Research ArticleAtherosclerosis

Insulin-induced vascular redox dysregulation in human atherosclerosis is ameliorated by dipeptidyl peptidase 4 inhibition

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Science Translational Medicine  29 Apr 2020:
Vol. 12, Issue 541, eaav8824
DOI: 10.1126/scitranslmed.aav8824

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From stress to sensitivity

Poor glycemic control drives cardiovascular disease, but aggressive blood glucose lowering does not improve cardiovascular risk. To understand the underlying mechanisms, Akoumianakis et al. studied the relationship between the local redox state of blood vessels and cardiovascular outcomes of patients with coronary atherosclerosis. They found that diseased vessels were insulin resistant and had increased oxidative stress and reduced nitric oxide bioavailability, which could be reversed by treatment with an inhibitor of dipeptidyl peptidase 4 (DPP4). Vascular insulin sensitivity was also restored in mice with atherosclerosis upon treatment with an oral DPP4 inhibitor. Results uncover how DPP4 inhibition induces insulin sensitization in the vascular wall and suggest that cotreatment with insulin may be therapeutic for patients with cardiometabolic disease.

Abstract

Recent clinical trials have revealed that aggressive insulin treatment has a neutral effect on cardiovascular risk in patients with diabetes despite improved glycemic control, which may suggest confounding direct effects of insulin on the human vasculature. We studied 580 patients with coronary atherosclerosis undergoing coronary artery bypass surgery (CABG), finding that high endogenous insulin was associated with reduced nitric oxide (NO) bioavailability ex vivo in vessels obtained during surgery. Ex vivo experiments with human internal mammary arteries and saphenous veins obtained from 94 patients undergoing CABG revealed that both long-acting insulin analogs and human insulin triggered abnormal responses of post–insulin receptor substrate 1 downstream signaling ex vivo, independently of systemic insulin resistance status. These abnormal responses led to reduced NO bioavailability, activation of NADPH oxidases, and uncoupling of endothelial NO synthase. Treatment with an oral dipeptidyl peptidase 4 inhibitor (DPP4i) in vivo or DPP4i administered to vessels ex vivo restored physiological insulin signaling, reversed vascular insulin responses, reduced vascular oxidative stress, and improved endothelial function in humans. The detrimental effects of insulin on vascular redox state and endothelial function as well as the insulin-sensitizing effect of DPP4i were also validated in high-fat diet-fed ApoE−/− mice treated with DPP4i. High plasma DPP4 activity and high insulin were additively related with higher cardiac mortality in patients with coronary atherosclerosis undergoing CABG. These findings may explain the inability of aggressive insulin treatment to improve cardiovascular outcomes, raising the question whether vascular insulin sensitization with DPP4i should precede initiation of insulin treatment and continue as part of a long-term combination therapy.

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