Effects of Early Intensive Insulin Therapy on Endothelial Progenitor Cells in Patients with Newly Diagnosed Type 2 Diabetes

Wei Zhang, Hongdong Wang, Fangcen Liu, Xiao Ye, Wenjuan Tang, Pengzi Zhang, Tianwei Gu, Dalong Zhu, Yan Bi, Wei Zhang, Hongdong Wang, Fangcen Liu, Xiao Ye, Wenjuan Tang, Pengzi Zhang, Tianwei Gu, Dalong Zhu, Yan Bi

Abstract

Aim: This study aimed to investigate the alteration of circulating CD34+KDR+CD133+ endothelial progenitor cells (EPCs) in patients with newly diagnosed type 2 diabetes and the mechanism of the effect of early intensive insulin therapy.

Methods: In this study, 36 patients with newly diagnosed type 2 diabetes and 22 control subjects matched by age and gender were enrolled. All of the patients with diabetes received intensive insulin therapy. The number of EPCs was assessed by flow cytometry based on the expression of CD34, CD133, and kinase insert domain-containing receptor (KDR).

Results: Levels of circulating CD34+KDR+CD133+ EPCs were higher in patients with diabetes compared to control subjects and significantly decreased after intensive insulin therapy. Levels of vascular endothelial growth factor (VEGF), a major contributor to EPC mobilization, were significantly higher in patients with diabetes compared to control subjects, and dramatically decreased after insulin therapy. Importantly, VEGF levels correlated with number of EPCs. Moreover, compared with control subjects, pro-inflammatory cytokines and oxidative stress were significantly higher in patients with diabetes and markedly decreased after intensive insulin therapy.

Conclusions: These results showed that type 2 diabetes is associated with an increase of circulating CD34+KDR+CD133+ EPCs at the onset of diabetes, indicating increased compensatory mobilization. Additionally, early intensive insulin therapy exerts a preserving effect on EPC level partly through improving inflammation status and oxidative stress, thereby implying a putative long-term beneficial effect on vascular integrity via suspending excessive EPC exhaustion.

Clinical trial number: NCT03710811.

Keywords: Endothelial progenitor cells; Inflammation; Type 2 diabetes; Vascular endothelial growth factor.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
a Representative identification of circulating CD34+KDR+CD133+ EPCs. After gating lymphocytes and monocytes in the FSC versus SSC morphologic plot, total CD34+ cells were identified and were then examined for expression of CD133 and KDR. b Circulating CD34+KDR+CD133+ EPCs for control subjects and patients with newly diagnosed type 2 diabetes. Data are mean ± standard error. **P < 0.01 vs. control group. ##P < 0.01 vs. T2DM baseline
Fig. 2
Fig. 2
a VEGF levels in control subjects and patients with newly diagnosed type 2 diabetes before and after intensive insulin therapy. Data are mean ± standard error. b Correlation between circulating CD34+KDR+CD133+ EPCs and VEGF levels. **P < 0.01 vs. control group. ##P < 0.01 vs. T2DM baseline

References

    1. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–967. doi: 10.1126/science.275.5302.964.
    1. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348(7):593–600. doi: 10.1056/NEJMoa022287.
    1. Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005;353(10):999–1007. doi: 10.1056/NEJMoa043814.
    1. Hur J, Yoon CH, Kim HS, et al. Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol. 2004;24(2):288–293. doi: 10.1161/01.ATV.0000114236.77009.06.
    1. Friedrich EB, Walenta K, Scharlau J, Nickenig G, Werner N. CD34-/CD133+/VEGFR-2+ endothelial progenitor cell subpopulation with potent vasoregenerative capacities. Circ Res. 2006;98(3):e20–25. doi: 10.1161/01.RES.0000205765.28940.93.
    1. Ye J, Ni P, Kang L, Xu B. Apelin and vascular endothelial growth factor are associated with mobilization of endothelial progenitor cells after acute myocardial infarction. J Biomed Res. 2012;26(6):400–409. doi: 10.7555/JBR.26.20120052.
    1. Moore MA, Hattori K, Heissig B, et al. Mobilization of endothelial and hematopoietic stem and progenitor cells by adenovector-mediated elevation of serum levels of SDF-1, VEGF, and angiopoietin-1. Ann N Y Acad Sci. 2001;938:36–45. doi: 10.1111/j.1749-6632.2001.tb03572.x.
    1. Fadini GP, Pucci L, Vanacore R, et al. Glucose tolerance is negatively associated with circulating progenitor cell levels. Diabetologia. 2007;50(10):2156–2163. doi: 10.1007/s00125-007-0732-y.
    1. Fadini GP, Boscaro E, de Kreutzenberg S, et al. Time course and mechanisms of circulating progenitor cell reduction in the natural history of type 2 diabetes. Diabetes Care. 2010;33(5):1097–1102. doi: 10.2337/dc09-1999.
    1. Tepper OM, Galiano RD, Capla JM, et al. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002;106(22):2781–2786. doi: 10.1161/01.CIR.0000039526.42991.93.
    1. Fadini GP, Sartore S, Albiero M, et al. Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol. 2006;26(9):2140–2146. doi: 10.1161/01.ATV.0000237750.44469.88.
    1. Weng J, Li Y, Xu W, et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008;371(9626):1753–1760. doi: 10.1016/S0140-6736(08)60762-X.
    1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837–53.
    1. American Diabetes Association 2. Classification and diagnosis of diabetes. Diabetes Care. 2017;40(Suppl 1):S11–S24. doi: 10.2337/dc17-S005.
    1. Xuan Y, Sun LH, Liu DM, et al. Positive association between serum levels of bone resorption marker CTX and HbA1c in women with normal glucose tolerance. J Clin Endocrinol Metab. 2015;100(1):274–281. doi: 10.1210/jc.2014-2583.
    1. Stickle D, Turk J. A kinetic mass balance model for 1,5-anhydroglucitol: applications to monitoring of glycemic control. Am J Physiol. 1997;273(4 Pt 1):E821–830.
    1. Isner JM, Asahara T. Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J Clin Investig. 1999;103(9):1231–1236. doi: 10.1172/JCI6889.
    1. Yue WS, Lau KK, Siu CW, et al. Impact of glycemic control on circulating endothelial progenitor cells and arterial stiffness in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2011;10:113. doi: 10.1186/1475-2840-10-113.
    1. Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J. 1999;18(14):3964–3972. doi: 10.1093/emboj/18.14.3964.
    1. Behl T, Kotwani A. Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy. Pharmacol Res. 2015;99:137–148. doi: 10.1016/j.phrs.2015.05.013.
    1. Klettner A, Roider J. Constitutive and oxidative-stress-induced expression of VEGF in the RPE are differently regulated by different mitogen-activated protein kinases. Graefes Arch Clin Exp Ophthalmol. 2009;247(11):1487–1492. doi: 10.1007/s00417-009-1139-x.
    1. Kim YS, Morgan MJ, Choksi S, Liu ZG. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell. 2007;26(5):675–687. doi: 10.1016/j.molcel.2007.04.021.
    1. Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert R, Jacob WA, Fiers W. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem. 1992;267(8):5317–5323. doi: 10.1016/S0021-9258(18)42768-8.
    1. Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440(7086):944–948. doi: 10.1038/nature04634.
    1. Tang W, Tang S, Wang H, Ge Z, Zhu D, Bi Y. Insulin restores UCP3 activity and decreases energy surfeit to alleviate lipotoxicity in skeletal muscle. Int J Mol Med. 2017;40(6):2000–2010.
    1. Fadini GP, Tura A, Pacini G, Avogaro A, de Vigili KS. Reduced circulating stem cells associate with excess fasting and post-load NEFA exposure in healthy adults with normal glucose tolerance. Atherosclerosis. 2017;261:117–123. doi: 10.1016/j.atherosclerosis.2017.03.002.
    1. Fadini GP, Bonora BM, Cappellari R, et al. Acute effects of linagliptin on progenitor cells, monocyte phenotypes, and soluble mediators in type 2 diabetes. J Clin Endocrinol Metab. 2016;101(2):748–756. doi: 10.1210/jc.2015-3716.
    1. Oikonomou D, Kopf S, von Bauer R, et al. Influence of insulin and glargine on outgrowth and number of circulating endothelial progenitor cells in type 2 diabetes patients: a partially double-blind, randomized, three-arm unicenter study. Cardiovasc Diabetol. 2014;13:137. doi: 10.1186/s12933-014-0137-4.
    1. Ai S, He Z, Ding R, et al. Reduced vitamin D receptor on circulating endothelial progenitor cells: a new risk factor of coronary artery diseases. J Atheroscler Thromb. 2018;25(5):410–421. doi: 10.5551/jat.40808.
    1. Lev EI, Singer J, Leshem-Lev D, et al. Effect of intensive glycaemic control on endothelial progenitor cells in patients with long-standing uncontrolled type 2 diabetes. Eur J Prev Cardiol. 2014;21(9):1153–1162. doi: 10.1177/2047487313488300.
    1. Hammer Y, Soudry A, Levi A, et al. Effect of vitamin D on endothelial progenitor cells function. PLoS ONE. 2017;12(5):e0178057. doi: 10.1371/journal.pone.0178057.

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