Skip to main content
SpringerLink
Log in

Enhanced Platelet Sensitivity to IGF-1 in Patients with Type 2 Diabetes Mellitus

  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Diabetes mellitus is characterized by increased platelet activation which is determined by many factors including changes in the expression of membrane proteins. The aim of this study was to investigate the sensitivity of human platelets to the insulin-like growth factor (IGF) system in patients with poorly controlled type 2 diabetes mellitus (DM2). Ligand binding was analyzed using 125I-labelled IGF-1 and insulin, and relative expression of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) was evaluated by Western blotting. Platelet aggregation in the presence of IGF-1 was studied by the plate aggregometry assay. We found that platelets from DM2 patients exhibited significantly higher IGF-1 binding and up regulation of IGF-1R expression in comparison with healthy individuals. Both insulin binding and IR expression were lower in the DM2 group, but the differences with the healthy control were statistically insignificant. The potentiating effect of IGF-1 on the thrombin-induced activation of platelets was detected in both groups but was significantly more pronounced in the DM2 patients. The initial rate of platelet activation in the presence of IGF-1 positively correlated with the concentration of glycated hemoglobin. Platelets isolated from DM2 patients displayed elevated expression of the IGF-1R subunits, which might have contributed to the higher sensitivity of these cells to IGF-1 in thrombin-initiated aggregation by increasing the rate of platelet activation. However, further experiments are needed to investigate the role of IGF-1 in thrombotic complications that usually accompany diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

DM2:

type 2 diabetes mellitus

HbA1c:

glycated hemoglobin

IGF:

insulin-like growth factor

IGF-1R:

insulin like growth factor 1 receptor

IR:

insulin receptor

References

  1. Tripodi, A., Branchi, A., Chantarangkul, V., Clerici, M., Merati, G., Artoni, A., and Mannucci, P. M. (2011) Hypercoagulability in patients with type 2 diabetes mellitus detected by a thrombin generation assay, J. Thromb. Thrombolysis, 31, 165–172.

    Article  CAS  Google Scholar 

  2. Carr, M. E. (2001) Diabetes mellitus. A hypercoagulable state, J. Diabetes Complications, 15, 44–54.

    Article  CAS  Google Scholar 

  3. Vazzana, N., Ranalli, P., Cuccurullo, C., and Davi, G. (2012) Diabetes mellitus and thrombosis, Thromb. Res., 129, 371–377.

    Article  CAS  Google Scholar 

  4. Dunn, E. J., Ariens, R. A., and Grant, P. J. (2005) The influence of type 2 diabetes on fibrin structure and function, Diabetologia, 48, 1198–1206.

    Article  CAS  Google Scholar 

  5. Dunn, E. J., Philippou, H., Ariens, R. A., and Grant, P. J. (2006) Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus, Diabetologia, 49, 1071–1080.

    Article  CAS  Google Scholar 

  6. Dunn, E. J., and Ariens, R. A. (2004) Fibrinogen and fibrin clot structure in diabetes, Herz, 29, 470–479.

    Article  Google Scholar 

  7. Kim, J. H., Bae, H. Y., and Kim, S. Y. (2013) Clinical marker of platelet hyperreactivity in diabetes mellitus, Diabetes Metab. J., 37, 423–428.

    Article  Google Scholar 

  8. Pomero, F., Di Minno, M. N. D., Fenoglio, L., Gianni, M., Ageno, W., and Dentali, F. (2015) Is diabetes a hypercoagu-lable state? A critical appraisal, Acta Diabetol., 52, 1007–1016.

    Article  CAS  Google Scholar 

  9. Kakouros, N., Rade, J. J., Kourliouros, A., and Resar, J. R. (2011) Platelet function in patients with diabetes mellitus: from a theoretical to a practical perspective, Int. J. Endocrinol., 2011, 742719.

    Article  Google Scholar 

  10. Hu, L., Chang, L., Zhang, Y., Zhai, L., Zhang, S., Qi, Z., Yan, H., Yan, Y., Luo, X., Zhang, S., Wang, Y., Kunapuli, S. P., Ye. H., and Ding, Z. (2017) Platelets express activated P2Y12 receptor in patients with diabetes mellitus, Circulation, 136, 817–833.

    Article  CAS  Google Scholar 

  11. Di Minno, M. N. D., Lupoli, R., Palmieri, N. M., Russolillo, A., Buonauro, A., and Di Minno, G. (2012) Aspirin resistance, platelet turnover, and diabetic angiopathy: a 2011 update, Thromb. Res., 129, 341–344.

    Article  Google Scholar 

  12. Randriamboavonjy, V., and Fleming, I. (2009) Insulin, insulin resistance, and platelet signaling in diabetes, Diab. Care, 32, 528–530.

    Article  CAS  Google Scholar 

  13. Ferreiro, J. L., Gomez-Hospital, J. A., and Angiolillo, D. J. (2010) Platelet abnormalities in diabetes mellitus, Diab. Vasc. Dis. Res., 7, 251–259.

    Article  Google Scholar 

  14. Annunziata, M., Granata, R., and Ghigo, E. (2011) The IGF system, Acta Diabetol., 48, 1–9.

    Article  CAS  Google Scholar 

  15. Aghdam, S. Y., Eming, S. A., Willenborg, S., Neuhaus, B., Niessen, C. M., Partridge, L., Krieg, T., and Bruning, J. C. (2012) Vascular endothelial insulin/IGF-1 signaling controls skin wound vascularization, Biochem. Biophys. Res. Commun., 421, 197–202.

    Article  CAS  Google Scholar 

  16. Hunter, R. W., and Hers, I. (2009) Insulin/IGF-1 hybrid receptor expression on human platelets: consequences for the effect of insulin on platelet function, J. Thromb. Haemost., 7, 2123–2130.

    Article  CAS  Google Scholar 

  17. Andersen, M., Norgaard-Pedersen, D., Brandt, J., Pettersson, I., and Slaaby, R. (2017) IGF1 and IGF2 specificities to the two insulin receptor isoforms are determined by insulin receptor amino acid 718, PLoS One, 12, e0178885.

    Article  Google Scholar 

  18. Kim, S., Garcia, A., Jackson, S. P., and Kunapuli, S. P. (2007) Insulin-like growth factor-1 regulates platelet activation through PI3-Kα isoform, Blood, 110, 4206–4213.

    Article  CAS  Google Scholar 

  19. Hers, I. (2007) Insulin-like growth factor-1 potentiates platelet activation via the IRS-PI3Kα pathway, Blood, 110, 4243–4252.

    Article  CAS  Google Scholar 

  20. Moore, S. F., Williams, C. M., Brown, E., Blair, T. A., Harper, M. T., Coward, R. J., Poole, A. W., and Hers, I. (2015) Loss of the insulin receptor in murine megakaryo-cytes/platelets causes thrombocytosis and alterations in IGF signaling, Cardiovasc. Res., 107, 9–19.

    Article  CAS  Google Scholar 

  21. Stolla, M. C., Li, D., Lu, L., and Woulfe, D. S. (2013) Enhanced platelet activity and thrombosis in a murine model of type I diabetes are partially insulin-like growth factor 1-dependent and phosphoinositide 3-kinase-dependent, J. Thromb. Haemost., 11, 919–929.

    Article  CAS  Google Scholar 

  22. Hunter, W. M., and Greenwood, F. C. (1963) Preparation of iodine-131 labelled human growth hormone of high specific activity, Biochem. J., 89, 114–123.

    Article  Google Scholar 

  23. Laemmli, U. K. (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4, Nature, 227, 680–685.

    Article  CAS  Google Scholar 

  24. Bednar, B., Condra, C., Gould, R. J., and Connolly, T. M. (1995) Platelet aggregation monitored in a 96 well microplate reader is useful for evaluation of platelet agonists and antagonists, Thromb. Res., 77, 453–463.

    Article  CAS  Google Scholar 

  25. Motani, A. S., Anggard, E. E., and Ferns, G. A. A. (1996) Recombinant insulin-like growth factor-1 modulates aggregation in human platelets via extracellular calcium, Life Sci., 58, 269–274.

    Article  Google Scholar 

  26. Blair, P., and Flaumenhaft, R. (2009) Platelet α-granules: basic biology and clinical correlates, Blood Rev., 23, 177–189.

    Article  CAS  Google Scholar 

  27. Taylor, V. L., and Spencer, E. M. (2001) Characterization of insulin-like growth factor-binding protein-3 binding to a novel receptor on human platelet membranes, J. Endocrinol., 168, 307–315.

    Article  CAS  Google Scholar 

  28. Simic, D., Bogdan, N., Teng, F., and Otieno, M. (2017) Blocking α5β1 integrin attenuates sCD40L-mediated platelet activation, Clin. Appl. Thromb. Hemost., 23, 607–614.

    Article  CAS  Google Scholar 

  29. Campbell, P. G., Durham, S. K., Hayes, J. D., Suwanichkul, A., and Powell, D. R. (1999) Insulin-like growth factor-binding protein-3 binds fibrinogen and fibrin, J. Biol. Chem., 274, 30215–30221.

    Article  CAS  Google Scholar 

  30. Gligorijevic, N., and Nedic, O. (2016) Interaction between fibrinogen and insulin-like growth factor-binding protein-1 in human plasma under physiological conditions, Biochemistry (Moscow), 81, 135–140.

    Article  CAS  Google Scholar 

  31. Udvardy, M., Pfliegler, G., and Rak, K. (1985) Platelet insulin receptor determination in non-insulin dependent diabetes mellitus, Experimentia, 41, 422–423.

    Article  CAS  Google Scholar 

  32. Boucher, J., Kleinridders, A., and Khan, R. (2014) Insulin receptor signaling in normal and insulin-resistant states, Cold Spring Harb. Perspect. Biol., 6, a009191.

    Article  Google Scholar 

  33. Vestergaard, P. F., Hansen, M., Frystyk, J., Espelund, U., Christiansen, J. S., Jorgensen, J. O., and Fisker, S. (2013) Serum levels of bioactive IGF1 and physiological markers of ageing in healthy adults, Eur. J. Endocrinol., 170, 229–236.

    Article  Google Scholar 

  34. Wilcox, G. (2005) Insulin and insulin resistance, Clin. Biochem. Rev., 26, 19–39.

    PubMed  PubMed Central  Google Scholar 

  35. Benyoucef, S., Katharina, H., Surinya, K. H., Hadaschik, D., and Siddle, K. (2007) Characterization of insulin/IGF hybrid receptors: contributions of the insulin receptor L2 and Fn1 domains and the alternatively spliced exon 11 sequence to ligand binding and receptor activation, Biochem. J., 403, 603–613.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the Ministry of Education, Science, and Technological Development of the Republic of Serbia (grant no. 173042).

Author information

Authors and Affiliations

  1. Institute for the Application of Nuclear Energy (INEP), University of Belgrade, 11080, Belgrade, Serbia

    N. Gligorijevic, D. Robajac & O. Nedic

Authors
  1. N. Gligorijevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Robajac
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. O. Nedic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. Gligorijevic.

Ethics declarations

Conflict of interest. The authors declare no conflict of interest in financial or any other area.

Compliance with ethical standards. This study was approved by the Ethical Committee of the Institute for the Application of Nuclear Energy (INEP). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Additional information

Published in Russian in Biokhimiya, 2019, Vol. 84, No. 10, pp. 1511–1518.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gligorijevic, N., Robajac, D. & Nedic, O. Enhanced Platelet Sensitivity to IGF-1 in Patients with Type 2 Diabetes Mellitus. Biochemistry Moscow 84, 1213–1219 (2019). https://doi.org/10.1134/S0006297919100109

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297919100109

Keywords

Search

Navigation