Serum and Plasma Levels of Vascular Endothelial Growth Factors in Relation to Quality of Glucose Control, Biomarkers of Inflammation, and Diabetic Nephropathy

M. Hanefeld; D. Appelt; K. Engelmann; D. Sandner; S. R. Bornstein; X. Ganz; E. Henkel; R. Haase; A. L. Birkenfeld

doi:10.1055/s-0042-106295

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2016; 48(08): 529-534
DOI: 10.1055/s-0042-106295

Endocrine Care

Serum and Plasma Levels of Vascular Endothelial Growth Factors in Relation to Quality of Glucose Control, Biomarkers of Inflammation, and Diabetic Nephropathy

M. Hanefeld

¹Study Center Professor Hanefeld, GWT TU-Dresden GmbH, Dresden, Germany

²Medical Clinic III, Universitätsklinikum “Carl Gustav Carus”, Paul Langerhans Institute Dresden (PLID), Technische Universität Dresden, Dresden, Germany

,

D. Appelt

¹Study Center Professor Hanefeld, GWT TU-Dresden GmbH, Dresden, Germany

,

K. Engelmann

³Klinik für Augenheilkunde, Klinikum Chemnitz gGmbH, Chemnitz, Germany

⁴Institut für Anatomie, Universitätsklinikum “Carl Gustav Carus”, Dresden, Germany

,

D. Sandner

⁵Augenklinik und Poliklinik, Universitätsklinikum “Carl Gustav Carus”, Technische Universität Dresden, Dresden, Germany

,

S. R. Bornstein

²Medical Clinic III, Universitätsklinikum “Carl Gustav Carus”, Paul Langerhans Institute Dresden (PLID), Technische Universität Dresden, Dresden, Germany

⁶German Center of Diabetes Research (DZD), Neuherberg, Germany

⁷Section of Diabetes and Nutritional Sciences, Rayne Institute, Denmark Hill Campus, King’s College London, UK

,

X. Ganz

¹Study Center Professor Hanefeld, GWT TU-Dresden GmbH, Dresden, Germany

,

E. Henkel

¹Study Center Professor Hanefeld, GWT TU-Dresden GmbH, Dresden, Germany

,

R. Haase

⁸Zentrum f. klin. Neurowissenschaften, eHealth Group, Universitätsklinikum “Carl Gustav Carus”, Technische Universität Dresden, Dresden, Germany

,

A. L. Birkenfeld

¹Study Center Professor Hanefeld, GWT TU-Dresden GmbH, Dresden, Germany

²Medical Clinic III, Universitätsklinikum “Carl Gustav Carus”, Paul Langerhans Institute Dresden (PLID), Technische Universität Dresden, Dresden, Germany

⁶German Center of Diabetes Research (DZD), Neuherberg, Germany

⁷Section of Diabetes and Nutritional Sciences, Rayne Institute, Denmark Hill Campus, King’s College London, UK

› Author Affiliations

Abstract

Levels of vascular endothelial growth factors (VEGF) are regulated in a complex network of adipokines, glucose control, and low grade inflammation together with activated platelets, leucocytes, and endothelial dysfunction. Increased levels of VEGF are associated with enhanced angiogenesis and impaired repair mechanisms of vascular lesions in endorgans. Little is known about the interaction of systemic VEGF levels with quality of diabetes control, biomarkers of inflammation, and diabetic nephropathy. Moreover, it is unclear, whether serum and plasma VEGF levels are similarly suited to reflect risk associated with VEGF.

In this case control study, we analyzed these parameters in serum and plasma of age and sex matched controls without diabetes (n=99) and type 2 diabetes (n=302). Serum VEGF-A was significantly increased in patients with T2DM while plasma levels were in the same range as for controls. Individual levels varied in a wide range. Serum levels were 4.9 times higher in controls and 7.3 times higher in T2DM as compared to plasma levels. T2DM was associated with significantly higher levels of hsCRP, ALAT, and albumin/creatinine ratio. When calculated for tertiles of HbA1c, we observed a highly significant increase from tertile one to the upper tertile for serum VEGF-A but not for plasma VEGF-A. Correlation analysis revealed a significant relationship between VEGF-A, HbA1c, inflammation, and diabetic nephropathy. Our results indicate that increased VEGF-A levels in T2DM significantly depend on quality of HbA1c control. Serum levels of VEGF-A, with a strong contribution of platelet derived VEGF, better reflect the glycemic burden than plasma levels of VEGF-A. Mechanistic studies are needed to explore links to inflammation and diabetic nephropathy.

Key words

VEGF - diabetes mellitus type 2 - diabetic nephropathy - diabetic retinopathy

Full Text

References

References
1 Investigators D . Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2000; 342: 381-389
2 Investigators U . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 837-853
3 Sardar P, Udell JA, Chatterjee S, Bansilal S, Mukherjee D, Farkouh ME. Effect of Intensive Versus Standard Blood Glucose Control in Patients With Type 2 Diabetes Mellitus in Different Regions of the World: Systematic Review and Meta-analysis of Randomized Controlled Trials. J Am Heart Assoc 2015; pii e001577
4 Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Group S-NTR . Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002; 359: 2072-2077
5 Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J 2015; 36: 2288-2296
6 Schlich R, Willems M, Greulich S, Ruppe F, Knoefel WT, Ouwens DM, Maxhera B, Lichtenberg A, Eckel J, Sell H. VEGF in the crosstalk between human adipocytes and smooth muscle cells: depot-specific release from visceral and perivascular adipose tissue. Mediat Inflam 2013; 982458
7 Mohle R, Green D, Moore MA, Nachman RL, Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA 1997; 94: 663-668
8 Ma JX, Zhang SX, Wang JJ. Down-regulation of angiogenic inhibitors: a potential pathogenic mechanism for diabetic complications. Curr Diabetes Rev 2005; 1: 183-196
9 Hovind P, Tarnow L, Oestergaard PB, Parving HH. Elevated vascular endothelial growth factor in type 1 diabetic patients with diabetic nephropathy. Kidney Int Suppl 2000; 75: S56-S61
10 Yamagishi S, Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharmaceut Des 2005; 11: 2279-2299
11 de Rooij SR, Nijpels G, Nilsson PM, Nolan JJ, Gabriel R, Bobbioni-Harsch E, Mingrone G, Dekker JM. for the Relationship Between Insulin S, Cardiovascular Disease (RISC) Invetigators. Low-grade chronic inflammation in the relationship between insulin sensitivity and cardiovascular disease (RISC) population: associations with insulin resistance and cardiometabolic risk profile. Diabetes Care 2009; 32: 1295-1301
12 Hanefeld M, Pistrosch F, Bornstein SR, Birkenfeld AL. The metabolic vascular syndrome - guide to an individualized treatment. Rev Endocr Metab Disord 2016; [Epub ahead of print]
13 Gattu AK, Birkenfeld AL, Jornayvaz F, Dziura J, Li F, Crawford SE, Chu X, Still CD, Gerhard GS, Chung C, Samuel V. Insulin resistance is associated with elevated serum pigment epithelium-derived factor (PEDF) levels in morbidly obese patients. Acta Diabetol 2012; 49 (Suppl. 01) S161-S169
14 Docke S, Lock JF, Birkenfeld AL, Hoppe S, Lieske S, Rieger A, Raschzok N, Sauer IM, Florian S, Osterhoff MA, Heller R, Herrmann K, Lindenmuller S, Horn P, Bauer M, Weickert MO, Neuhaus P, Stockmann M, Mohlig M, Pfeiffer AF, von Loeffelholz C. Elevated hepatic chemerin mRNA expression in human non-alcoholic fatty liver disease. Eur J Endocrinol 2013; 169: 547-557
15 Mirhafez SR, Pasdar A, Avan A, Esmaily H, Moezzi A, Mohebati M, Meshkat Z, Mehrad-Majd H, Eslami S, Rahimi HR, Ghazavi H, Ferns GA, Ghayour-Mobarhan M. Cytokine and growth factor profiling in patients with the metabolic syndrome. The Br J Nutr 2015; 113: 1911-1919
16 Zhou Z, Ju H, Sun M, Chen H, Ji H, Jiang D, Ji Y, Ji J. Serum fetuin-A concentrations are positively associated with serum VEGF levels in patients with newly diagnosed type 2 diabetes. Endocr J 2015; 62: 879-885
17 Schlingemann RO, Van Noorden CJ, Diekman MJ, Tiller A, Meijers JC, Koolwijk P, Wiersinga WM. VEGF levels in plasma in relation to platelet activation, glycemic control, and microvascular complications in type 1 diabetes. Diabetes Care 2013; 36: 1629-1634
18 Xie M, He G, Wang R, Shi S, Chen J, Ye Y, Xie L, Yi X, Tang A. Matrine-induced apoptosis of human nasopharyngeal carcinoma cells via in vitro vascular endothelial growth factor-A/extracellular signal-regulated kinase1/2 pathway inactivation. Horm Metab Res 2014; 46: 556-560
19 van Herpen NA, Sell H, Eckel J, Schrauwen P, Mensink RP. Prolonged fasting and the effects on biomarkers of inflammation and on adipokines in healthy lean men. Horm Metab Res 2013; 45: 378-382
20 Rickham PP. Human Experimentation. Code of Ethics of the World Medical Association. Declaration of Helsinki. Br Med J 1964; 2: 177
21 Pistrosch F, Ganz X, Bornstein SR, Birkenfeld AL, Henkel E, Hanefeld M. Risk of and risk factors for hypoglycemia and associated arrhythmias in patients with type 2 diabetes and cardiovascular disease: a cohort study under real-world conditions. Acta Diabetol 2015; 52: 889-895
22 Nandy D, Mukhopadhyay D, Basu A. Both vascular endothelial growth factor and soluble Flt-1 are increased in type 2 diabetes but not in impaired fasting glucose. J Invest Med 2010; 58: 804-806
23 Kakizawa H, Itoh M, Itoh Y, Imamura S, Ishiwata Y, Matsumoto T, Yamamoto K, Kato T, Ono Y, Nagata M, Hayakawa N, Suzuki A, Goto Y, Oda N. The relationship between glycemic control and plasma vascular endothelial growth factor and endothelin-1 concentration in diabetic patients. Metabolism 2004; 53: 550-555
24 Zehetner C, Kirchmair R, Kralinger M, Kieselbach G. Correlation of vascular endothelial growth factor plasma levels and glycemic control in patients with diabetic retinopathy. Acta Ophthalmol 2013; 91: e470-e473
25 Chiarelli F, Spagnoli A, Basciani F, Tumini S, Mezzetti A, Cipollone F, Cuccurullo F, Morgese G, Verrotti A. Vascular endothelial growth factor (VEGF) in children, adolescents and young adults with Type 1 diabetes mellitus: relation to glycaemic control and microvascular complications. Diabet Medicine 2000; 17: 650-656
26 Gunsilius E, Petzer A, Stockhammer G, Nussbaumer W, Schumacher P, Clausen J, Gastl G. Thrombocytes are the major source for soluble vascular endothelial growth factor in peripheral blood. Oncology 2000; 58: 169-174
27 Davidovic SP, Nikolic SV, Curic NJ, Latinovic SL, Draskovic DO, Cabarkapa VS, Stosic ZZ. Changes of serum VEGF concentration after intravitreal injection of Avastin in treatment of diabetic retinopathy. Eur J Ophthalmol 2012; 22: 792-798
28 Schroeder C, Birkenfeld AL, Mayer AF, Tank J, Diedrich A, Luft FC, Jordan J. Norepinephrine transporter inhibition prevents tilt-induced pre-syncope. J Am College Cardiol 2006; 48: 516-522
29 American Diabetes Association . 6. Glycemic targets. Diabetes Care 2015; 38 (Suppl) S33-S40
30 O’Hare JP, Hanif W, Millar-Jones D, Bain S, Hicks D, Leslie RD, Barnett AH. NICE guidelines for Type 2 diabetes: revised but still not fit for purpose. Diabet Med 2015; 32: 1398-1403