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

Markolf Hanefeld, Katrin Engelmann, Dieter Appelt, Dirk Sandner, Ingo Weigmann, Xenia Ganz, Frank Pistrosch, Carsta Köhler, Antje Gasparic, Andreas L Birkenfeld, Markolf Hanefeld, Katrin Engelmann, Dieter Appelt, Dirk Sandner, Ingo Weigmann, Xenia Ganz, Frank Pistrosch, Carsta Köhler, Antje Gasparic, Andreas L Birkenfeld

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.

Conflict of interest statement

Competing Interests: The study was partly funded by an unrestricted grant from Novartis Pharma. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Specifically, this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Study design.
Fig 1. Study design.
Fig 2
Fig 2
A) Boxplot of VEGF-A concentrations in serum of subjects with normal glucose tolerance (NGT) and patients with type 2 diabetes mellitus (T2DM) over an observation period of 6 months. B) Boxplot of VEGF-A concentrations in CTAD plasma of subjects with normal glucose tolerance (NGT) and patients with type 2 diabetes mellitus (T2DM) over an observation period of 6 months. The lower border of the box plots represent the 25th percentile and the upper border represents the 75th percentile ± SD. ° = patient with a value

Fig 3

A) Boxplots of VEGF-C concentrations…

Fig 3

A) Boxplots of VEGF-C concentrations in plasma of subjects with normal glucose tolerance…

Fig 3
A) Boxplots of VEGF-C concentrations in plasma of subjects with normal glucose tolerance (NGT) and patients with type 2 diabetes mellitus (T2DM) over an observation period of 6 months B) Boxplots of PLGF concentrations in plasma of subjects with normal glucose tolerance (NGT) and patients with type 2 diabetes mellitus (T2DM) over an observation period of 6 months. The lower border of the box plots represent the 25th percentile and the upper border represents the 75th percentile ± SD. ° = patient with a value

Fig 4

A) Circadian rhythm of VEGF-A…

Fig 4

A) Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in serum of…

Fig 4
A) Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in serum of subjects with normal glucose tolerance (NGT). B) Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in serum of patients with type 2 diabetes mellitus (T2DM). C). Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in plasma of subjects with normal glucose tolerance (NGT). D). Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in plasma of patients with type 2 diabetes mellitus (T2DM).

Fig 5

A) Circadian rhythm of VEGF-C…

Fig 5

A) Circadian rhythm of VEGF-C levels (arithmetic mean and 95% CI) in plasma…

Fig 5
A) Circadian rhythm of VEGF-C levels (arithmetic mean and 95% CI) in plasma of subjects with normal glucose tolerance (NGT). B). Circadian rhythm of VEGF-C levels (arithmetic mean and SD) in plasma of patients with type 2 diabetes mellitus (T2DM). C). Circadian rhythm of PLGF levels (arithmetic mean and SD) in plasma of subjects with normal glucose tolerance (NGT). D) Circadian rhythm of PLGF levels (arithmetic mean and SD) in plasma of patients with type 2 diabetes mellitus (T2DM).
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Fig 3
Fig 3
A) Boxplots of VEGF-C concentrations in plasma of subjects with normal glucose tolerance (NGT) and patients with type 2 diabetes mellitus (T2DM) over an observation period of 6 months B) Boxplots of PLGF concentrations in plasma of subjects with normal glucose tolerance (NGT) and patients with type 2 diabetes mellitus (T2DM) over an observation period of 6 months. The lower border of the box plots represent the 25th percentile and the upper border represents the 75th percentile ± SD. ° = patient with a value

Fig 4

A) Circadian rhythm of VEGF-A…

Fig 4

A) Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in serum of…

Fig 4
A) Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in serum of subjects with normal glucose tolerance (NGT). B) Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in serum of patients with type 2 diabetes mellitus (T2DM). C). Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in plasma of subjects with normal glucose tolerance (NGT). D). Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in plasma of patients with type 2 diabetes mellitus (T2DM).

Fig 5

A) Circadian rhythm of VEGF-C…

Fig 5

A) Circadian rhythm of VEGF-C levels (arithmetic mean and 95% CI) in plasma…

Fig 5
A) Circadian rhythm of VEGF-C levels (arithmetic mean and 95% CI) in plasma of subjects with normal glucose tolerance (NGT). B). Circadian rhythm of VEGF-C levels (arithmetic mean and SD) in plasma of patients with type 2 diabetes mellitus (T2DM). C). Circadian rhythm of PLGF levels (arithmetic mean and SD) in plasma of subjects with normal glucose tolerance (NGT). D) Circadian rhythm of PLGF levels (arithmetic mean and SD) in plasma of patients with type 2 diabetes mellitus (T2DM).
Fig 4
Fig 4
A) Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in serum of subjects with normal glucose tolerance (NGT). B) Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in serum of patients with type 2 diabetes mellitus (T2DM). C). Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in plasma of subjects with normal glucose tolerance (NGT). D). Circadian rhythm of VEGF-A levels (arithmetic mean and SD) in plasma of patients with type 2 diabetes mellitus (T2DM).
Fig 5
Fig 5
A) Circadian rhythm of VEGF-C levels (arithmetic mean and 95% CI) in plasma of subjects with normal glucose tolerance (NGT). B). Circadian rhythm of VEGF-C levels (arithmetic mean and SD) in plasma of patients with type 2 diabetes mellitus (T2DM). C). Circadian rhythm of PLGF levels (arithmetic mean and SD) in plasma of subjects with normal glucose tolerance (NGT). D) Circadian rhythm of PLGF levels (arithmetic mean and SD) in plasma of patients with type 2 diabetes mellitus (T2DM).

References

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