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Cardiac dysfunction in rats with dietary-induced insulin resistance associated with pharmacologically-induced
Stéphane Tanguy1, Marie-Claire Toufektsian, Stéphane Grauzam
1Laboratoire TIMC-IMAG, UMR5525 CNRS, Bâtiment Jean Roget - Domaine de la Merci, Université Joseph Fourier, 38706 La Tronche Cedex, France. Francois.Boucher@ujf-grenoble.fr.
Abstract:
Metabolic disorders such as insulin resistance (IR) and dyslipidemia (DL) might contribute to the induction of diabetic cardiomyopathy (DCM). However, few relevant animal models are currently available for studying the time-course of DCM and evaluating experimental therapeutics. The present study proposes a rodent model of dietary-induced IR combined or not with DL in order to investigate the impact of chronic IR and DL on in vivo myocardial function. Male rats were fed a western-type diet (65% fat; 15% fructose; WD). DL was induced by combining the western diet with i.p. injections of a nonionic surface-active agent (P-407; 0.2 mg/kg, 3 times/wk; P-407). A chow diet was used as control. At 11 and 14 weeks, cardiac function was assessed by echocardiography. Fasting blood glucose increased in WD group while plasma lipids markedly accumulated in P-407 treated rats. Echocardiographic data showed no significant difference in cardiac geometry under basal conditions. Diastolic dysfunction was evidenced at 14 weeks by a significant decrease in E/A ratio in the P-407 group. Moreover, fractional shortening was significantly depressed under dobutamine stress in WD group at 14 weeks whereas systolic dysfunction appeared as early as 11 weeks and worsened at 14 weeks in P-407 animals. Finally, myocardial TNF-alpha tissue content increased in P-407 group. In conclusion, DL exacerbated cardiac lipotoxicity and functional complications associated with IR. This experimental model of combined IR and DL closely mimics the main clinical manifestations of DCM and might therefore constitute a useful tool for the evaluation of pharmacological treatments.
Insights
This study developed a new rodent model for diabetic cardiomyopathy (DCM) by inducing insulin resistance and dyslipidemia. The model effectively mimics human DCM, aiding in therapeutic evaluation.
Area of Science:
- Cardiovascular Research
- Metabolic Disease Research
- Animal Models
Background:
- Diabetic cardiomyopathy (DCM) is linked to metabolic disorders like insulin resistance (IR) and dyslipidemia (DL).
- Existing animal models for studying DCM progression and therapeutic efficacy are limited.
- A robust model is needed to investigate the chronic effects of IR and DL on heart function.
Purpose of the Study:
- To establish and validate a rodent model of dietary-induced IR with or without DL.
- To assess the impact of chronic IR and DL on in vivo myocardial function over time.
- To evaluate the utility of this model for testing experimental therapeutics for DCM.
Main Methods:
- Male rats were fed a Western-type diet (WD) to induce IR, with some receiving P-407 injections to induce DL.
- Cardiac function was assessed using echocardiography at 11 and 14 weeks.
- Biochemical markers (blood glucose, plasma lipids) and myocardial TNF-alpha were analyzed.
Main Results:
- WD feeding increased blood glucose; P-407 treatment led to significant lipid accumulation.
- Diastolic dysfunction (decreased E/A ratio) was observed at 14 weeks in the DL group.
- Systolic dysfunction (depressed fractional shortening) appeared early (11 weeks) and worsened in the DL group, with increased TNF-alpha.
Conclusions:
- Dyslipidemia exacerbates cardiac lipotoxicity and functional decline in the context of insulin resistance.
- This combined IR and DL model accurately reflects key clinical features of DCM.
- The model serves as a valuable tool for evaluating pharmacological treatments for DCM.
