Incretin treatment and atherosclerotic plaque stability: Role of adiponectin/APPL1 signaling pathway

Aims: Glucagon like peptide 1 (GLP-1) analogues and dipeptidyl peptidase IV (DPP-4) inhibitors reduce atherosclerosis progression in type 2 diabetes mellitus (T2DM) patients and are associated with morphological and compositional characteristics of stable plaque phenotype. GLP-1 promotes the secretion of adiponectin which exerts anti-inflammatory effects through the adaptor protein PH domain and leucine zipper containing 1 (APPL1). The potential role of APPL1 expression in the evolution of atherosclerotic plaque in TDM2 patients has not previously evaluated. Methods: The effect of incretin therapy in the regulation of adiponectin/APPL1 signaling was evaluated both on carotid plaques of asymptomatic diabetic (n = 71) and non-diabetic patients (n = 52), and through in vitro experiments on endothelial cell (EC). Results: Atherosclerotic plaques of T2DM patients showed lower adiponectin and APPL1 levels compared with non-diabetic patients, along with higher oxidative stress, tumor necrosis factor-alpha (TNF-alpha), vimentin, and matrix metalloproteinase-9 (MMP-9) levels. Among T2DM subjects, current incretin-users presented higher APPL1 and adiponectin content compared with never incretin-user's. Similarly, in vitro observations on endothelial cells co-treated with high-glucose (25 mM) and GLP-1 (100 nM) showed a greater APPL1 protein expression compared with high-glucose treatment alone. Conclusions: Our findings suggest a potential role of adiponectin/APPL1 signaling in mediating the effect of incretin in the prevention of atherosclerosis progression or plaque vulnerability in T2DM. (C) 2017 The Authors. Published by Elsevier Inc.