Intra-individual variability and circadian rhythm of vascular endothelial growth factors in subjects with normal glucose tolerance and type 2 diabetes

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

Transporters, <b><i>TBC1D4</i></b>, and <b><i>ARID5B</i></b> Variants to Explain Glycated Hemoglobin Variability in Patients with Type 2 Diabetes

“…Two variants were located on coding regions of VEGFA and NRXN1 . VEGFA has been previously associated to HbA1c and diabetes duration and although no specific genetic variants have been related to these single-nucleotide variants, it is known that VEFGA rs3025029 does impact protein levels [25]. Moreover, NRXN1 together with VEGFA have been associated with cardiovascular disease through miRNA [26].…”

Adult Neurogenesis under Control of the Circadian System

“…VEGF seems to be directly regulated by the molecular clockwork as Bmal1 directly targets the Vegf gene promoter leading to enhanced expression of VEGF in zebra fish [ 118 ]. In humans, VEGF is increased during the postprandial phase, associated with increased glucose level [ 119 ]. Taken all together, the rhythms in neurotrophic factors are driven by the circadian system either directly downstream of the molecular clockwork or indirectly via light/dark cycles, rhythmic hormones, e.g., cortisol and melatonin, as well as rhythmic behavior, e.g., feeding/fasting or locomotor activity.…”

Chronic, acute and protocol-dependent effects of exercise on psycho-physiological health during long-term isolation and confinement

“…There is evidence for temporary, transient and local (central) exercise-induced releases of BDNF (30,38,82,83), IGF-1 (84,85) and VEGF (86,87). Moreover, day time/circadian variations were found for serum BDNF (88,89) and for free serum IGF-1 levels (90), whereas no circadian variation was shown for VEGF (91,92). Blood draws for pre-exercise assessments took place in the morning, whereas post-exercise blood draw was executed about ve minutes after exercise on a separate day at various daytimes.…”