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

• Published in: Free radical biology & medicine 2015-04, Vol.81, p.1-12
• Main Authors: Ravassa, Susana, Beaumont, Javier, Huerta, Ana, Barba, Joaquín, Coma-Canella, Isabel, González, Arantxa, López, Begoña, Díez, Javier
• Format: Article
• Language: English
• Subjects: Aged; Animals; Antioxidants - metabolism; Antioxidants - pharmacology; Atrial Remodeling; Cardiac remodeling; Cardiomegaly - blood; Cardiomegaly - etiology; Cardiomegaly - physiopathology; Cardiovascular events; Cardiovascular System - metabolism; Cardiovascular System - physiopathology; Case-Control Studies; Cell Line; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - blood; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - physiopathology; Dipeptidyl Peptidase 4 - blood; Female; GLP-1; Glucagon-Like Peptide 1 - blood; Glucagon-Like Peptide 1 - pharmacology; Humans; Male; Mice; Middle Aged; Mitochondria - drug effects; Mitochondria - metabolism; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Oxidative Stress; Palmitic Acid - antagonists & inhibitors; Palmitic Acid - pharmacology; Pilot Projects; Retrospective Studies; Type 2 diabetes mellitus; Tyrosine - analogs & derivatives; Tyrosine - blood; Ventricular Remodeling
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2015.01.002

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. •Oxidative stress is an important contributor to cardiac damage in type 2 diabetes mellitus (T2DM).•GLP-1 prevents cardiac damage through antioxidant actions.•Low GLP-1 and high nitrotyrosine circulating levels associate with cardiac remodeling and occurrence of cardiovascular events in T2DM patients.•GLP-1 reduces palmitate-induced oxidative damage in HL-1 cardiomyocytes.