal function (eGFR < 60 mL/min/1.73 m2) after covariate adjustment, respectively. Approximately 32% of the participants experienced progressive kidney function decline, while 38% had albuminuria worsening over time. Longitudinal analysis revealed that baseline AAR (hazard ratio: 1.56; 95% CI 1.15-2.11) and BARD (hazard ratio: 1.16, 95% CI 1.04-1.28) predicted progressive kidney function decline, partly mediated by LRG1. In contrast, liver steatosis (HSI and ZJU) but not liver fibrosis (AAR and BARD) indices were independently associated with albuminuria progression. CONCLUSIONS: Increased liver steatosis scores were associated with albuminuria deterioration. Conversely, liver fibrosis indices may be associated with progressive kidney function decline, potentially driven by increased inflammation and angiogenesis.

Association between lower phase angle and chronic kidney disease progression in type 2 diabetes patients.

Introduction: Phase angle (PhA), derived from bioelectrical impedance analysis (BIA), is the angle of vector determined by the body's resistance and reactance. It indicates cellular integrity and hydration status. Though extracellular volume excess was associated with chronic kidney disease (CKD) progression, the association between PhA and CKD progression is unknown. Matrix metalloproteinase-2 (MMP-2) is a member of zinc-dependent endopeptidase family and promotes renal interstitial fibrosis. We investigated association between PhA and CKD progression, and whether the association was through MMP-2 in patients with type 2 diabetes mellitus (T2DM). Method: We conducted a prospective study on 1,078 patients with T2DM (mean age 58.9±9.1 years). PhA was measured using BIA. CKD progression was defined as ≥25% decrease in estimated glomerular filtration rate (eGFR) from baseline with deterioration across eGFR categories. Multiplex immunoassay was used to quantitate MMP-2. We examined association between PhA and CKD progression using Cox proportional hazards model, adjusting for demographics, clinical parameters and medications. Results: Over 8.6 years of follow-up, 43.7% of participants had CKD progression. Compared to tertile 3 PhA (higher level), tertiles 1 and 2 PhA were associated with higher hazards of CKD progression, with corresponding unadjusted hazard ratios (HRs) of 2.27 (95% confidence interval [CI] 1.80-2.87, P<0.001) and 1.57 (95% CI 1.24-2.01, P<0.001). The positive association between tertiles 1 and 2 PhA with CKD progression persisted in the fully adjusted model with corresponding HRs of 1.71 (95% CI 1.30-2.26, P<0.001) and 1.46 (95% CI 1.13-1.88, P=0.004). MMP-2 accounted for 14.7% of association between tertile 1 PhA and CKD progression. Conclusion: Our findings revealed a previously unobserved association between BIA-derived lower PhA and CKD progression through MMP-2 in patients with T2DM.

Roux-en-Y gastric bypass versus best medical treatment for type 2 diabetes mellitus in adults with body mass index between 27 and 32 kg/m2: A 5-year randomized controlled trial.

AIMS: To evaluate the effects of Roux-en-Y gastric bypass (RYGB) versus best medical treatment in Asians with type 2 diabetes mellitus (T2DM) and class I obesity. METHODS: In this 5-year single-centre, open-label randomized controlled trial, participants were randomized to RYGB or medical treatment including newer classes of diabetes medications (ClinicalTrials.gov:NCT02041234). The primary endpoint was diabetes remission defined as HbA1c ≤ 6% (≤42 mmol/mol) and discontinuation of glucose-lowering medication at 12 months post-intervention and beyond. Glycaemia and weight changes were assessed. Continuous glucose monitoring was performed. RESULTS: Of 28 subjects randomized, 26 were analyzed in the final cohort (14 medical, 12 RYGB; age:44 ± 10 years, 34.6% males, BMI:29.4 ± 1.6 kg/m2). At 12 months, 50% of RYGB subjects achieved diabetes remission; 83% stopped all glucose-lowering medications. By year 5, 42% were in remission. None attained diabetes remission in the medical group. Percentage declines in fasting plasma glucose, HbA1c and BMI were significantly greater in the RYGB arm (all P < 0.05). Early improvements in glycaemic variability and time in range were similar in both treatment arms. Hypoglycaemia and surgical complications were observed in some RYGB subjects. CONCLUSIONS: Over 5 years, RYGB outperforms best medical treatment in glycemia and weight improvements for Asians with T2DM and class I obesity.

Association of early-onset Type 2 diabetes with cognitive impairment is partially mediated by increased pulse pressure.

AIMS: Type 2 diabetes mellitus (T2DM) has been shown to be associated with cognitive decline and dementia. As earlier onset of diabetes implies a longer disease duration and an increased risk to complications, we sought to investigate the effect of T2DM onset on cognitive function of our patients. METHODS: We administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to T2DM patients aged 45-85 from our SMART2D cohort. We assessed the association of the T2DM onset age (both continuous and stratified into 3 groups: early-onset ≤40 (n = 326), middle-aged onset 41-64 (n = 703) and late-onset ≥65 years old (n = 38)) and RBANS cognitive indices in 1067 patients. Potential mediation of this association by vascular compliance using mediation analysis was investigated. RESULTS: T2DM onset associates significantly with RBANS total score. Patients with early T2DM onset have lower RBANS total score as compared to patients with middle-aged onset (ß = -2.01, p = 0.0102) and those with late-onset (ß = -5.80, p = 0.005). This association was partially mediated by pulse pressure index (25.8%), with indirect effect of 0.028 (Bootstrapped-CI: 0.008-0.047). CONCLUSIONS: Association of early-onset T2DM with cognitive impairment is partly mediated by diminished vascular compliance. Appropriate screening and assessment of cognitive function is important for early intervention and management of cognitive impairment.

Ethnic-Specific Type 2 Diabetes Risk Factor PAX4 R192H Is Associated with Attention-Specific Cognitive Impairment in Chinese with Type 2 Diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) has been shown to increase the risks of cognitive decline and dementia. Paired box gene 4 (PAX4), a transcription factor for beta cell development and function, has recently been implicated in pathways intersecting Alzheimer's disease and T2DM. OBJECTIVE: In this report, we evaluated the association of the ethnic-specific PAX4 R192H variant, a T2DM risk factor for East Asians which contributes to earlier diabetes onset, and cognitive function of Chinese T2DM patients. METHODS: 590 Chinese patients aged 45-86 from the SMART2D study were genotyped for PAX4 R192H variation using Illumina OmniExpress-24 Array. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) which had been validated in the Singapore population was administered to assess five cognitive domains: immediate memory, visuospatial/constructional, language, attention, and delayed memory. Multiple linear regression was used to assess the association of the R192H risk allele and cognitive domains. RESULTS: Patients with two PAX4 R192H risk alleles showed significantly lower attention index score (ß= -8.46, 95% CI [-13.71, -3.21], p = 0.002) than patients with wild-type alleles after adjusting for age, gender, diabetes onset age, HbA1c, body-mass index, renal function, lipid profiles, systolic blood pressure, metformin usage, smoking history, education level, Geriatric Depression Scale score, and presence of APOEɛ4 allele. CONCLUSION: Ethnic-specific R192H variation in PAX4 is associated with attention-specific cognitive impairment in Chinese with T2DM. Pending further validation studies, determining PAX4 R192H genotype may be helpful for early risk assessment of early-onset T2DM and cognitive impairment to improve diabetes care.

A real-world study on SGLT2 inhibitors and diabetic kidney disease progression.

Background: Randomized controlled trials have demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in people with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). However, real-world data on CKD progression and the development of end-stage kidney disease (ESKD) remains scarce. Our aim was to study renal outcomes of people with diabetic kidney disease (DKD) using SGLT2is in a highly prevalent DKD population. Methods: Between 2016 and 2019 we recruited T2DM patients in the renal and diabetic clinics in a regional hospital in Singapore. Patients prescribed SGLT2is were compared with those on standard anti-diabetic and renoprotective treatment. The outcome measures were CKD progression [a ≥25% decrease from baseline and worsening of estimated glomerular filtration rate (eGFR) categories according to the Kidney Disease: Improving Global Outcomes guidelines] and ESKD (eGFR <15 mL/min/1.73 m2). Results: We analysed a total of 4446 subjects; 1598 were on SGLT2is. There was a significant reduction in CKD progression {hazard ratio [HR] 0.60 [95% confidence interval (CI) 0.49-0.74]} with SGLT2is. The HR for eGFR ≥45 mL/min/1.73 m2 and 15-44 mL/min/1.73 m2 was 0.60 (95% CI 0.47-0.76) and 0.43 (95% CI 0.23-0.66), respectively. There was also a reduction in risk for developing ESKD for the entire cohort [HR 0.33 (95% CI 0.17-0.65)] and eGFR 15-44 mL/min/1.73 m2 [HR 0.24 (95% CI 0.09-0.66)]. Compared with canagliflozin and dapagliflozin, empagliflozin showed a sustained risk reduction of renal outcomes across CKD stages 1-4. Conclusions: This real-world study demonstrates the benefits of SGLT2is on CKD progression and ESKD. The effect is more pronounced in moderate to advanced CKD patients.