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

Forcheron F, Basset A, Abdallah P, Del Carmine P, Gadot N, Beylot M - Cardiovasc Diabetol (2009)

Bottom Line: Metformin and fenofibrate decreased plasma TAG concentrations.LV TAG content was decreased by metformin (14 and 21 weeks) and by fenofibrate (14 weeks).Among the mRNA measured, fenofibrate increased Acyl-CoA Oxidase mRNA level, metformin decreased Acyl-CoA Synthase and increased AdipoR1 and pro-inflammatory mRNA levels.

View Article: PubMed Central - HTML - PubMed

Affiliation: EA4173-ERI22 Agressions vasculaires et réponses tissulaires Faculté Rockefeller, UCBLyon1 and INSERM, Lyon, France. fforcheron@yahoo.fr

ABSTRACT

Background: 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). 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).

Methods: ZDF 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.

Results: ZDF 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.

Conclusion: Fenofibrate had favourable actions on DCM. Metformin had beneficial effect on TAG content but not on fibrosis. PPARalpha agonists could be useful for the prevention and treatment of DCM.

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Related in: MedlinePlus

Histological quantification of fibrosis (expressed as per cent of total areas) in control and ZDF rats. ZDF rats were untreated (ZDF) or received fenofibrate (ZDF+F) or metformin (ZDF+M) after the first metabolic investigation at the age of 7 weeks. These parameters were measured only in rats sacrificed for tissue sampling (n = 5 for each group), therefore they were measured at 7 weeks only in a group of control and ZDF rats. * p < 0.05 vs the corresponding control group; € p < 0.05 vs the 7 week value of the group; $ p < 0.05 vs the corresponding untreated ZDF group.
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Figure 2: Histological quantification of fibrosis (expressed as per cent of total areas) in control and ZDF rats. ZDF rats were untreated (ZDF) or received fenofibrate (ZDF+F) or metformin (ZDF+M) after the first metabolic investigation at the age of 7 weeks. These parameters were measured only in rats sacrificed for tissue sampling (n = 5 for each group), therefore they were measured at 7 weeks only in a group of control and ZDF rats. * p < 0.05 vs the corresponding control group; € p < 0.05 vs the 7 week value of the group; $ p < 0.05 vs the corresponding untreated ZDF group.

Mentions: Histological studies showed that collagen deposition (both interstitial and perivascular) was increased (p < 0.05) in 7-week ZDF rats compared to 7-week control rats (figure 2, see additional file 3). Collagen deposition increased moderately with age in control rats (p < 0.05 at 21 weeks). It increased more in untreated ZDF rats with values always higher than in controls (p < 0.05). This fibrosis was reduced in the ZDF group receiving fenofibrate with a significant decrease at 21 weeks (p < 0.05). On the contrary, despite the marked decrease in TAG accumulation, fibrosis was not reduced by metformin and was even increased at 21 weeks (p < 0.05).


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

Forcheron F, Basset A, Abdallah P, Del Carmine P, Gadot N, Beylot M - Cardiovasc Diabetol (2009)

Histological quantification of fibrosis (expressed as per cent of total areas) in control and ZDF rats. ZDF rats were untreated (ZDF) or received fenofibrate (ZDF+F) or metformin (ZDF+M) after the first metabolic investigation at the age of 7 weeks. These parameters were measured only in rats sacrificed for tissue sampling (n = 5 for each group), therefore they were measured at 7 weeks only in a group of control and ZDF rats. * p < 0.05 vs the corresponding control group; € p < 0.05 vs the 7 week value of the group; $ p < 0.05 vs the corresponding untreated ZDF group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2664796&req=5

Figure 2: Histological quantification of fibrosis (expressed as per cent of total areas) in control and ZDF rats. ZDF rats were untreated (ZDF) or received fenofibrate (ZDF+F) or metformin (ZDF+M) after the first metabolic investigation at the age of 7 weeks. These parameters were measured only in rats sacrificed for tissue sampling (n = 5 for each group), therefore they were measured at 7 weeks only in a group of control and ZDF rats. * p < 0.05 vs the corresponding control group; € p < 0.05 vs the 7 week value of the group; $ p < 0.05 vs the corresponding untreated ZDF group.
Mentions: Histological studies showed that collagen deposition (both interstitial and perivascular) was increased (p < 0.05) in 7-week ZDF rats compared to 7-week control rats (figure 2, see additional file 3). Collagen deposition increased moderately with age in control rats (p < 0.05 at 21 weeks). It increased more in untreated ZDF rats with values always higher than in controls (p < 0.05). This fibrosis was reduced in the ZDF group receiving fenofibrate with a significant decrease at 21 weeks (p < 0.05). On the contrary, despite the marked decrease in TAG accumulation, fibrosis was not reduced by metformin and was even increased at 21 weeks (p < 0.05).

Bottom Line: Metformin and fenofibrate decreased plasma TAG concentrations.LV TAG content was decreased by metformin (14 and 21 weeks) and by fenofibrate (14 weeks).Among the mRNA measured, fenofibrate increased Acyl-CoA Oxidase mRNA level, metformin decreased Acyl-CoA Synthase and increased AdipoR1 and pro-inflammatory mRNA levels.

View Article: PubMed Central - HTML - PubMed

Affiliation: EA4173-ERI22 Agressions vasculaires et réponses tissulaires Faculté Rockefeller, UCBLyon1 and INSERM, Lyon, France. fforcheron@yahoo.fr

ABSTRACT

Background: 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). 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).

Methods: ZDF 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.

Results: ZDF 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.

Conclusion: Fenofibrate had favourable actions on DCM. Metformin had beneficial effect on TAG content but not on fibrosis. PPARalpha agonists could be useful for the prevention and treatment of DCM.

Show MeSH
Related in: MedlinePlus