Incretin Treatment and Atherosclerotic Plaque Stability: Role of Adiponectin/Appl1 Signaling Pathway

• Published in: Journal of diabetes and its complications 2017-02, Vol.31 (2), p.295-303
• Main Authors: Barbieri, Michelangela, Marfella, Raffaele, Esposito, Antonietta, Rizzo, Maria Rosaria, Angellotti, Edith, Mauro, Ciro, Siniscalchi, Mario, Chirico, Fabio, Caiazzo, Pasquale, Furbatto, Fulvio, Bellis, Alessandro, D'Onofrio, Nunzia, Vitiello, Milena, Ferraraccio, Franca, Paolisso, Giuseppe, Balestrieri, Maria Luisa
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - agonists; Adaptor Proteins, Signal Transducing - metabolism; Adiponectin; Adiponectin - metabolism; Aged; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Antioxidants - pharmacology; Antioxidants - therapeutic use; APPL1; Atherosclerosis; Blood pressure; Cardiovascular disease; Carotid Stenosis - complications; Carotid Stenosis - epidemiology; Carotid Stenosis - prevention & control; Carotid Stenosis - surgery; Cells, Cultured; Cholesterol; Coronary vessels; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetic Angiopathies - epidemiology; Diabetic Angiopathies - pathology; Diabetic Angiopathies - prevention & control; Diabetic Angiopathies - surgery; Endarterectomy, Carotid; Endocrinology & Metabolism; Endothelium, Vascular - drug effects; Endothelium, Vascular - immunology; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Family medical history; Female; Glucagon-Like Peptide 1 - metabolism; Humans; Hyperglycemia; Incretins; Incretins - pharmacology; Incretins - therapeutic use; Inflammation; Insulin resistance; Italy - epidemiology; Male; Metabolism; Oxidative Stress - drug effects; Patients; Plaque stability; Plaque, Atherosclerotic - complications; Plaque, Atherosclerotic - epidemiology; Plaque, Atherosclerotic - pathology; Plaque, Atherosclerotic - prevention & control; Plasma; Proteins; Questionnaires; Risk Factors; Secondary Prevention; Signal Transduction - drug effects; Studies; Substance abuse treatment; Triglycerides; Type 2 diabetes
• ISSN: 1056-8727; 1873-460X
• DOI: 10.1016/j.jdiacomp.2016.10.001

Abstract 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-α (TNF-α), vimentin, and matrix metalloproteinase-9 (MMP-9) levels. Among T2DM subjects, current incretin-users presented higher APPL1 and adiponectin content compared with never incretin-users. 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.