MicroRNA profiling in sera of patients with type 2 diabetes mellitus reveals an upregulation of miR-31 expression in subjects with microvascular complications

Guido Sebastiani, Laura Nigi, Isabella Spagnuolo, Elena Morganti, Cecilia Fondelli, Francesco Dotta

Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.

DOI: 10.4236/jbise.2013.65A009                

Abstract

Type 2 diabetes (T2D) is a metabolic disease characterized by chronic hyperglycaemia due to a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. Chronic hyperglycemia is associated with long-term micro- and macrovascular complications leading to dysfunction of several organs including kidney, heart, eye and nervous system. Early identification of chronic diabetic complications is necessary in order to prevent dysfunction and failure of these different organs. MicroRNAs (or miRNAs) are small endogenous RNAs, which negatively regulate gene expression. Recently, it has been demonstrated that miRNAs can be secreted by cells, thus being detectable in serum and in other biological fluids. Circulating microRNAs have been proposed as possible biomarkers of several diseases. Here, we performed a miRNAs expression profiling in the sera of T2D patients with or without vascular complications in order to find specific biomarkers to characterize T2D complications. We analyzed the expression of 384 microRNAs in serum pools from 3 groups of T2D patients: 12 T2D patients without any chronic complications, 12 T2D patients with macrovascular complications and 12 with microvascular complications. We found 223 miRNAs expressed in T2D,224 inT2D with microvascular and221 inT2D with macrovascular complications. Among expressed microRNAs, 45 resulted upregulated and 23 downregulated in microvascular patients sera, while 13 upregulated and 41 downregulated in macrovascular T2D patients compared to those without complications. We focused and validated microRNA miR-31 expression in single sera from each group, which resulted significantly upregulated in patients with microvascular complications and may be indeed related to the presence of microangiopathy. In conclusion, our study has identified miR-31 as a promising biomarker for diabetic microvascular complications; further prospective studies in the clinical setting are however required to establish the real utility of measuring serum circulating levels of this microRNA.

Keywords

Type 2 Diabetes; microRNAs; Diabetic Chronic Complications; Microangiopathy

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	ADA Statement (2013) Diagnosis and classification of diabetes mellitus. Diabetes Care, 36, 67-74. doi:10.2337/dc13-S067
[2]	Kahn, S.E. (2003) The relative contributions of insulin resistance and beta cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia, 46, 193-194.
[3]	Steppel, J.H. and Horton, E.S. (2004) Beta-cell failure in the pathogenesis of type 2 diabetes mellitus. Current Diabetes Report, 4, 169-175. doi:10.1007/s11892-004-0019-3
[4]	Fong, D.S., Aiello, L.P., Ferris, F.L., et al. (2004) Diabetic retinopathy. Diabetes Care, 27, 2540-2553. doi:10.2337/diacare.27.10.2540
[5]	Gross, J.L., de Azevedo, M.J., Silveiro, S.P., et al. (2005) Diabetic nephropathy: Diagnosis, prevention and treatment. Diabetes Care, 28, 164-176. doi:10.2337/diacare.28.1.164
[6]	Zachary, T. and Bloomgarden, M.D. (2004) Diabetes complications. Diabetes Care, 27, 1506-1514. doi:10.2337/diacare.27.6.1506
[7]	Kim, V.N. and Nam, J.W. (2006) Genomics of microRNAs. Trends in Genetics, 22, 165-173. doi:10.1016/j.tig.2006.01.003
[8]	Sebastiani, G., Vendrame, F. and Dotta, F. (2011) MicroRNAs as new tools for exploring type-1 Diabetes: Relevance for immunomodulation and transplantation therapy. Transplntation Proceedings, 43, 330-332. doi:10.1016/j.transproceed.2010.09.104
[9]	Mitchell, P.S., Patrik, K.M., Kroh, E.M., et al. (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proceedings National Academy of Science of the United States of America, 105, 1051310518. doi:10.1073/pnas.0804549105
[10]	Adachi, T., Nakanishi, M., Otsuka, J., et al. (2010) Plasma microRNA 499 as a biomarker of acute myocardial infarction. Clinical Chemistry, 56, 1733-1741. doi:10.1373/clinchem.2010.144121
[11]	Wang, K., Zhang, S., Marzolf, B., et al. (2009) Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proceedings National Academy of Science of the United States of America, 106, 4402-4407. doi:10.1073/pnas.0813371106
[12]	Zampetaki, A., Kiechl, S., Drozdov, I., et al. (2012) Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circulation Research, 107, 810-817. doi:10.1161/CIRCRESAHA.110.226357
[13]	Kong, L., Zhu, J., Han, W., et al. (2011) Significance of serum microRNA in pre-diabetes and newly diagnosed type 2 diabetes: A clinical study. Acta Diabetologica, 48, 61-69. doi:10.1007/s00592-010-0226-0
[14]	Wang, K., Yuan, Y., Cho, J.H., et al. (2012) Com paring the microRNA spectrum between serum and plasma. PLoS ONE, 7, e14561.
[15]	Kovacs, B., Lumayag, S., Cowan, C., et al. (2011) MicroRNAs in early diabetic retinopathy in streptozotocininduced diabetic rats. Investigative Ophthalmology and Visual Science, 52, 4402-4409. doi:10.1167/iovs.10-6879
[16]	Avogaro, A., Albiero, M., Menegazzo, L., et al. (2011) Endothelial dysfunction in diabetes: the role of reparatory mechanisms. Diabetes Care, 34, 285-290. doi:10.2337/dc11-s239
[17]	Egan, C.G., Lavery, R., Caporali, F., et al. (2008) Genera lised reduction of putative endothelial progenitors and CXCR4 positive peripheral blood cells in type 2 diabetes. Diabetologia, 51, 1296-1305. doi:10.1007/s00125-008-0939-6
[18]	Hasegawa, G., Nakano, K., Sawada, M., et al. (1991) Possible role of tumor-necrosis-factor and interleukin-1 in the development of diabetic nephropathy. Kidney International, 40, 1007-1012. doi:10.1038/ki.1991.308
[19]	Satoh, J., Yagihashi, S. and Toyota, T., (2003) The possible role of tumor necrosis factor-alpha in diabetic polyneuropathy. Experimental Diabesity Research, 4, 65-71. doi:10.1155/EDR.2003.65
[20]	Suarez, Y., Fernandez-Hernando, C., Yu, J., et al. (2008) Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis. Proceedings National Academy of Science of the United States of America, 105, 14082-14087. doi:10.1073/pnas.0804597105