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

Abstract

Monji A, Mitsui T, Bando YK, Aoyama M, Shigeta T, Murohara T. Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes. Am J Physiol Heart Circ Physiol 305: H295-H304, 2013. First published May 24, 2013 doi:10.1152/ajpheart.00990.2012.-Glucagonlike 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 Ϫ1 ·day Ϫ1 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.

The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver Disease

“…48) GLP-1, a glucose-dependent incretin, exerts its beneficial effects by increasing fatty acid oxidation, improving insulin resistance and decreasing lipogenesis. 49,50) Liraglutide, as a GLP-1 analogue, is approved by the U.S. Food and Drug Administration and marketed since 2010 for the treatment of type 2 diabetes due to its glucose-lowering effect. 51) Liraglutide has also been reported to reduce hepatic steatosis and endoplasmic reticulum (ER) stress in mice fed with a high fat diet.…”

Honokiol protects against renal ischemia/reperfusion injury via the suppression of oxidative stress, iNOS, inflammation and STAT3 in rats

“…The Wistar rats were used to perform the renal ischemia/reperfusion surgery, as described previously (24,25). Briefly, the rats were anesthetized by intraperitoneal (i.p.)…”

Glucagon-like peptide-1 receptor agonists inhibit hepatic stellate cell activation by blocking the p38 MAPK signaling pathway

“…GLP-1Rs have been detected in the heart, liver, and thyroid, where they may play many important physiological roles (Gupta et al, 2010;Gier et al, 2012;Monji et al, 2013;Lockie, 2013). In addition to regulating insulin secretion in relation to blood sugar levels, GLP-1 has also been shown to play protective and anti-fibrotic roles in the cardiovascular system.…”