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Objectives Lead exposure causes neurocognitive dysfunction in children, but its association with neurocognition in adults at current occupational exposure levels is uncertain mainly due to the lack of longitudinal studies. In the Study for Promotion of Health in Recycling Lead (NCT02243904), we assessed the two-year responses of neurocognitive function among workers without previous known occupational exposure newly hired at lead recycling plants. Methods Workers completed the digit-symbol test (DST) and Stroop test (ST) at baseline and annual follow-up visits. Blood lead (BL) was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 mu g/dL). Statistical methods included multivariable-adjusted mixed models with participants modelled as random effect. Results DST was administered to 260 participants (11.9% women; 46.9%/45.0% whites/Hispanics; mean age 29.4 years) and ST to 168 participants. Geometric means were 3.97 and 4.13 mu g/dL for baseline BL, and 3.30 and 3.44 for the last-follow-up-to-baseline BL ratio in DST and ST cohorts, respectively. In partially adjusted models, a doubling of the BL ratio was associated with a 0.66% [95% confidence interval (CI) 0.03-1.30%; P=0.040] increase in latency time (DST) and a 0.35% (95% CI -1.63-1.63%; P=0.59) decrease in the inference effect (ST). In fully adjusted models, none of the associations of the changes in the DST and ST test results with the blood lead changes reached statistical significance (P=0.12). Conclusions An over 3-fold increase in blood lead over two years of occupational exposure was not associated with a relevant decline in cognitive performance. The International Lead Association (www.ila-lead.org) provided an unrestricted grant to the Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, partially supporting database management and statistical analysis. The non-profit research institute Alliance for the Promotion of Preventive Medicine (www.appremed.org) received a grant from OMRON Healthcare Co. Ltd., Kyoto, Japan. The funding source had no role in the study design; in the collection, analysis, and interpretation of the data; or in the writing of the report. The corresponding author had full access to all data and had the final responsibility for the decision to submit for publication. Staessen, JA (corresponding author), Res Inst Assoc Promot Prevent Med, Leopoldstr 59, BE-2800 Mechelen, Belgium. jan.staessen@appremed.org

Supplemental Digital Content is available in the text., Arterial stiffness and wave reflection predict cardiovascular mortality and morbidity and are associated with renal microvascular disease. We hypothesized that the retinal microvascular traits might be associated with central hemodynamic properties. In 735 randomly recruited Flemish (mean age, 50.3 years; 47.1% women), we derived central pulse pressure and carotid-femoral pulse wave velocity by applanation tonometry and calculated forward (Pf) and backward (Pb) pulse waves, using an automated pressure-based wave separation algorithm. We measured central retinal arteriolar (CRAE) and venular equivalent and their ratio, using IVAN software (Vasculomatic ala Nicola, version 1.1). Mean values for pulse wave velocity (n=554), Pf and Pb were 7.50 m/s, 32.0 mm Hg, and 21.5 mm Hg, respectively. In multivariable-adjusted analyses, CRAE was 4.62 µm and 1.26 µm smaller (P≤0.034) for a 1-SD increment in central mean arterial pressure (+11.3 mm Hg) and central pulse pressure (+15.2 mm Hg); a 1-SD increment in the augmentation ratio (+7.0%), aortic pulse wave velocity (+1.66 m/s), Pf (+10.0 mm Hg), and Pb (+8.5 mm Hg), was associated with smaller CRAE; the association sizes were −1.91 µm, −1.59 µm, −1.45 µm, and −2.38 µm (P≤0.014), respectively. Associations of arteriole-to-venule diameter ratio with the central hemodynamic traits mirrored those of CRAE. None of the multivariable-adjusted associations of central retinal venular diameter with the central hemodynamic traits reached significance with the exception of central diastolic blood pressure (−1.62 µm; P=0.030). In conclusion, in the general population, higher central pulse pressure, pulse wave velocity, Pf, and Pb were associated with smaller CRAE.

ObjectivesPrevious studies relating nervous activity to blood lead (BL) levels have limited relevance, because over time environmental and occupational exposure substantially dropped. We investigated the association of heart rate variability (HRV) and median nerve conduction velocity (NCV) with BL using the baseline measurements collected in the Study for Promotion of Health in Recycling Lead (NCT02243904).MethodsIn 328 newly hired men (mean age 28.3 years; participation rate 82.7%), we derived HRV measures (power expressed in normalised units (nu) in the high-frequency (HF) and low-frequency (LF) domains, and LF/HF) prior to long-term occupational lead exposure. Five-minute ECG recordings, obtained in the supine and standing positions, were analysed by Fourier transform or autoregressive modelling, using Cardiax software. Motor NCV was measured at the median nerve by a handheld device (Brevio Nerve Conduction Monitoring System, NeuMed, West Trenton, NJ, USA). BL was determined by inductively coupled plasma mass spectrometry.ResultsMean BL was 4.54 µg/dL (IQR 2.60–8.90 µg/dL). Mean supine and standing values of LF, HF and LF/HF were 50.5 and 21.1 nu and 2.63, and 59.7 and 10.9 nu and 6.31, respectively. Orthostatic stress decreased HF and increased LF (pConclusionsAt the exposure levels observed in our study, autonomous nervous activity and NCV were not associated with BL.Trial registration numberNCT02243904

Objectives Higher than contemporary exposure levels and advanced age of study participants have limited the interpretation of previous studies relating neurocognitive function to lead exposure. We reassessed this association in young American men prior to chronic occupational exposure at lead recycling plants, using baseline measurements of the Study for Promotion of Health in Recycling Lead (NCT02243904). Methods We administered the Stroop test (ST) and the digit-symbol test (DST) to 339 men (mean age, 28.6 years; participation rate 82.7%). Whole blood lead (BL) was determined by inductively coupled plasma mass spectrometry and related ST and DST test results using multivariable-adjusted regression. Results Average values were 4.26 mu g/dL for BL, 1624 ms and 1474 ms for mean reaction time in incongruent and congruent ST trials, and 109 sec for mean total latency in DST. The number of participants with fully correct answers amounted to 281 (82.9%) and 334 (98.5%) in incongruent and congruent ST trials, respectively, and to 198 (58.4%) in the DST. In multivariable-adjusted analyses, there was no association between cognitive performance and BL except for a weak but opposite association in DST; for a 10-fold BL increment, mean total latency was 5.4% (95% confidence interval, -0.4-11.5%; P=0.066) higher, whereas the error score was 42% (-10-69%; P=0.096) lower. To exclude an effect of the cumulative lead dose, sensitivity analyses restricted to workers

Because of the falling lead exposure, the literature relating autonomous nervous function to blood lead (BL) has limited relevance. In the longitudinal Study for Promotion of Health in Recycling Lead (URL: ; Unique identifier: NCT02243904), we recorded the 2-year responses of heart rate (HR), HR variability (HRV; Cardiax, International Medical Equipment Developing, Budapest, Hungary), and median nerve conduction velocity (Brevio, NeuMed, West Trenton, NJ), a routine test in occupational medicine, to first lead exposure in 195 newly hired workers (91.3% men; mean age, 27.8 years). High- and low-frequency HRV power and orthostatic HRV responses were derived from 5-minute ECGs in the supine and standing positions by Fourier transform and autoregression. BL was determined by inductively coupled plasma mass spectrometry. From baseline to follow-up, BL increased from 4.22 to 14.1 mu g/dL and supine/standing HR from 63.6/75.5 to 67.1/78.8 beats per minute. In analyses stratified by fourths of BL changes, trends in HR and Fourier/autoregressive HRV did not reveal a dose-response curve (0.074 3-fold BL increment did not affect autonomous neural function as captured by HRV. The International Lead Association (www.ila-lead.org) provided an unrestricted grant to the Research Unit Hypertension and Cardiovascular Epidemiology partially supporting data collection and management and statistical analysis. The Non-Profit Research Association Alliance for the Promotion of Preventive Medicine, Mechelen, Belgium (www.appremed.ord) received a nonbinding grant from OMRON Healthcare Co Ltd, Kyoto, Japan. Staessen, JA (corresponding author), Alliance Promot Prevent Med, Leopoldstr 59, BE-2800 Mechelen, Belgium. jan.staessen@appremed.org

Supplemental Digital Content is available in the text., Lead exposure causing hypertension is the mechanism commonly assumed to set off premature death and cardiovascular complications. However, at current exposure levels in the developed world, the link between hypertension and lead remains unproven. In the Study for Promotion of Health in Recycling Lead (URL: https://www.clinicaltrials.gov; Unique identifier: NCT02243904), we recorded the 2-year responses of office blood pressure (average of 5 consecutive readings) and 24-hour ambulatory blood pressure to first occupational lead exposure in workers newly employed at lead recycling plants. Blood lead (BL) was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 µg/dL). Hypertension was defined according to the 2017 American College of Cardiology/American Heart Association guideline. Statistical methods included multivariable-adjusted mixed models with participants modeled as a random effect and interval-censored Cox regression. Office blood pressure was measured in 267 participants (11.6% women, mean age at enrollment, 28.6 years) and ambulatory blood pressure in 137 at 2 follow-up visits. Geometric means were 4.09 µg/dL for baseline BL and 3.30 for the last-follow-up-to-baseline BL ratio. Fully adjusted changes in systolic/diastolic blood pressure associated with a doubling of the BL ratio were 0.36/0.28 mm Hg (95% CI, −0.55 to 1.27/−0.48 to 1.04 mm Hg) for office blood pressure and −0.18/0.11 mm Hg (−2.09 to 1.74/−1.05 to 1.27 mm Hg) for 24-hour ambulatory blood pressure. The adjusted hazard ratios of moving up across hypertension categories for a doubling in BL were 1.13 (0.93–1.38) and 0.84 (0.57–1.22) for office blood pressure and ambulatory blood pressure, respectively. In conclusion, the 2-year blood pressure responses and incident hypertension were not associated with the BL increase on first occupational exposure.

Purpose: Arterial stiffness predicts cardiovascular complications. The association between arterial stiffness and blood lead (BL) remains poorly documented. We aimed to assess the association of central hemodynamic measurements, including pulse wave velocity (aPWV), with blood lead in a Flemish population. Materials and Methods: In this Flemish population study (mean age, 37.0 years; 48.3% women), 267 participants had their whole BL and 24-h urinary cadmium (UCd) measured by electrothermal atomic absorption spectrometry in 1985-2005. After 9.4 years (median), they underwent applanation tonometry to estimate central pulse pressure (cPP), the augmentation index (AI), pressure amplification (PA), and aPWV. The amplitudes of the forward (Pf) and backward (Pb) pulse waves and reflection index (RI) were derived by a pressure-based wave separation algorithm. Results: BL averaged 2.93 mu g/dL (interquartile range, 1.80-4.70) and UCd 4.79 mu g (2.91-7.85). Mean values were 45.0 +/- 15.2 mm Hg for cPP, 24.4 +/- 12.4% for AI, 1.34 +/- 0.21 for PA, 7.65 +/- 1.74 m/s for aPWV, 32.7 +/- 9.9 mm Hg for Pf, 21.8 +/- 8.4 mm Hg for Pb, and 66.9 +/- 18.4% for RI. The multivariable-adjusted association sizes for a 2-fold higher BL were: +3.03% (95% confidence interval, 1.56, 4.50) for AI; -0.06 (-0.08, -0.04) for PA; 1.02 mm Hg (0.02, 2.02) for Pb; and 3.98% (1.71, 6.24) for RI (p

Our objective was to gain insight in the calculation and interpretation of population health metrics that inform disease prevention. Using as model environmental exposure to lead (ELE), a global pollutant, we assessed population health metrics derived from the Third National Health and Nutrition Examination Survey (1988 to 1994), the GBD (Global Burden of Disease Study 2010), and the Organization for Economic Co-operation and Development. In the National Health and Nutrition Examination Survey, the hazard ratio relating mortality over 19.3 years of follow-up to a blood lead increase at baseline from 1.0 to 6.7 µg/dL (10th-90th percentile interval) was 1.37 (95% CI, 1.17-1.60). The population-attributable fraction of blood lead was 18.0% (10.9%-26.1%). The number of preventable ELE-related deaths in the United States would be 412 000 per year (250 000-598 000). In GBD 2010, deaths and disability-adjusted life-years globally lost due to ELE were 0.67 million (0.58-0.78 million) and 0.56% (0.47%-0.66%), respectively. According to the 2017 Organization for Economic Co-operation and Development statistics, ELE-related welfare costs were $1 676 224 million worldwide. Extrapolations from the foregoing metrics assumed causality and reversibility of the association between mortality and blood lead, which at present-day ELE levels in developed nations is not established. Other issues limiting the interpretation of ELE-related population health metrics are the inflation of relative risk based on outdated blood lead levels, not differentiating relative from absolute risk, clustering of risk factors and exposures within individuals, residual confounding, and disregarding noncardiovascular disease and immigration in national ELE-associated welfare estimates. In conclusion, this review highlights the importance of critical thinking in translating population health metrics into cost-effective preventive strategies. ispartof: HYPERTENSION vol:75 issue:3 pages:603-614 ispartof: location:United States status: published

Background Prematurity disrupts the perinatal maturation of the microvasculature and macrovasculature and confers high risk of vascular dysfunction later in life. No previous studies have investigated the crosstalk between the microvasculature and macrovasculature in childhood. Methods and Results In a case‐control study, we enrolled 55 children aged 11 years weighing P P =0.029), and smaller central retinal arteriolar equivalent (163.2 versus 175.4 µm, P P =0.011]) and forward (−2.57 µm; CI, −4.81 to −0.32 µm [ P =0.026]) and backward (−3.20 µm; CI, −5.47 to −0.94 µm [ P =0.006]) wave amplitudes. Greater renal resistive index was associated with higher backward wave amplitude (0.92 mm Hg, P =0.036). Conclusions In childhood, prematurity compared with term birth is associated with higher central systolic BP and forward/backward wave amplitudes. Higher renal resistive index likely moves reflection points closer to the heart, thereby explaining the inverse association of central retinal arteriolar equivalent with central systolic BP and backward wave amplitude. These observations highlight the crosstalk between the microcirculation and macrocirculation in children. Registration URL: http://www.clinicaltrials.gov . Unique Identifier: NCT02147457.

We reanalyzed previous data to develop a more simplified decision tree model as a screening tool for unrecognized diabetes, using basic information in Beijing community health records. Then, the model was validated in another rural town. Only three non-laboratory-based risk factors (age, BMI, and presence of hypertension) with fewer branches were used in the new model. The sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve (AUC) for detecting diabetes were calculated. The AUC values in internal and external validation groups were 0.708 and 0.629, respectively. Subjects with high risk of diabetes had significantly higher HOMA-IR, but no significant difference in HOMA-B was observed. This simple tool will help general practitioners and residents assess the risk of diabetes quickly and easily. This study also validates the strong associations of insulin resistance and early stage of diabetes, suggesting that more attention should be paid to the current model in rural Chinese adult populations.

The new American College of Cardiology/American Heart Association guideline reclassified office blood pressure and proposed thresholds for ambulatory blood pressure (ABP). We derived outcome-driven ABP thresholds corresponding with the new office blood pressure categories. We performed 24-hour ABP monitoring in 11 152 participants (48.9% women; mean age, 53.0 years) representative of 13 populations. We determined ABP thresholds resulting in multivariable-adjusted 10-year risks similar to those associated with elevated office blood pressure (120/80 mm Hg) and stages 1 and 2 of office hypertension (130/80 and 140/90 mm Hg). Over 13.9 years (median), 2728 (rate per 1000 person-years, 17.9) people died, 1033 (6.8) from cardiovascular disease; furthermore, 1988 (13.8), 893 (6.0), and 795 (5.4) cardiovascular and coronary events and strokes occurred. Using a composite cardiovascular end point, systolic/diastolic outcome-driven thresholds indicating elevated 24-hour, daytime, and nighttime ABP were 117.9/75.2, 121.4/79.6, and 105.3/66.2 mm Hg. For stages 1 and 2 ambulatory hypertension, thresholds were 123.3/75.2 and 128.7/80.7 mm Hg for 24-hour ABP, 128.5/79.6 and 135.6/87.1 mm Hg for daytime ABP, and 111.7/66.2 and 118.1/72.5 mm Hg for nighttime ABP. ABP thresholds derived from other end points were similar. After rounding, approximate thresholds for elevated 24-hour, daytime, and nighttime ABP were 120/75, 120/80, and 105/65 mm Hg, and for stages 1 and 2, ambulatory hypertension 125/75 and 130/80 mm Hg, 130/80 and 135/85 mm Hg, and 110/65 and 120/70 mm Hg. Outcome-driven ABP thresholds corresponding to elevated blood pressure and stages 1 and 2 of hypertension are similar to those proposed by the current American College of Cardiology/American Heart Association guideline. ispartof: HYPERTENSION vol:74 issue:4 pages:776-783 ispartof: location:United States status: published

Background: Aortic pulse wave velocity (aPWV) predicts cardiovascular complications, but the association of central arterial properties with blood lead level (BL) is poorly documented. We therefore assessed their association with BL in 150 young men prior to occupational lead exposure, using baseline data of the Study for Promotion of Health in Recycling Lead (NCT02243904). Methods: Study nurses administered validated questionnaires and performed clinical measurements. Venous blood samples were obtained after 8-12h of fasting. The radial, carotid and femoral pulse waves were tonometrically recorded. We accounted for ethnicity, age, anthropometric characteristics, mean arterial pressure, heart rate, smoking and drinking, and total and high-density lipoprotein serum cholesterol, as appropriate. Results: Mean values were 4.14 mu g/dL for BL, 27 years for age, 108/79/28 mm Hg for central systolic/diastolic/pulse pressure, 100/10% for the augmentation ratio/index, 1.63 for pressure amplification, 5.94 m/s for a PWV, 27/11 mm Hg for the forward/backward pulse pressure height, and 43% for the reflection index. Per 10-fold BL increase, central diastolic pressure and the augmentation ratio were respectively 5.37 mm Hg (95% confidence interval [CI], 1.00-9.75) and 1.57 (CI, 0.20-2.94) greater, whereas central pulse pressure and the forward pulse pressure height were 3.74 mm Hg (CI, 0.60-6.88) and 3.37mm Hg (CI, 0.22-6.53) smaller (p

Type 2 diabetes mellitus (T2DM) patients are often accompanied with hypertension. However, the association of antihypertensive drugs with β-cell function has not been well studied. To investigate this question, the authors performed a cross-sectional study involving 882 hypertensive T2DM patients. To assess β-cell function, patients were given 75g glucose orally and C-peptide levels before and 1, 2, and 3 hours after glucose intake were measured. Homa-β was computed by Homeostasis Model Assessment model to evaluate β-cell function using fasting C-peptide and glucose levels in the plasma. Multivariable-adjusted analysis was performed to evaluate the association of antihypertensive drugs with C-peptide levels, HbA1c, and Homa-β. Among 882 hypertensive patients, 547 (62.0%) received antihypertensive treatment. Multivariate-adjusted analysis demonstrated that use of calcium channel blockers (CCBs) was negatively associated with HbA1c levels (CCBs: 0.95 [95% CI: 0.92-0.98], P = 0.002). Our data further illustrated that the C-peptide levels before and 1, 2, and 3 hours of OGTT were 1.10-, 1.18-, 1.19-, and 1.15-fold increase in T2DM patients taking CCBs (P = 0.084 for fasting C-peptide levels; P ≤ 0.024 for C-peptide levels at 1, 2, and 3 hours after OGTT) in comparison with non-CCB users. Nevertheless, usage of any other antihypertensive drugs did neither associated with HbA1c nor associated with C-peptide levels (P ≥ 0.11). In conclusion, CCB treatment was negatively associated with HbA1c levels but positively associated with β-cell function in hypertensive T2DM patients, implying that CCBs could be considered to treat hypertensive T2DM patients with reduced β-cell function.

Background: Hashimoto’s thyroiditis (HT) is an autoimmune disease and often complicated with other metabolic disorders. It has been shown that HT patients have higher levels of antibodies against proinsulin than controls. The incidence of HT in T2DM patients is unclear and has never been studied whether beta cell function differ between T2DM patients alone and complexed with HT. Methods: 8T2DM patients who were recruited between November 2015 till June 2016 to Endocrinology Center in Lu He hospital were analyzed. HT was diagnosed if either serum TPO antibody or TG antibody exceeded the normal range. After a 12-hour overnight fast, venous blood samples were obtained to measure total cholesterol, triglyceride, HDL-c, FBG, insulin and Scr. Oral glucose tolerance test (OGTT) was examined in the patients and serum c-peptide levels were quantified at 0, 1, 2, and 3 hours after glucose administration. Results: 8T2DM patients were included in the study. 249 patients were diagnosed HT.Compared with non-HT subjects, T2DM with HT were more males (44.7% vs. 35.2%, p=0.02) and had higher values of systolic blood pressure (133.8 mm Hg vs. 131.1 mmHg, p=0.03). Although age, body mass index, HbA1c, serum cholesterol and serum triglyceride did not differ between two groups (p≥0.17 for all), fasting C-peptide levels were lower in T2DM complicated with HT than T2DM alone (1.09 ±0.90 nmol/L vs. 1.28±0.98 nmol/L, p=0.004). To further compare beta cell function, patients were performed OGTT test. Serum C-peptide levels remained lower at 1 and 2 hours after oral administration of 75-g glucose in T2DM with HT than T2DM alone (1 hour: 2.10±1.77 nMol/L vs. 2.33 ±1.84 nMol/L, p=0.03; 2 hours: 3.04±2.56 vs. 3.47±2.77 nmol/L, p=0.02). Serum C-peptide levels were comparable three hours after 75-g glucose intake (3.16±2.45 nmol/L vs. 3.50±2.78 nMol/L, p=0.49). Conclusion: The prevalence of HT is relatively high in T2DM patients, which was associated with reduced beta cell function. Disclosure Y. Zhang: None. R. Sun: None. L. Zhang: None. Y. Fang: None. C. Yu: None. S. Yuan: None. Y. Feng: None. D. Zhao: None.

Background: Urinary angiopoietin-like protein 4 (ANGPTL4) levels were positively associated with the amount of albuminuria in streptozotocin (STZ)-injected rats and patients with type 2 diabetic mellitus (T2DM). We investigated the association of serum ANGPTL4 levels and the severity of diabetic kidney disease (DKD) in T2DM patients. Methods: Totalled 1207 T2DM patients were analysed in the cross-sectional study. DKD index included estimated glomerular filtration rate (eGFR), the stages of chronic kidney disease (CKD), and the grades of albuminuria. Normal-to-mild, moderate or severe albuminuria was defined by urinary albumin-to-creatinine ratio 300 mg/g, respectively. Serum levels of ANGPTL4 and other biomarkers were quantified by ELISA. Multivariable-adjusted linear and logistic analysis were performed to study the association of each biomarker with individual DKD index. ANGPTL4 expression was assessed in kidney sections and cultivated tubular cells by immunostaining and/or western blot. Findings: In 1207 T2DM patients (47·3% women, 57·7 ± 14·1 years), one-SD increased of the value of serum ANGPTL4 levels was associated with 6·62 ml/min/1·73m2 eGFR reduction (p

Purpose To investigate whether angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) are differentially associated with the severity of retinopathy in patients with type 2 diabetes mellitus (T2DM). Design Cross-sectional study. Methods Serum levels of ANGPTL3, ANGPTL4, high-sensitivity C-reactive protein (CRP), vascular adhesion molecule–1 (VCAM-1), intracellular adhesion molecule–1 (ICAM-1) and vascular endothelial growth factor (VEGF) were quantified by ELISA. Retinal images were recorded to assess the grade of diabetic retinopathy (DR). Multivariable-adjusted logistic analysis was performed to estimate the association of each biomarker and DR stage. Results Among 1192 T2DM patients, 426 (35.7%) had non-proliferative diabetic retinopathy (NPDR) and 56 (4.5%) had proliferative diabetic retinopathy (PDR). After adjusting for covariables, the odds ratios expressing the risk of having DR vs . no DR ( n =710 vs . 482) was 1.23 (95% CI, 1.08-1.40, p=0.002) for ANGPTL3; 0.90 (95% CI, 0.79-1.02; p=0.095) for ANGPTL4; and 1.14 (95% CI, 1.00-1.29; p=0.044) for VEGF. The risk of having no DR vs . NPDR ( n =710 vs. 426) was 1.16 (95% CI, 1.01-1.32; p=0.036) for ANGPTL3; 0.90 (95% CI, 0.79-1.04; p=0.15) for ANGPTL4; and 1.14 (95% CI, 1.00-1.31; p=0.045) for VEGF. The odds ratios of having NPDR vs . PDR ( n =426 vs . 56) was 1.47 (95% CI, 1.03-2.10; p=0.035) for serum ANGPTL3; 0.96 (95% CI, 0.69-1.35; p=0.83) for ANGPTL4; and 1.05 (95% CI, 0.77-1.45; p=0.74) for VEGF. Conclusions ANGPTL3 is independently and strongly associated with DR progression in all stages. Blockade of ANGPTL3 signal in retina might postpone the onset and development of DR in T2DM patients.

Background ANGPTL 4 (angiopoietin‐like protein 4) is a LPL (lipoprotein lipase) inhibitor and is present in high‐density lipoprotein ( HDL ). However, it is not defined whether ANGPTL 4 in HDL s could affect HDL metabolism and function in type 2 diabetes mellitus (T2 DM ). Methods and Results ANGPTL 4 levels in the circulation and HDL s were quantified in nondiabetic participants (n=201, 68.7% females) and T2 DM patients (n=185, 66.5% females). HDL s were isolated from nondiabetic controls and T2 DM patients to assess cholesterol efflux or subjected to endothelial lipase ( EL )‐overexpressed HEK 293 cells for EL hydrolysis in vitro. The association between ANGPTL 4 in HDL s and HDL components and function was analyzed in nondiabetic participants or diabetic patients, respectively. Plasma or HDL s of ANGPTL 4+/+ and ANGPTL 4−/− mice was subjected for cholesterol efflux or EL hydrolysis, respectively. ANGPTL 4 levels in the plasma and HDL s were 1.7‐ and 2.0‐fold higher in T2 DM patients than nondiabetic controls, respectively ( P ANGPTL 4 levels in HDL s, the changes amounted to +0.27% cholesterol efflux ( P =0.03), +0.06 μg/mL apolipoprotein A‐I ( P =0.09) and −9.41 μg/L serum amyloid A ( P =0.02) in nondiabetic controls. In T2 DM patients, the corresponding estimates were −0.06% cholesterol efflux ( P =0.10), −0.06 μg/mL apolipoprotein A‐I ( P =0.38), and +3.64 μg/L serum amyloid A ( P =0.72). HDL s isolated from ANGPTL 4−/− mice showed accelerated hydrolysis by EL and reduced cholesterol efflux compared with ANGPTL 4+/+ littermates. Conclusions Physically, ANGPTL 4 in HDL s protected HDL s from hydrolysis. Resulting from increased circulating ANGPTL 4 levels in T2 DM , ANGPTL 4 levels in HDL s were elevated but with compromised inhibitory effect on EL , leading to increased HDL hydrolysis and dysfunction.

Background: Type-2 diabetes mellitus accounts for 80-90% of diabetic patients. So far, the treatment of diabetes mainly aims at elevating insulin level and lowering glucose level in the peripheral blood and mitigating insulin resistance. Physiologically, insulin secretion from pancreatic β cells is delicately regulated. Thus, how insulin-related therapies could titrate blood glucose appropriately and avoid the occurrence of hypoglycemia remains an important issue for decades. Similar question is addressed on how to attenuate vascular complication in diabetic subjects. Methods: We overviewed the evolution of each class of anti-diabetic drugs that have been used in clinical practice, focusing on their mechanisms, clinical results and cautions. Results: Glucagon-like peptide-1 receptor agonists stimulate β cells for insulin secretion in response to diet but not in fasting stage, which make them superior than conventional insulinsecretion stimulators. DPP-4 inhibitors suppress glucagon-like peptide-1 degradation. Sodium/ glucose co-transporter 2 inhibitors enhance glucose clearance through urine excretion. The appearance of these new drugs provides new information about glycemic control. We update the clinical findings of Glucagon-like peptide-1 receptor agonists, DPP-4 inhibitors and Sodium/glucose cotransporter 2 inhibitors in glycemic control and the risk or progression of cardiovascular disease in diabetic patients. Stem cell therapy might be an alternative tool for diabetic patients to improve β cell regeneration and peripheral ischemia. We summarize the clinical results of mesenchymal stem cells transplanted into patients with diabetic limb and foot. Conclusion: A stepwise intensification of dual and triple therapy for individual diabetic patient is required to achieve therapeutic target.

Background Angiopoietin-like protein 3 (ANGPTL3) is a major lipoprotein regulator and shows positive correlation with high-density lipoprotein-cholesterol (HDL-c) in population studies and ANGPTL3 mutated subjects. However, no study has looked its correlation with HDL components nor with HDL function in patients with type 2 diabetes mellitus (T2DM). Methods We studied 298 non-diabetic subjects and 300 T2DM patients who were randomly recruited in the tertiary referral centre. Plasma levels of ANGPTL3 were quantified by ELISA. Plasma samples were fractionated to obtain HDLs. HDL components including apolipoprotein A-I (apoA-I), triglyceride, serum amyloid A (SAA), phospholipid and Sphingosine-1-phosphate were measured. HDLs were isolated from female controls and T2DM patients by ultracentrifugation to assess cholesterol efflux against HDLs. A Pearson unadjusted correlation analysis and a linear regression analysis adjusting for age, body mass index and lipid lowering drugs were performed in male or female non-diabetic participants or diabetic patients, respectively. Results We demonstrated that plasma level of ANGPTL3 was lower in female T2DM patients than female controls although no difference of ANGPTL3 levels was detected between male controls and T2DM patients. After adjusting for confounding factors, one SD increase of ANGPTL3 (164.6 ng/ml) associated with increase of 2.57 mg/dL cholesterol and 1.14 μg/mL apoA-I but decrease of 47.07 μg/L of SAA in HDL particles of non-diabetic females (p

Additional file 1. Additional figure and table.

Despite being featured as metabolic disorder, diabetic patients are largely affected by hyperglycemia-induced vascular abnormality. Accumulated evidence has confirmed the beneficial effect of endothelial progenitor cells (EPCs) in coronary heart disease. However, antivascular endothelial growth factor (anti-VEGF) treatment is the main therapy for diabetic retinopathy and nephropathy, indicating the uncertain role of EPCs in the pathogenesis of diabetic microvascular disease. In this review, we first illustrate how hyperglycemia induces metabolic and epigenetic changes in EPCs, which exerts deleterious impact on their number and function. We then discuss how abnormal angiogenesis develops in eyes and kidneys under diabetes condition, focusing on “VEGF uncoupling with nitric oxide” and “competitive angiopoietin 1/angiopoietin 2” mechanisms that are shared in both organs. Next, we dissect the nature of EPCs in diabetic microvascular complications. After we overview the current EPCs-related strategies, we point out new EPCs-associated options for future exploration. Ultimately, we hope that this review would uncover the mysterious nature of EPCs in diabetic microvascular disease for therapeutics.

Background We demonstrated in experimental studies that hypercholesterolaemia enhances the proliferation of haematopoietic stem cells and the subsequent differentiation to neutrophils, whereas HDL-cholesterol inhibits these processes. To translate our experimental findings to clinical practice, we investigated in Chinese type-2 diabetic patients and in Flemish non-diabetic people the independent and joint associations of insulin resistance with markers of dyslipidaemia and inflammation, while looking for consistency between ethnicities and across the spectrum of insulin resistance. Methods We studied 798 Chinese patients with type-2 diabetes (53.6% women; mean age, 60.6 years) admitted to a tertiary referral centre and 1060 white Flemish (50.5%; 51.1 years) randomly recruited in Northern Belgium. Fasting insulin resistance (HOMA-IR) was derived from C-peptide in Chinese and from insulin in Flemish using the Homeostasis Model of Assessment algorithm. In multivariable-adjusted analyses, HOMA-IR was regressed on triglycerides, HDL-cholesterol and neutrophil count. Results In Chinese patients, the percentage changes in HOMA-IR associated with triglycerides, HDL-cholesterol and neutrophils (per 1-SD increment) amounted to 8.1 (95% confidence interval, 3.0 to 13.4; p = 0.0015), -8.7 (-13.0 to -4.2; p = 0.0002) and 5.6 (1.0 to 10.4; p = 0.017). In non-diabetic Flemish, the corresponding estimates were 11.7 (8.3 to 15.1; p

Little is known about the relationship between lower extremity peripheral arterial disease (PAD) and proliferative diabetic retinopathy (PDR) in type 2 diabetes (T2D). Here, we explored the relationship between sight-threatening PDR and PAD. We screened for diabetic retinopathy (DR) and PAD in hospitalized patients with T2D. Patients with a diabetic duration of more than 10 years, HbA1c ≥7.5%, eGFR ≥60 mL/min/1.73 m2 and with PDR or with no diabetic retinopathy (NDR) were eligible for this cross-sectional study. Severities of DR were graded by digital retinal photographs according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. We assessed PAD by measuring Ankle Brachial Index (ABI), Toe Brachial Index (TBI) and Doppler ultrasound. Statistical analyses were performed using SPSS 17.0 software. Of the 1544 patients, 169 patients with extreme eye (57 PDR and 112 NDR) phenotypes met the inclusion criteria. Patients with PDR had a significantly higher proportion of low ABI (≤0.99) and high ABI (≥1.3) than patients with NDR (28.1% and 15.8% vs. 14.3% and 6.2% respectively, P