Received: 10 September  2018; Published on-line: 30 December 2018

Influence of local and systemic factors of type 2 diabetes mellitus on the functional status of platelets in patients with diabetic retinopathy and maculopathy

S.Iu. Mogilevskyy1, Dr Sc (Med), Prof.; Yu.O. Panchenko1, Cand Sc (Med); 

S.V. Ziablitsev2, Dr Sc (Med), Prof.; D.S. Ziablitsev3, Cand Sc (Med)

1  Shupik National Medical Academy of Postgraduate Education;  Kyiv (Ukraine) 

2 Bogomolets National Medical University; Kyiv (Ukraine) 

3 Kyiv Medical University; Kyiv (Ukraine) 

E-mail: sergey.mogilevskyy@gmail.com


Background: To date, there is no information on relationships of systemic (activation of the sympathoadrenal and renin- angiotensin systems, SAS and RAS, respectively) and local (inflammation and remodeling of the retinal extracellular matrix and activation of the ocular purinergic system) mechanisms of the development of diabetic maculopathy (DMP) and diabetic macular edema (DME).

Purpose: To identify the influence of systemic and local factors of type 2 diabetes mellitus (DM) on functional status of platelets in DMP and DME under conditions of severe nonproliferative (NPDR) or proliferative diabetic retinopathy (PDR).

Materials and Methods: This study included 42 type 2 DM patients (42 eyes), of which 31 patients (31 eyes) and 11 patients (11 eyes) were found to have DMP in the presence of PDR and severe NPDR, respectively. Platelet aggregation in vitro to ADP, adrenaline, angiotensin 2 (Ang2), platelet activation factor (PAF) and collagen were assessed spectrophotometrically with a Chrono-Log aggregometer.

Results: As platelet hyperreactivity to AN II, adrenalin, PAF and collagen were found in all study patients, activation of the RAS and SAS, and inflammation and remodeling of retinal extracellular matrix are non-specific pathogenetic mechanisms of DMP. Platelet reactivity to ADP was higher in PDR than in severe NPDR (р=0.008), which reflected the features of the pathogenesis of PDR. Development of DME in patients with DMP could be caused by a pronounced dysregulation of purinergic signaling in the eye, activation of the RAS and inflammation, which was reflected by platelet hyperreactivity to ADP, AN II and PAF, whereas a high platelet reactivity to collagen was characteristic of the absence of DME.

Conclusion: The analysis of functional status of platelets allowed elucidating platelet activation mechanisms and identifying major platelet agonists that enabled platelet involvement in progression of DMP and development of DME in type 2 DM patients with proliferative diabetic retinopathy.

Keywords: type 2 diabetes mellitus, diabetic maculopathy, diabetic macular edema, proliferative and non-proliferative diabetic retinopathy


1.Willermain F, Scifp L, Weber C, Caspers L, Perret J, Delporte C. Potential interplay between hyperosmolarity and inflammation on retinal pigment epithelium in pathogenesis of diabetic retinopathy. Int J Mol Sci. 2018 Apr 2;19(4). pii: E1056.
Crossref   Pubmed

2.Scholl S, Augustin A, Loewenstein A, Rizzo S, Kuppermann B. General pathophysiology of macular edema. Eur J Ophthalmol. 2011;21 Suppl 6:S10-9.
Crossref   Pubmed

3.Xu J, Chen LJ, Yu J, Wang HJ, Zhang F, Liu Q, Wu J. Involvement of advanced glycation end products in the pathogenesis of diabetic retinopathy. Cell Physiol Biochem.  2018;48:705–17.
Crossref   Pubmed

4.Urias EA, Urias GA, Monickaraj F, McGuire P, Das A. Novel therapeutic targets in diabetic macular edema: Beyond VEGF. Vision Res. 2017 Oct;139:221-7.
Crossref   Pubmed

5.Sorrentino FS, Matteini S, Bonifazzi C, Sebastiani A, Parmeggiani F. Diabetic retinopathy and endothelin system: microangiopathy versus endothelial dysfunction. Eye (Lond). 2018;32(7):1157-1163. 2018 Jul;32(7):1157-1163.
Crossref   Pubmed

6.Jiang Y, Zhang Q, Steinle JJ. Beta-adrenergic receptor agonist decreases VEGF levels through altered eNOS and PKC signaling in diabetic retina. Growth Factors. 2015;33(3):192-9. doi: 10.3109/08977194.2015.1054990.

7.Kim JH, Kim JH, Yu YS, Cho CS, Kim KW.  Blockade of angiotensin II attenuates VEGF-mediated blood-retinal barrier breakdown in diabetic retinopathy. J Cereb Blood Flow Metab. 2009 Mar;29(3):621-8. doi: 10.1038/jcbfm.2008.154. 

8.Dagher Z, Gerhardinger C, Vaz J, Goodbridge M, Tecilazich F, Lorenzi M.  The increased transforming growth factor-β signaling induced by diabetes protects retinal vessels. Am J Pathol. 2017 Mar;187(3):627-638. doi: 10.1016/j.ajpath.2016.11.007.

9.Somilleda-Ventura SA, Garcia-Rubio YZ, Razo Blanco-Hernandez DM, Lima-Gomez V.[Association between visual improvement after photocoagulation and the use of angiotensin converting enzyme inhibitors in diabetic macular oedema]. Cir Cir. 2016 Jul-Aug;84(4):269-74. doi: 10.1016/j.circir.2015.09.004. Spanish

10.Barinov EF, Sulaieva ON, Gnilorybov AM. [Platelets]. Donetsk: Novyi Mir; 2012. Russian.

11.Ed Rainger G, Chimen M, Harrison MJ, Yates CM, Harrison P, Watson SP, et al. The role of platelets in the recruitment of leukocytes during vascular disease. Platelets. 2015 Aug 18; 26(6): 507–520. doi:  [10.3109/09537104.2015.1064881]

12.Hudz AS, Mogilevskyy SIu, Maksymtsiv ML. Functional status of platelets in type 2 diabetes patients showing no diabetic fundus changes. J. Ophthalmol. (Ukraine). 2017;1:20-4.

13.Hudz AS, Maksymtsiv ML. [Platelets functional state and microcirculation disorders in patients with diabetes mellitus 2 type]. Arkhiv oftalmologii Ukrainy. 2017; 2(8):27-32. Ukrainian.

14.Hudz AS, Maksymtsiv ML, Ziablitsev SV, Mogilevskyy SIu. [Prothrombogenic phenotype of platelets in patients with nonproliferative diabetic retinopathy]. Mizhnarodnyi Endocrinologichnyi Zhurnal. 2018; 14 (2):doi: http://dx.doi.org/10.22141/2224-0721.14.2.2018.130558. Ukrainian.

15.Loukovaara S, Sahanne S, Jalkanen S, Yegutkin GG. Increased intravitreal adenosine 5'-triphosphate, adenosine 5'-diphosphate and adenosine 5'-monophosphate levels in patients with proliferative diabetic retinopathy. Acta Ophthalmol. 2015 Feb;93(1):67-73. doi: 10.1111/aos.12507.

16.Loukovaara S, Sandholm J, Aalto K, Liukkonen J, Jalkanen S, Yegutkin GG. Deregulation of ocular nucleotide homeostasis in patients with diabetic retinopathy. J Mol Med (Berl). 2017 Feb;95(2):193-204. doi: 10.1007/s00109-016-1472-6.

17.Portillo JC, Lopez Corcino Y, Dubyak GR, Kern TS, Matsuyama S, Subauste CS. Ligation of cd40 in human müller cells induces P2X7 receptor-dependent death of retinal endothelial cells. Invest Ophthalmol Vis Sci. 2016 Nov; 57(14): 6278–6286.doi:  [10.1167/iovs.16-20301].

18.Reichenbach A, Bringmann A. Purinergic signaling in retinal degeneration and regeneration. Neuropharmacology. 2016 May;104:194-211. doi: 10.1016/j.neuropharm.2015.05.005.

19.Vindeirinho J, Santiago AR, Cavadas C, Ambrósio AF, Santos PF. The adenosinergic system in diabetic retinopathy. J Diabetes Res. 2016;2016:4270301. doi: 10.1155/2016/4270301. 

20.Galvao J, Elvas F, Martins T, Cordeiro MF, Ambrósio AF, Santiago AR. Adenosine A3 receptor activation is neuroprotective against retinal neurodegeneration. Exp Eye Res.  2015 Nov;140:65-74. doi: 10.1016/j.exer.2015.08.009.

21.Santilli F, Liani R, Di Fulvio P, Formoso G, Simeone P, Tripaldi R, et al. Increased circulating resistin is associated with insulin resistance, oxidative stress and platelet activation in type 2 diabetes mellitus. Thromb Haemost.  2016 Nov 30;116(6):1089-1099.