ZDF (fa/fa) rats show increasing heterogeneity in main parameters during ageing, as confirmed by biometrics, oxidative stress markers and MMP activity.

Abstract

What is the central question of this study? The aim was to characterize Zucker diabetic fatty [ZDF (fa/fa)] rats and two control strains [Wistar and lean ZDF (fa/+) rats] during ageing. What is the main finding and its importance? Zucker diabetic fatty (fa/fa) rats with lower glycaemia have higher body and left ventricular weights and lower plasma gelatinase activity compared with hyperglycaemic rats. Given that type2 diabetes is a heterogeneous metabolic disorder, the inhomogeneity of ZDF (fa/fa) rats might be beneficial in the study of its different aspects. Our experiments might promote a discussion regarding suitable normoglycaemic control animals for aged ZDF (fa/fa) rats, especially in experiments focused on myocardial tissue. Zucker diabetic fatty [ZDF (fa/fa)] rats, which are an animal model for the study of type 2 diabetes, are considered as a uniform group in most experimental studies; however, there are indications of their increasing inhomogeneity over time. The main objective of our study was to monitor biometric and biochemical parameters of ZDF (fa/fa) rats during their development of type 2 diabetes and compare them with two control strains [Wistar and lean ZDF (fa/+) rats]. According to fasting glycaemia, ZDF (fa/fa) rats were split arbitrarily into two phenotypes: obese, ZDF (fa/fa) FAT; and diabetic, ZDF (fa/fa) DIA. Glycaemia increased progressively only in the ZDF (fa/fa) DIA animals, which also exhibited higher cholesterol levels compared with ZDF (fa/fa) FAT animals. In addition, ZDF (fa/fa) FAT rats revealed more pronounced left ventricular hypertrophy and higher body weight, differentiating them from ZDF (fa/fa) DIA rats. We also investigated the activity of matrix metalloproteinases (MMPs), which are multifunctional enzymes involved in tissue remodelling. Rats in the ZDF (fa/fa) FAT group revealed lower plasma MMP2 and MMP9 activity compared with the ZDF (fa/fa) DIA group. However, increased myocardial MMP2 activity indicated left ventricular remodelling in both ZDF phenotypes. Given that type 2 diabetes in humans is a heterogeneous metabolic disorder, the heterogeneity of ZDF (fa/fa) rats might be beneficial in the study of different aspects of this pathology. Moreover, Wistar rats could serve as a more appropriate control for aged ZDF (fa/fa) rats than the commonly used ZDF fa/+ rats, which showed an increase in left ventricular weight, carbonyl stress markers in the left myocardium and MMP2 activity in both ventricles, indicating heart remodelling processes compared with the Wistar control group.