Abstract
Increased levels of systemic vascular endothelial growth factors (VEGFs) in patients with diabetes are associated with increased risk of microvessel disease. On the other hand, low VEGF levels after intravitreal antibody application may be associated with acute cardiovascular complications and treatment failure. Individual levels of systemic VEGF vary in a wide range depending on analytical methods and quality of diabetes control. So far only limited information exists on intraindividual fluctuations over longer periods and circadian rhythms. We analysed the intraindividual variance of VEGF-A, VEGF-C and placental growth factor (PLGF) in CTAD (citrate-theophylline-adenine-dipyridamol) plasma as well as VEGF-A in serum over a period of 6 months in patients with stable controlled type 2 diabetes (10 M, 10 F) and age and sex matched subjects with normal glucose tolerance (NGT). Furthermore, circadian levels of VEGFs were controlled hourly from 7:30 a.m. to 7:30 p.m. under standardized metabolic ward conditions. In addition, the relationship to metabolic, hormonal and inflammatory biomarkers was analyzed. VEGF-A, VEGF-C and PLGF remained stable in plasma and VEGF-A in serum over 6 months in both groups. No circadian change was observed in VEGF-A serum and plasma concentrations. A minor decrease of VEGF-C plasma levels was evident after 5 p.m. in both groups and a significant peak of PLGF concentrations occurred after lunch, which was more pronounced in T2DM. In multivariate analysis, only serum VEGF-A correlated to diabetes duration, whereas VEGF-C only correlated to HbA1c and fasting blood glucose. We did not observe significant intraindividual variances for VEGF-A in serum and VEGF-A, VEGF-C and PLGF in CTAD plasma over a period of 6 months. Taken together, a single morning measurement of systemic VEGF levels after 7:30 am appears to be a reliable parameter for the individual risk associated with abnormal VEGF concentrations in blood.Trial Registration: NCT02325271
Highlights
Vascular endothelial growth factors (VEGF) are important regulators of endothelial function, regulating blood-retinal barrier, filtration of macromolecules in the kidney and neo-angiogenesis in endorgans in the case of hypoxia [1,2]
Our data show that all three VEGF fractions were stable in individuals under real world conditions controlled for possible biases
In both cohorts we observed a wide interindividual variation of VEGF concentrations in serum and plasma, which was more pronounced in patients with diabetes
Summary
Vascular endothelial growth factors (VEGF) are important regulators of endothelial function, regulating blood-retinal barrier, filtration of macromolecules in the kidney and neo-angiogenesis in endorgans in the case of hypoxia [1,2]. Clinical studies in patients with diabetes have established a pivotal role of VEGF in the incidence and progression of diabetic retinopathy (DR) [3,4] This has led to the development of specific anti VEGF antibodies as a successful intravitreal treatment of proliferative retinopathy and diabetic macular edema (DME) [3,5,6]. Since anti-VEGF therapy is available for the treatment of age related macular degeneration (ARMD) and DME, the high incidence of blindness could be reduced [7]. It is still matter of debate how the anti-VEGF therapy can be best guided. A systematic screening of potential biomarkes of the diabetic population with and without retinal disorders seems to be inevitable for an optimal guidance of the patients through the long lasting therapy
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