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Free Radic Biol Med. 2015 Apr;81:1-12. doi: 10.1016/j.freeradbiomed.2015.01.002. Epub 2015 Jan 13.

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.

Author information

1
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain. Electronic address: sravassa@unav.es.
2
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
3
Department of Internal Medicine, University of Navarra Clinic, University of Navarra, Pamplona, Spain.
4
Department of Cardiology and Cardiac Surgery, University of Navarra Clinic, University of Navarra. Pamplona, Spain.
5
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.

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.

KEYWORDS:

Cardiac remodeling; Cardiovascular events; GLP-1; Oxidative stress; Type 2 diabetes mellitus

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