title: Association of low GLP-1 with oxidative stress is related to cardiac disease and outcome in patients with type 2 diabetes mellitus: a pilot study.
abstract: Oxidative stress (OS) contributes to cardiovascular damage in type 2 diabetes mellitus (T2DM). The peptide glucagon-like peptide-1 (GLP-1) inhibits OS and exerts cardiovascular protective actions. Our aim was to investigate whether cardiac remodeling (CR) and cardiovascular events (CVE) are associated with circulating GLP-1 and biomarkers of OS in T2DM patients. We also studied GLP-1 antioxidant effects in a model of cardiomyocyte lipotoxicity. We examined 72 T2DM patients with no coronary or valve heart disease and 14 nondiabetic subjects. A median of 6 years follow-up information was obtained in 60 patients. Circulating GLP-1, dipeptidyl peptidase-4 activity, and biomarkers of OS were quantified. In T2DM patients, circulating GLP-1 decreased and OS biomarkers increased, compared with nondiabetics. Plasma GLP-1 was inversely correlated with serum 3-nitrotyrosine in T2DM patients. Patients showing high circulating 3-nitrotyrosine and low GLP-1 levels exhibited CR and higher risk for CVE, compared to the remaining patients. In palmitate-stimulated HL-1 cardiomyocytes, GLP-1 reduced cytosolic and mitochondrial oxidative stress, increased mitochondrial ATP synthase expression, partially restored mitochondrial membrane permeability and cytochrome c oxidase activity, blunted leakage of creatine to the extracellular medium, and inhibited oxidative damage in total and mitochondrial DNA. These results suggest that T2DM patients with reduced circulating GLP-1 and exacerbated OS may exhibit CR and be at higher risk for CVE. In addition, GLP-1 exerts antioxidant effects in HL-1 palmitate-overloaded cardiomyocytes. It is proposed that therapies aimed to increase GLP-1 may counteract OS, protect from CR, and prevent CVE in patients with T2DM.
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain. Electronic address: sravassa@unav.es.
authors.forename: Susana
authors.initials: S
authors.lastname: Ravassa
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Beaumont
authors.affiliation: Department of Internal Medicine, University of Navarra Clinic, University of Navarra, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Huerta
authors.affiliation: Department of Cardiology and Cardiac Surgery, University of Navarra Clinic, University of Navarra. Pamplona, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Barba
authors.affiliation: Department of Cardiology and Cardiac Surgery, University of Navarra Clinic, University of Navarra. Pamplona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Coma-Canella
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Arantxa
authors.initials: A
authors.lastname: González
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: López
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain; Department of Cardiology and Cardiac Surgery, University of Navarra Clinic, University of Navarra. Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D064752:Atrial Remodeling; D006332:Cardiomegaly / Q000097:blood* / Q000209:etiology / Q000503:physiopathology; D002319:Cardiovascular System / Q000378:metabolism / Q000503:physiopathology; D016022:Case-Control Studies; D002460:Cell Line; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010865:Pilot Projects; D012189:Retrospective Studies; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood; D020257:Ventricular Remodeling
chemical_list: D000975:Antioxidants; D019308:Palmitic Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D003849:Deoxyguanosine
keywords: Cardiac remodeling; Cardiovascular events; GLP-1; Oxidative stress; Type 2 diabetes mellitus