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Metabolism and Physiology
Session Title: Redox Mechanisms in Cardiovascular Dysfunction and Repair

Abstract 19899: Insulin Treatment Induces Oxidative Stress in the Vascular Wall of Patients With Atherosclerosis Independently of Diabetes or Systemic Insulin Resistance: The Protective Role of DPP-IV Inhibition

Originally publishedCirculation. 2017;136:A19899

    Background: Insulin has protective roles in vascular cells, but its vascular effects in patients with atherosclerosis are unknown. We investigate the direct effects of insulin on human vascular redox signaling, and its' interaction with dipeptidyl peptidase IV inhibitors (DPPIV-i).

    Methods: Saphenous vein (SV) and internal mammary artery (IMA) segements obtained from 72 patients undergoing coronary bypass surgery, were incubated with insulin glargine active metabolite M1 (insulin), insulin degludec (DEG) and human insulin (HI) (1-100nM as stated), +/- pre-incubation with DPPIV-i KR62436 70μM. Vascular superoxide (O2.-) was quantified by lucigenin chemiluminescence, and nitric oxide bioavailability by acetylcholine vasorelaxations ex vivo.

    Results: Insulin increased NADPH-oxidases-derived O2.- in SV and IMA from diabetics and non-diabetics, effects reversed in vessels from patients treated with oral DPPIV-i (A). Pre-incubation of these vessels with DPPIV-i reversed this effect of insulin (B), improving eNOS coupling (C) and NO bioavailability (D). These class effects were replicated using DEG/HI (not shown). While insulin activated vascular MAPK (Erk1&2), DPPIV-i pre-treatment modified insulin signalling, leading to Akt activation (E). DPPIV-i reduced insulin receptor substrate 1 (IRS1) ser307 phosphorylation, improving cellular insulin sensitivity (F).

    Conclusions: We demonstrate for the first time that insulin induces vascular oxidative stress and endothelial dysfunction in human atherosclerosis, independently of systemic insulin resistance. This may partially explain the inability of insulin treatment to improve cardiovascular outcomes in patients with moderately elevated blood glucose. Pre-treatment with DPPIV-i, restores vascular insulin sensitivity modulating the response to insulin. These findings suggest that vascular sensitisation may be crucial for the treatment of diabetics in secondary prevention.

    Footnotes

    Author Disclosures: I. Akoumianakis: Research Grant; Significant; Sanofi-Aventis Deutshcland GmbH. L. Herdman: None. M. Margaritis: None. F. Sanna: None. R. Sayeed: None. G. Krasopoulos: None. N. Tennagels: Employment; Significant; Sanofi-Aventis Deutschland GmbH. P. Wohlfart: Employment; Significant; Sanofi-Aventis Deutschland GmbH. K.M. Channon: Research Grant; Significant; Sanofi-Aventis Deutschland GmbH. C. Antoniades: Research Grant; Significant; Sanofi-Aventis Deutschland GmbH.

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