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Vascular redox state: The role of insulin treatment and of insulin sensitizers

Edited by Dimitris Tousoulis

Diabetes and the Heart
Sports Cardiology


Diabetes mellitus (DM) is a major risk factor for cardiovascular disease causing both microvascular and macrovascular impairment [1, 2]. Despite the abundant data on the beneficial effect of strict glycemic control on microvascular disease [3] the management of macrovascular disease is less well established. The Action to Control Cardiovascular Risk in Diabetes Study (ACCORD) [4], mostly based on insulin treatment, did not confirm that aggressive glycemic control reduces the incidence of macrovascular events. Beyond a possible U-shape association of glycemic control with atherosclerosis progression, insulin resistance and the type of treatment may be implicated in this unexpected finding. Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors) have also been tested for their hypoglycemic control and have recently been found ineffective in reducing cardiovascular events [5].

In light of these observations, Akoumianakis I. et al. recently examined the role of insulin-induced vascular redox dysregulation [6]. From this study we have learnt that in patients with coronary artery disease endogenous insulin status was associated with reduced nitric oxide bioavailability and that in the vasculature exposed to insulin there is activation of NADPH oxidases and uncoupling of endothelial NO synthase leading to reduced bioavailability of endogenous NO. Indeed, insulin drives oxidative atherosclerotic damage in the vessel wall which may explain not only the accelerated atherosclerotic lesions in patients with DM but also the minimum effects of insulin treatment. Downstream, insulin damage may be reversed by insulin sensitization, using DPP-4 inhibitors, and these finding may explain how the combined treatment with DDP-4 inhibitors and insulin can reduce incidence of strokes [7].

Beyond confirming the pathophysiologic mechanism implicated in the redox vascular damage in the presence of insulin resistance, this study also raises several questions that merit further investigation. Firstly, it remains to be answered how redox status in the vasculature is implicated in the different effects of hypoglycemic treatment in the microvascular and macrovascular complications and whether NOX isoenzymes, Rac1 and phosphatidylinositol 3­kinase/Akt are regulated by insulin. The role of Glucagon-like peptide-1 receptor antagonists (GLP-1ra), which have a direct impact on insulin sensitivity and have documented atherosclerosis protection, in the restoration of oxidative vascular damage may provide further insights in the complex interplay between insulin treatment and macrovascular disease status [8].

Despite the vast majority of data concerning DM and atherosclerosis, the underlying pathophysiologic mechanisms driving macrovascular and microvascular complications and the interplay between treatment agents and vascular injury continue to focus research interest and merit clinical attention. 


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  2. Siasos G, Gouliopoulos N, Moschos MM, Oikonomou E, Kollia C, Konsola T, et al. Role of endothelial dysfunction and arterial stiffness in the development of diabetic retinopathy. Diabetes Care 2015; 38: e9-e10. 10.2337/dc14-1741.

  3. 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: 837-53.

  4. Action to Control Cardiovascular Risk in Diabetes Study G, Gerstein HC, Miller ME, Byington RP, Goff DC, Jr., Bigger JT, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-59. 10.1056/NEJMoa0802743.

  5. Zheng SL, Roddick AJ, Aghar-Jaffar R, Shun-Shin MJ, Francis D, Oliver N, et al. Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis. JAMA 2018; 319: 1580-1591. 10.1001/jama.2018.3024.

  6. Akoumianakis I, Badi I, Douglas G, Chuaiphichai S, Herdman L, Akawi N, et al. Insulin-induced vascular redox dysregulation in human atherosclerosis is ameliorated by dipeptidyl peptidase 4 inhibition. Sci Transl Med 2020; 12. 10.1126/scitranslmed.aav8824.

  7. Yen FS, Chiang JH, Pan CW, Lin BJ, Wei JC, Hsu CC. Cardiovascular outcomes of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes on insulin therapy. Diabetes Res Clin Pract 2018; 140: 279-287. 10.1016/j.diabres.2018.04.012.

  8. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Furtado RHM, et al. Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus. Circulation 2019; 139: 2022-2031. 10.1161/CIRCULATIONAHA.118.038868.


The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.