Association of fasting glucagon-like peptide-1 with oxidative stress and subclinical atherosclerosis in type 2 diabetes

AbstractGlucagon-like peptide 1 receptor agonists have shown cardioprotective effects which have been suggested to be mediated through inhibition of oxidative stress. We investigated the effect of treatment with a glucagon-like peptide 1 receptor agonist (liraglutide) on oxidative stress measured as urinary nucleic acid oxidation in persons with type 2 diabetes. Post-hoc analysis of two independent, randomised, placebo-controlled and double-blinded clinical trials. In a cross-over study where persons with type 2 diabetes and microalbuminuria (LIRALBU, n = 32) received liraglutide (1.8 mg/day) or placebo for 12 weeks in random order, separated by 4 weeks of wash-out. In a parallel-grouped study where obese persons with type 2 diabetes (SAFEGUARD, n = 56) received liraglutide (1.8 mg/day), sitagliptin (100 mg/day) or placebo for 12 weeks. Endpoints were changes in the urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG)) and RNA oxidation [8-oxo-7,8-dihydroguanosine (8-oxoGuo)]. In LIRALBU, we observed no significant differences between treatment periods in urinary excretion of 8-oxodG [0.028 (standard error (SE): 0.17] nmol/mmol creatinine, p = 0.87) or of 8-oxoGuo [0.12 (0.12) nmol/mmol creatinine, p = 0.31]. In SAFEGUARD, excretion of 8-oxodG was not changed in the liraglutide group [2.8 (− 8.51; 15.49) %, p = 0.62] but a significant decline was demonstrated in the placebo group [12.6 (− 21.3; 3.1) %, p = 0.02], resulting in a relative increase in the liraglutide group compared to placebo (0.16 nmol/mmol creatinine, SE 0.07, p = 0.02). Treatment with sitagliptin compared to placebo demonstrated no significant difference (0.07 (0.07) nmol/mmol creatinine, p = 0.34). Nor were any significant differences for urinary excretion of 8-oxoGuo liraglutide vs placebo [0.09 (SE: 0.07) nmol/mmol creatinine, p = 0.19] or sitagliptin vs placebo [0.07 (SE: 0.07) nmol/mmol creatinine, p = 0.35] observed. This post-hoc analysis could not demonstrate a beneficial effect of 12 weeks of treatment with liraglutide or sitagliptin on oxidatively generated modifications of nucleic acid in persons with type 2 diabetes.

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4324Effects of the glucagon like peptide-1 receptor agonist on arterial stiffness, LV myocardial deformation and oxidative stress in newly diagnosed type 2 diabetes after 6-month treatment

European Heart Journal ◽

10.1093/eurheartj/ehy563.4324 ◽

2018 ◽

Vol 39 (suppl_1) ◽

Author(s):

I Ikonomidis ◽

G Pavlidis ◽

V Lambadiari ◽

F Kousathana ◽

H Triantafyllidi ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Arterial Stiffness ◽

Receptor Agonist ◽

Myocardial Deformation ◽

Newly Diagnosed ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

And Oxidative Stress

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Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00990.2012 ◽

2013 ◽

Vol 305 (3) ◽

pp. H295-H304 ◽

Cited By ~ 59

Author(s):

Akio Monji ◽

Toko Mitsui ◽

Yasuko K. Bando ◽

Morihiko Aoyama ◽

Toshimasa Shigeta ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Diabetic Cardiomyopathy ◽

Cardiac Remodeling ◽

Receptor Activation ◽

Left Ventricular ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

And Oxidative Stress

Glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) is a remedy for type 2 diabetes mellitus (T2DM). Ex-4 ameliorates cardiac dysfunction induced by myocardial infarction in preclinical and clinical settings. However, it remains unclear whether Ex-4 may modulate diabetic cardiomyopathy. We tested the impact of Ex-4 on two types of diabetic cardiomyopathy models, genetic (KK) and acquired T2DM induced by high-fat diet [diet-induced obesity (DIO)], to clarify whether Ex-4 may combat independently of etiology. Each type of mice was divided into Ex-4 (24 nmol·kg−1·day−1 for 40 days; KK-ex4 and DIO-ex4) and vehicle (KK-v and DIO-v) groups. Ex-4 ameliorated systemic and cardiac insulin resistance and dyslipidemia in both T2DM models. T2DM mice exhibited systolic (DIO-v) and diastolic (DIO-v and KK-v) left ventricular dysfunctions, which were restored by Ex-4 with reduction in left ventricular hypertrophy. DIO-v and KK-v exhibited increased myocardial fibrosis and steatosis (lipid accumulation), in which were observed cardiac mitochondrial remodeling and enhanced mitochondrial oxidative damage. Ex-4 treatment reversed these cardiac remodeling and oxidative stress. Cytokine array revealed that Ex-4-sensitive inflammatory cytokines were ICAM-1 and macrophage colony-stimulating factor. Ex-4 ameliorated myocardial oxidative stress via suppression of NADPH oxidase 4 with concomitant elevation of antioxidants (SOD-1 and glutathione peroxidase). In conclusion, GLP-1R agonism reverses cardiac remodeling and dysfunction observed in T2DM via normalizing imbalance of lipid metabolism and related inflammation/oxidative stress.

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