OBJECTIVE We investigated endotrophin, a profibrotic signaling molecule reflecting collagen VI formation, in serum and urine as risk marker for complications to type 2 diabetes. RESEARCH DESIGN AND METHODS Endotrophin was measured in 774 individuals with type 2 diabetes. Outcomes included a composite kidney end point, first major adverse cardiovascular event (MACE), mortality, progression of albuminuria, incident heart failure, and sight-threatening eye disease. Adjusted Cox proportional hazards models were applied. RESULTS Doubling of serum endotrophin was associated with the kidney end point (n = 49; hazard ratio 1.80 [95% CI 1.13–2.87]), first MACE (n = 66; 1.54 [1.04–2.28]), mortality (n = 156; 1.69 (1.31–2.19]), and incident heart failure (n = 42; 1.63 [1.02–2.60]). A doubling of urine endotrophin was associated with progression of albuminuria (n = 85; 1.20 [1.04–1.39]). CONCLUSIONS Serum endotrophin was a risk marker for mortality and kidney and cardiovascular complications in type 2 diabetes. Urine endotrophin was a marker for albuminuria progression.
Background: Persons with diabetes have a high risk of complications related to the micro- and macrovascular circulation. One of the pathological processes involved in these complications is the onset of abnormal extracellular matrix (ECM) remodeling in different organs, leading to fibrosis. The quantification of ECM remodeling may identify patients that are at higher risk for adverse outcomes. Method: We measured biomarkers of collagen type III (PRO-C3) and VI (PRO-C6) formation and MMP-mediated degradation of type I (C1M) , III (C3M) , and IV (C4M and Tumstatin; TUM) in serum from 267 persons with T2DM from the CMR in T2DM study (NCT02684331) . Myocardial fibrosis (LGE) and ECV were determined by gadolinium-contrast CMR. Serum samples from 79 healthy controls were measured for comparison. Results: Levels of all biomarkers were significantly elevated in persons with T2DM compared to healthy controls (all P<0.0001) . Some of the markers were associated with complications, PRO-C6 levels were: significantly elevated in patients with hypertension compared to persons without known CVD (P<0.0001) ; could discriminate patients with CKD - eGFR < 60 ml/min/1.73m2 with an AUC of 0.83 (P<0.001) ; were significantly increased in patients with ischemic LGE (P<0.05) , suggesting an association of PRO-C6 with fibrosis; and in a multiple linear regression analysis, higher PRO-C6 levels were significantly associated with higher HbA1c (r=0.15, P=0.0397) , lower eGFR (r=−0.41, P<0.0001) , higher proANP (r=0.24, P=0.0005) , and higher ECV (r=0.24, P=0.0006) . PRO-C3 levels were significantly elevated in patients with CKD compared to non-CKD, and levels of C3M and C4M increased significantly with presence of albuminuria. Conclusion: Biomarkers of ECM remodeling, particularly PRO-C6, may identify persons with active pro-fibrotic processes at risk for complications related to T2DM. The potential of the biomarkers to predict adverse outcomes will be investigated once follow-up data have been collected. Disclosure A.Møller: None. A.S.Bojer: None. F.Genovese: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S. M.H.Sørensen: None. P.Gæde: Advisory Panel; AstraZeneca, Research Support; Novo Nordisk. M.A.Karsdal: Employee; Nordic Bioscience A/S, Nordic Bioscience A/S, Nordic Bioscience A/S. P.L.Madsen: None. D.G.Rasmussen: Employee; Nordic Bioscience A/S.
<p> </p> <p><strong>Objective</strong><br> We investigated endotrophin, a profibrotic signaling molecule reflecting collagen VI formation, in serum and urine as risk marker for complications to type 2 diabetes.<br> <strong>Research Design and Methods</strong><br> Endotrophin was measured in 774 persons with type 2 diabetes. Outcomes included a composite kidney endpoint, first major adverse cardiovascular event (MACE), mortality, progression of albuminuria, incident heart failure and sight-threatening eye disease. Adjusted cox proportional hazards models were applied.<br> <strong>Results</strong></p> <p>Doubling of serum endotrophin was associated with the kidney endpoint (n=49, HR:1.80 (95% CI: 1.13-2.87), first MACE (n=66, HR:1.54 (1.04-2.28)), mortality (n=156, HR:1.69 (1.31-2.19)) and incident heart failure (n=42, HR:1.63 (1.02-2.60)). A doubling of urine endotrophin was associated with progression of albuminuria (n=85, HR:1.20 (1.04-1.39)) and incident heart failure (n=40, HR:1.79 (1.09-2.95)).</p> <p><strong>Conclusions </strong><br> Serum endotrophin was a risk marker for mortality, kidney and cardiovascular complications in type 2 diabetes. Urine endotrophin was a marker for albuminuria progression and heart failure.</p>
Table 2. The potassium contents ranges of single preparations with different officinal partsConclusions: All of the tested PCMs contain potassium and 42% of them had potassium content >10 mg$g -1 (or mg$mL -1 ). Lots of PCMs would provide a very high potassium load for CKD patients, which leads to an urgent problem in CKD management. We should be aware that many CKD patients also took additional Chinese herbs while using PCM.
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