Diabetic cardiomyopathy: effects of fenofibrate and metformin in an experimental model – the Zucker diabetic rat

Fabien Forcheron,Michel Beylot,Nicolas Gadot,Pauline Abdallah,Alexandra Basset,Peggy Del Carmine

doi:10.1186/1475-2840-8-16

Fabien Forcheron, Michel Beylot + Show 4 more

Open Access

https://doi.org/10.1186/1475-2840-8-16

Copy DOI

Abstract

BackgroundDiabetic cardiomyopathy (DCM) contributes to cardiac failure in diabetic patients. It is characterized by excessive lipids accumulation, with increased triacylglycerol (TAG) stores, and fibrosis in left ventricle (LV). The mechanisms responsible are incompletely known and no specific treatment is presently defined. We evaluated the possible usefulness of two molecules promoting lipid oxidation, fenofibrate and metformin, in an experimental model of DCM, the Zucker diabetic rat (ZDF).MethodsZDF and controls (C) rats were studied at 7, 14 and 21 weeks. After an initial study at 7 weeks, ZDF rats received no treatment, metformin or fenofibrate until final studies (at 14 or 21 weeks). C rats received no treatment. Each study comprised measurements of metabolic parameters (plasma glucose, TAG, insulin levels) and sampling of heart for histology and measurements of TAG content and relevant mRNA concentration.ResultsZDF rats were insulin-resistant at 7 weeks, type 2 diabetic at 14 weeks and diabetic with insulin deficiency at 21 weeks. Their plasma TAG levels were increased. ZDF rats had at 7 weeks an increased LV TAG content with some fibrosis. LV TAG content increased in untreated ZDF rats at 14 and 21 weeks and was always higher than in C. Fibrosis increased also moderately in untreated ZDF rats. Metformin and fenofibrate decreased plasma TAG concentrations. LV TAG content was decreased by metformin (14 and 21 weeks) and by fenofibrate (14 weeks). Fibrosis was reduced by fenofibrate only and was increased by metformin. Among the mRNA measured, fenofibrate increased Acyl-CoA Oxidase mRNA level, metformin decreased Acyl-CoA Synthase and increased AdipoR1 and pro-inflammatory mRNA levels.ConclusionFenofibrate had favourable actions on DCM. Metformin had beneficial effect on TAG content but not on fibrosis. PPARα agonists could be useful for the prevention and treatment of DCM.

Highlights

Diabetic cardiomyopathy (DCM) contributes to cardiac failure in diabetic patients
Fatty acid oxidation is increased in diabetic heart [10,19] but the rise in fatty acid uptake could be still more important resulting in accumulation of lipids [20]
The rise in uptake could result from increased availability of plasma substrates (TAG and non esterified fatty acids (NEFA)) during diabetes, increased expression of molecules involved in fatty acid uptake [10,21] or an association of both

Summary

Introduction

Diabetic cardiomyopathy (DCM) contributes to cardiac failure in diabetic patients It is characterized by excessive lipids accumulation, with increased triacylglycerol (TAG) stores, and fibrosis in left ventricle (LV). Mechanisms responsible for DCM are still poorly understood but abnormalities in lipid metabolism with increased accumulation in left ventricle (LV) of intra-cellular lipids, demonstrated by the increase in triglycerides (TAG) content [6,7], play an important role [3,8,9,10,11,12,13] These abnormalities in lipid metabolism could contribute in particular to the apoptosis of cardiomyocytes and the development of fibrosis [3,8,10]. The rise in uptake could result from increased availability of plasma substrates (TAG and non esterified fatty acids (NEFA)) during diabetes, increased expression of molecules involved in fatty acid uptake [10,21] or an association of both

Methods

Results

Conclusion