Abstract 15806: The Glp-1 Analogue Liraglutide Inhibits the Advanced Glycation End-Product Cml and Nox2 in the Diabetic Heart and Brain
Background: Diabetes mellitus type 2 (DM2) can induce heart failure and inflammation of the brain, resulting in cognitive dysfunction. Accumulation of advanced glycation end-products (AGE) in blood vessels plays an important role herein. It has been hypothesized that the AGE N(epsilon)-(carboxymethyl)lysine (CML) can be formed by reactive oxygen species derived from the NADPH-oxidase 2 (NOX2) and vice versa. Glucagon-like peptide 1 (GLP-1) analogues such as liraglutide have cardiovascular protective effects, although the exact underlying mechanisms are unknown. In this study we investigated whether liraglutide has an effect on CML and NOX2 levels in the vasculature of the diabetic heart and brain.
Methods: Diabetes was successfully induced in 15 Sprague Dawley rats via intraperitoneal streptozotocin (STZ, 60 mg/kg bw) injection on day 0. From day 8 to day 28, 7 of these rats received daily subcutaneous liraglutide (200 μg/kg bw) injections. Afterwards, heart and brain sections were collected from all rats, fixed in 4% formaldehyde and embedded in paraffin. Tissue slides from the cerebrum, cerebellum and ventricles and atria of the heart were analyzed immunohistochemically for the presence of CML and NOX2. For both CML and NOX2, the expression levels were scored as the number of positive vessels per mm2. For CML the intensity of the staining was included in the score.
Main results: STZ-induced diabetes caused an increase in CML and NOX2 in the brain and heart compared to healthy control rats. When diabetic rats were treated with liraglutide however, a significant (p<0.05) decrease in CML was observed in cerebrum, cerebellum, ventricle and atria (63%, 64%, 73% and 66% lower scores respectively) compared to untreated diabetic rats. Similarly, NOX2 scores were significantly (p<0.05) decreased as well (80%, 61%, 86% and 80% lower scores respectively for cerebrum, cerebellum, ventricle and atria).
Conclusion: In diabetic rats, liraglutide significantly reduced CML and NOX2 levels in the vasculature of both the heart and the brain. This indicates that its effect on the CML-NOX2 axis might explain the protective function of liraglutide against DM2-induced heart failure and inflammation of the brain.
- © 2013 by American Heart Association, Inc.