title: Incretin treatment and atherosclerotic plaque stability: Role of adiponectin/APPL1 signaling pathway.
abstract: OBJECTIVE
  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 (25mM) and GLP-1 (100nM) 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.
authors: Department of Medical, Surgical, Neurological, Aging and Metabolic Sciences, Second University of Naples, Piazza Miraglia 2, 80138, Naples, Italy. Electronic address: michelangela.barbieri@unina2.it.
authors: Michelangela
authors: M
authors: Barbieri
authors: Department of Medical, Surgical, Neurological, Aging and Metabolic Sciences, Second University of Naples, Piazza Miraglia 2, 80138, Naples, Italy.
authors: Raffaele
authors: R
authors: Marfella
authors: Department of Medical, Surgical, Neurological, Aging and Metabolic Sciences, Second University of Naples, Piazza Miraglia 2, 80138, Naples, Italy.
authors: Antonietta
authors: A
authors: Esposito
authors: Department of Medical, Surgical, Neurological, Aging and Metabolic Sciences, Second University of Naples, Piazza Miraglia 2, 80138, Naples, Italy.
authors: Maria Rosaria
authors: MR
authors: Rizzo
authors: Department of Medical, Surgical, Neurological, Aging and Metabolic Sciences, Second University of Naples, Piazza Miraglia 2, 80138, Naples, Italy.
authors: Edith
authors: E
authors: Angellotti
authors: Department of Cardiology, Cardarelli Hospital, Via Antonio Cardarelli, 9, 80131, Naples, Italy.
authors: Ciro
authors: C
authors: Mauro
authors: Department of Cardiology, Cardarelli Hospital, Via Antonio Cardarelli, 9, 80131, Naples, Italy.
authors: Mario
authors: M
authors: Siniscalchi
authors: Department of Neurosurgery, Cardarelli Hospital, Via Antonio Cardarelli, 9, 80131, Naples, Italy.
authors: Fabio
authors: F
authors: Chirico
authors: Department of Neurosurgery, Cardarelli Hospital, Via Antonio Cardarelli, 9, 80131, Naples, Italy.
authors: Pasquale
authors: P
authors: Caiazzo
authors: Department of Cardiology, Cardarelli Hospital, Via Antonio Cardarelli, 9, 80131, Naples, Italy.
authors: Fulvio
authors: F
authors: Furbatto
authors: Department of Cardiology, Cardarelli Hospital, Via Antonio Cardarelli, 9, 80131, Naples, Italy.
authors: Alessandro
authors: A
authors: Bellis
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, via De Crecchio 7, S. Andrea delle Dame, 80138, Naples, Italy.
authors: Nunzia
authors: N
authors: D'Onofrio
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, via De Crecchio 7, S. Andrea delle Dame, 80138, Naples, Italy.
authors: Milena
authors: M
authors: Vitiello
authors: Department of Clinical, Public and Preventive Medicine Second University of Naples, Largo Madonna delle Grazie n. 1, 80138 Naples, Italy.
authors: Franca
authors: F
authors: Ferraraccio
authors: Department of Medical, Surgical, Neurological, Aging and Metabolic Sciences, Second University of Naples, Piazza Miraglia 2, 80138, Naples, Italy.
authors: Giuseppe
authors: G
authors: Paolisso
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, via De Crecchio 7, S. Andrea delle Dame, 80138, Naples, Italy.
authors: Maria Luisa
authors: ML
authors: Balestrieri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000819:agonists* / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism*; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D016893:Carotid Stenosis / Q000150:complications / Q000453:epidemiology / Q000517:prevention & control / Q000601:surgery; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000453:epidemiology / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D016894:Endarterectomy, Carotid; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006801:Humans; D054795:Incretins / Q000494:pharmacology / Q000627:therapeutic use*; D007558:Italy / Q000453:epidemiology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000150:complications / Q000453:epidemiology / Q000473:pathology / Q000517:prevention & control*; D012307:Risk Factors; D055502:Secondary Prevention; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C499918:ADIPOQ protein, human; C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D054795:Incretins; D052216:Glucagon-Like Peptide 1
keywords: APPL1; Adiponectin; Atherosclerosis; Incretins; Plaque stability; Type 2 diabetes