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Published online September 18, 2007
Diabetes Care 30:3086-3087, 2007
DOI: 10.2337/dc07-0629
© 2007 by the American Diabetes Association
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Pathophysiology/Complications
Original Research

Low Serum Angiogenin Concentrations in Patients With Type 2 Diabetes

Janusz Siebert, MD, PHD1, Magdalena Reiwer-Gostomska, MD1, Zofia Babinska, MD1, Jolanta Mysliwska, MD, PHD2, Andrzej Mysliwski, MD, PHD3, Ewa Skopinska-Rózewska, MD, PHD4, Ewa Sommer, MD4 and Piotr Skopinski, MD5,6

1 University Centre for Cardiology, Department of Family Medicine, Medical University of Gdansk, Gdansk, Poland
2 Department of Immunology, Medical University of Gdansk, Gdansk, Poland
3 Department of Histology, Medical University of Gdansk, Gdansk, Poland
4 Department of Pathology, Biostructure Centre, Medical University of Warsaw, Warsaw, Poland
5 Department of Histology, Embriology, Biostructure Centre, Medical University of Warsaw, Warsaw, Poland
6 2nd Department of Ophthalmology, Medical University of Warsaw, Warsaw, Poland

Address correspondence and reprint requests to Prof. Janusz Siebert, Medical University of Gdansk, 2 Debinki St., Gdansk 80952, Poland. E-mail: jsiebert{at}amg.gda.pl

Abbreviations: SIA, serum-induced angiogenesis


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
Premature development of microvascular and macrovascular disease is the most frequent complication of diabetes. It is responsible for diabetic retinopathy, nephropathy, and neuropathy (1). Moreover, diabetes leads to reduced collateralization in ischemic tissues, which causes impaired wound healing, exacerbation of peripheral limb ischemia, and a three- to fourfold increase in cardiac mortality in comparison with nondiabetic patients (2,3).

The pathophysiological mechanisms responsible for impaired angiogenic activity in diabetes remain unknown. Although angiogenesis impairment has been attributed to alterations in the gene regulatory network, which can be involved in the physiological revascularization process, the role of angiogenin in this process has not been clarified (2,4).

The aim of this study therefore was to compare angiogenin serum levels in healthy and type 2 diabetic age-matched individuals. The cutaneous angiogenesis in vivo (serum-induced angiogenesis [SIA]) test in mice was performed in parallel to determine the functional differences between the groups examined.


   RESEARCH DESIGN AND METHODS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
A total of 43 patients with type 2 diabetes and 43 age-matched healthy control subjects volunteered for the study. Patients suffering from acute and chronic infections and neoplastic diseases were excluded. Diabetes was defined according to American Diabetes Association criteria (5). All patients had blood glucose levels >7 mmol/l. Serum angiogenin levels were measured in duplicate with the ELISA Quantikine kit (R&D System, Minneapolis, MN). The SIA test was performed on Balb/c mice according to the method of Sidky and Auerbach (6) with own modifications (7–9).

The results were analyzed using Statistica software, Version 7 (StatSoft Polska). The level of significance was set at P < 0.05, and two-sided tests were performed as the standard.


   RESULTS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
The diabetic patients were characterized by significantly higher levels of triglycerides and serum creatinine and lower levels of LDL cholesterol, while BMI and total as well as HDL cholesterol concentrations were not significantly different from those of healthy individuals (Table 1).


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  		Table 1— Basic parameters in diabetic patients and healthy control subjects

 
Serum angiogenin levels were significantly lower in type 2 diabetic patients in relation to control subjects (P = 0.000002). At the same time, sera from diabetic patients induced significantly fewer newly formed blood vessels on the inner surface of skin from Balb/c mice (P = 0.03).

Serum angiogenin levels as well as SIA values were significantly lower in the patients with late complications (retinopathy and nephropathy) in relation to those without complicated disease (P = 0.04 for angiogenin and P = 0.02 for SIA).

There were no differences, however, in angiogenin and SIA values between the patients receiving statins (P = 0.93 for angiogenin and P = 0.74 for SIA) or ACE inhibitors (P = 0.70 for angiogenin and P = 0.51 for SIA) and those not treated with either. The multivariate linear stepwise regression analysis confirmed the previous results revealing that none of the parameters examined, including medicines, exerted an effect on angiogenin or SIA values (P = 0.70). The angiogenin and SIA values were not correlated with the A1C concentrations (P = 0.4).


   CONCLUSIONS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
Angiogenin, a 14-kDa protein, is implicated in immunological and inflammatory angiogenesis (10). The level of angiogenin in human plasma is strictly regulated (11); the protein is a normal constituent of blood, and its level usually remains unchanged. However, in some pathological conditions such as peripheral vascular disease, inflammatory bowel disease, rheumatoid arthritis, obesity, proliferative diabetic retinopathy, and proliferative vitreopathy, it can intensify the induction of new blood vessel formation (10).

We discovered that the serum angiogenin level is markedly decreased in type 2 diabetic patients in comparison with age-matched healthy subjects. The lower angiogenic potential of sera from type 2 diabetic patients was confirmed by the in vivo SIA test. The more severe disease, i.e., complicated with retinopathy or nephropathy, was associated with lower values of both angiogenin and SIA. On the other hand, the differences in values of both indicators of angiogenesis were not related, in our analysis, to any of the other clinical parameters examined in the diabetic patients. Since the number of diabetic patients was limited in our study and almost all patients had poorly controlled A1C levels, we can assume that they constituted a very homogenous group. The angiogenin and SIA values were in a rather narrow range. Therefore, they most likely reached a point when any treatment ceased to play a role. The most important finding was that neither statins nor angiotensin inhibitors influenced the values of both angiogenesis indicators.

Our data are compatible with the known phenomenon of limited collateral vessel development in coronary heart disease, which is associated with a pronounced myocardial ischemia in diabetic patients (2). In experimental in vitro and in vivo models of retinal angiogenesis assays, Stitt et al. (1) discovered that sera of type 2 diabetic patients have strong anti-angiogenic effects. The poorer the glycemic control of patients, the more evident the inhibition of angiogenesis. The authors documented that advanced glycation end products and their receptors may be mediators in retinal angiogenesis inhibition. Adding to that, Chou et al. (12) suggest a possible explanation for impaired collateral formation in cardiac tissue by reduction in vascular endothelial growth factor in ventricles from diabetic patients compared with those in control subjects. Similar results were obtained by Chung et al. (13). Their report indicates a 48% reduction of vascular endothelial growth factor in internal mammary artery of diabetic patients undergoing coronary artery bypass graft surgery. Our results imply, additionally, that angiogenesis inhibition may be realized through a reduction in angiogenin level. Whether such a relation really exists is a matter for further investigation.


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 18 September 2007. DOI: 10.2337/dc07-0629.

Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/dc07-0629.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication March 30, 2007. Accepted for publication September 12, 2007.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

  1. Stitt AW, McGoldrick C, Rice- McCaldin A, McCance DR, Glenn JV, Hsu DK, Fu-Tong Liu, Thorpe SR, Gardiner TA: Impaired retinal angiogenesis in diabetes: role of advanced glycation end products and galectin-3. Diabetes 53:857–794, 2005
  2. Abaci A, Oguzhan A, Kahraman S, Eryol NK, UnalS, Arinc H, Egrin A: Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation 99:2239–2242, 1999[Abstract/Free Full Text]
  3. Schiekofer S, Gallasso G, Sato K, Kraus BJ, Walsh K: Impaired revascularization in a mouse model of type 2 diabetes is associated with dysregulation of complex angiogenic-regulatory network. Arteriscler Thromb Vasc Biol 25:1603–1609, 2005[Abstract/Free Full Text]
  4. Taniyama Y, Morishita R, Hiraoka K, Aoki M, Nakagami H, Yamasaki K, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T: Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model: molecular mechanisms of delayed angiogenesis in diabetes. Circulation 104:2344–2350, 2001[Abstract/Free Full Text]
  5. American Diabetes Association: Diagnosis and classification of diabetes mellitus. Diabetes Care 28 (Suppl. 1):S37–S47, 2005
  6. Sidky YA, Auerbach R: Lymphocyte-induced angiogenesis: a quantitative and sensitive assay of the g-v-h reaction. J Exp Med 141:1084–1100, 1975[Abstract/Free Full Text]
  7. Skopinski P, Rogala E, Duda-Król B, Lipinska A, Sommer E, Chorostowska-Wynimko J, Szaflik J, Partyka I, Skopinska-Rózewska E: Increased interleukin 18 content and angiogenic activity of sera from diabetic (type 2) patients with background retinopathy. J Diabetes Complications 19:335–338, 2005[Medline]
  8. Skopinski P, Szaflik J, Partyka I, Chorostowska- Wynimko J, Duda-Król B, Lipinska A, Sommer E, Skopinska-Rózewska E: Serum in vivo angiogenic activity and some pro-angiogenic cytokine levels in diabetes mellitus type 2 (DM2) patients with or without background retinopathy. Centr Eur J Immunol 32:48–52, 2007
  9. Skopinski P, Szaflik J, Duda-Król B, Nartowska J, Sommer E, Chorostowska-Wynimko J, Demkow U, Skopinska-Rózewska E: Suppression of angiogenic activity of sera from diabetic patients with non-proliferative retinopathy by compounds of herbal origin and sulindac sulfone. Int J Mol Med 14:707–711, 2004[Medline]
  10. Hu G, Riordan JF., Vallee BL: Angiogenin promotes invasiveness of cultured endothelial cells by stimulation of cell-associated proteolytic activities. Proc Natl Acad Sci U S A 91:12096–12100, 1994[Abstract/Free Full Text]
  11. Hu G: Neomycin inhibits angiogenin-induced angiogenesis. Proc Natl Acad Sci U S A 95:9791–9795, 1998[Abstract/Free Full Text]
  12. Chou E, Suzuma I, Way KJ, Opland D, Clemont AC, Naruse K, Suzuma K, Bowling NL, Vlahos CJ, Aiello LP, King GL: Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states. Circulation 105:373–379, 2002[Abstract/Free Full Text]
  13. Chung AWY, Hsiang YN, Matzke LA, McManus BM, van Breemen C, Okon EB: Reduced expression of vascular endothelial growth factor paralleled with the increased angiostatin expression resulting from the upregulatd activities of matrix metalloproteinase-2 and -9 in human type 2 diabetic arterial vasculature. Circ Res 99:140–148, 2006[Abstract/Free Full Text]

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This Article
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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
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