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

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

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.

Publication types

  • Clinical Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Aged
  • Animals
  • Antioxidants / metabolism*
  • Antioxidants / pharmacology
  • Atrial Remodeling
  • Cardiomegaly / blood*
  • Cardiomegaly / etiology
  • Cardiomegaly / physiopathology
  • 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
  • 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
  • Tyrosine / analogs & derivatives
  • Tyrosine / blood
  • Ventricular Remodeling

Substances

  • Antioxidants
  • Palmitic Acid
  • 3-nitrotyrosine
  • Tyrosine
  • 8-Hydroxy-2'-Deoxyguanosine
  • Glucagon-Like Peptide 1
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Deoxyguanosine