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Background: To evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease. Methods: 200 participants followed for 6.1 years. SDMA and ADMA were measured at baseline. Endpoints included (1) composite cardiovascular endpoint (n = 40); (2) all-cause mortality (n = 26); and (3) decline in eGFR of >30% (n = 42). Cox models were unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDLcholesterol, smoking, HbA1c, creatinine and urinary albumin excretion rate). To assess if SDMA or ADMA improved risk prediction beyond traditional risk factors we calculated c statistics and relative integrated discrimination improvement (rIDI). C statistic (area under the curve) quantifies the model's improved ability to discriminate events from non-events. rIDI quantifies the increase in separation of events and non-events on a relative scale. Results: Higher SDMA was associated with increased risk of all three endpoints (unadjusted: p ≤ 0.001; adjusted: p ≤ 0.02). Higher ADMA was associated with all-cause mortality (unadjusted: p = 0.002; adjusted: p = 0.006), but not cardiovascular disease or decline in eGFR (p ≥ 0.29).The c statistic was not significant for any of the endpoints for either SDMA or ADMA (p ≥ 0.10). The rIDI for SDMA was 15.0% (p = 0.081) for the cardiovascular endpoint, 52.5% (p = 0.025) for all-cause mortality and 48.8% (p = 0.007) for decline in eGFR; for ADMA the rIDI was 49.1% (p = 0.017) for all-cause mortality. Conclusion: In persons with type 2 diabetes and microalbuminuria higher SDMA was associated with incident cardiovascular disease, all-cause mortality and deterioration in renal function. Higher ADMA was associated with all-cause mortality. SDMA and ADMA significantly improved risk prediction for all-cause mortality, and SDMA for deterioration in renal function beyond traditional risk factors. [ABSTRACT FROM AUTHOR]

Background: When patients experience large weight loss, muscle mass may be affected followed by changes in plasma creatinine (pCr). The MDRD and CKD-EPI equations for estimated GFR (eGFR) include pCr. We hypothesised that a large weight loss reduces muscle mass and pCr causing increase in eGFR (creatinine-based equations), whereas measured GFR (mGFR) and cystatin C-based eGFR would be unaffected if adjusted for body surface area.Methods: Prospective, intervention study including 19 patients. All attended a baseline visit before gastric bypass surgery followed by a visit six months post-surgery. mGFR was assessed during four hours plasma 51Cr-EDTA clearance. GFR was estimated by four equations (MDRD, CKD-EPI-pCr, CKD-EPI-cysC and CKD-EPI-pCr-cysC). DXA-scans were performed at baseline and six months post-surgery to measure changes in lean limb mass, as a surrogate for muscle mass.Results: Patients were (mean ± SD) 40.0 ± 9.3 years, 14 (74%) were female and 5 (26%) had type 2 diabetes, baseline weight was 128 ± 19 kg, body mass index 41 ± 6 kg/m2 and absolute mGFR 122 ± 24 ml/min. Six months post-surgery weight loss was 27 (95% CI: 23; 30) kg, mGFR decreased by 9 (-17; -2) from 122 ± 24 to 113 ± 21 ml/min (p = 0.024), but corrected for current body surface area (BSA) mGFR was unchanged by 2 (-5; 9) ml/min/1.73 m2 (p = 0.52). CKD-EPI-pCr increased by 12 (6; 17) and MDRD by 13 (8; 18) (p < 0.001 for both), while CKD-EPI-cysC was unchanged by 2 (-8; 4) ml/min/1.73 m2 (p = 0.51). Lean limb mass was reduced by 3.5 (-4.4;-2.6; p < 0.001) kg and change in lean limb mass correlated with change in plasma creatinine (R 2 = 0.28, p = 0.032).Conclusions: Major weight reductions are associated with a reduction in absolute mGFR, which may reflect resolution of glomerular hyperfiltration, while mGFR adjusted for body surface area was unchanged. Estimates of GFR based on creatinine overestimate renal function likely due to changes in muscle mass, whereas cystatin C based estimates are unaffected.Trial Registration: ClinicalTrials.gov, NCT02138565 . Date of registration: March 24, 2014. [ABSTRACT FROM AUTHOR]

Background: Low-grade systemic inlammation is considered to participate in the progression of type 2 diabetes (T2D) and in diabetic complications. Methods: To determine if circulating leukocytes were abnormally regulated in T2D patients, 8-color low-cytometry (FACS) analysis was performed in a cross-sectional study of 37 T2D patients and 16 controls. Data obtained from the FACS analysis were compared to coronary low reserve (CFR), assessed by Rb82-PET-imaging, to uncover inflammatory signatures associated with impaired CFR. Results: Presence of T2D was associated with T cell attenuation characterized by reduced overall T cell, Th17, IL-21R+, Treg's and TLR4+ T cells, while the monocyte population showed enhanced TLR4 expression. Further, our data revealed reduced M1-like CD11c expression in T2D which was associated with impaired CFR. In contrast, we show, for the first time in T2D, increased TLR4 expression on CD8 T cells, increased Treg cell number and Treg maturation and reduced IL-21R expression on CD8 T cells to be functionally associated with impaired CFR. Conclusions: Our demonstration that HbA1c inversely correlates to several T cell populations suggests that T cells may play disease modulating roles in T2D. Further, the novel association between impaired CFR and regulatory T cells and IL-21R+ T cells imply an intricate balance in maintaining tissue homeostasis in vascular diabetic complications. [ABSTRACT FROM AUTHOR]

Background: In patients with type 2 diabetes, cardiovascular disease (CVD) is the major cause of morbidity and mortality. We evaluated the combination of NT-proBNP and coronary artery calcium score (CAC) for prediction of combined fatal and non-fatal CVD and mortality in patients with type 2 diabetes and microalbuminuria (>30 mg/24-h), but without known coronary artery disease. Moreover, we assessed the predictive value of a predefined categorisation of patients into a high- and low-risk group at baseline. Methods: Prospective study including 200 patients. All received intensive multifactorial treatment. Patients with baseline NT-proBNP >45.2 ng/L and/or CAC ≥400 were stratified as high-risk patients (n = 133). Occurrence of fatal- and nonfatal CVD (n =40) and mortality (n = 26), was traced after 6.1 years (median). Results: High-risk patients had a higher risk of the composite CVD endpoint (adjusted hazard ratio [HR] 10.6 (95 % confidence interval [CI] 2.4-46.3); p = 0.002) and mortality (adjusted HR 5.3 (95 % CI 1.2-24.0); p = 0.032) compared to low-risk patients. In adjusted continuous analysis, both higher NT-proBNP and CAC were strong predictors of the composite CVD endpoint and mortality (p ≤ 0.0001). In fully adjusted models mutually including NT-proBNP and CAC, both risk factors remained associated with risk of CVD and mortality (p ≤ 0.022). There was no interaction between NT-proBNP and CAC for the examined endpoints (p ≥ 0.31). Conclusions: In patients with type 2 diabetes and microalbuminuria but without known coronary artery disease, NT-proBNP and CAC were strongly associated with fatal and nonfatal CVD, as well as with mortality. Their additive prognostic capability holds promise for identification of patients at high risk. [ABSTRACT FROM AUTHOR]