Effect of test article in type 2 diabetes cardiomyopathy development
Cardiovascular complications are the leading cause of diabetes-related morbidity and mortality. Type 2 diabetes cardiomyopathy is one of the major cardiovascular complications independent of coronary artery disease and hypertension. This has led to a ventricular dysfunction with diastolic and systolic issues. The prevalence of which may be as high as 60% even in well-controlled type 2 diabetes patients.
Non-GLP compliant. The study is best suited to demonstrate efficacy in discovery-phase preclinical development strategies.
Purpose of the Study
The underlying mechanism of type 2 diabetes is driven by a phenomenon called “lipotoxicity”. The normal heart derives its energy mainly from oxidation of fatty acids (60–70%), glucose (30–40%) and lactate (10%). In contrast, T2DM is accompanied by increased lipolysis, hypertriglyceridemia, and reduced insulin-mediated myocardial glucose uptake and utilization. This results in a shift of myocardial substrate use towards even higher FA utilization leading to hypoxia, endothelial cell dysfunction, apoptosis and increasing heart’s repolarization. Altogether, these modifications generate heart remodeling involved in cardiomyopathy development.
Male Wistar rats (10 weeks old)
Group 1. Six T2D rats with vehicle
Group 2. Six T2D rats with test article (Dose 1)
Group 3. Six lean age-matched rats with vehicle
- Changes in left ventricular remodeling and function (Doppler m-Mode)
- Changes in diastolic function (pulsed wave Doppler analyses)
- Changes in systemic arterial pressure (Diastolic, systolic, mean SAP) and heart rate
- Changes in right ventricular pressure (RVP) and blood oxygen saturation
- Body temperature, body weight, weight gain, food intake and feed efficiency
- Blood biomarkers for diabetes (glucose, insulin, lipids profile)
Tables and Figures
All data will be expressed as the mean ± standard error of the mean (S.E.M.). Changes will be expressed as raw data and % of control.
One-way ANOVA and paired Student's t-tests will be used to verify statistical significance.
- One week to finalize the protocol/formulation
- In vivo disease development phase: 6 weeks
- Terminal surgery and acquisition: 1 day of surgery per experimental group
- Analysis of functional parameters: 14 days
- Morphometric and histopathological examination: 14 days following reception of the slides
- Quantification specific biomarkers: TBD (in parallel with histology)
Non-audited report 2 weeks following the last functional measurement.