Development and characterization of a high fat diet-streptozotocin induced type 2 diabetes model in nude athymic rats

Abstract

People with diabetes mellitus (DM) are at an increased risk for myocardial infarction (MI) than age matched people without DM. However, assays for pre-clinical therapy are performed in animal models of ischemia that lack the co-morbid conditions present in patients with MI, such as DM. This contributes to the failure to translate pre-clinical trials results to the clinic. Thus, to increase the clinical relevance of xenograft studies in pre-clinical models, it is important to have a DM model in animals that are immunodeficient. Here, we developed a type 2 diabetes mellitus (T2D) model in nude athymic rats using high-fat diet and streptozotocin (HFD-STZ). Nude athymic rats were randomized into a control group (normal chow) or a HFD (45% fat, 20% protein and 35% carbohydrate)-STZ group. STZ (35 mg/kg i.v.) or vehicle was administered 8 weeks after HFD feeding started. Assessments were done longitudinally and at week 9 (endpoint). The HFD-STZ group showed mild hyperglycemia pre STZ administration (7.7 {+/-} 0.3 mM vs 5.8 {+/-} 0.2 mM in control) by week 8. In addition, plasma insulin levels were increased and the HOMA index was 2.5-times higher in the HFD-STZ. The HFD-STZ group showed increased fasting (147%) triglycerides. After STZ-administration, blood glucose levels increased substantially (23.6 {+/-} 1.4 mM vs 5.5 {+/-} 0.3 mM in control). The HFD-STZ treated animals also showed increased left ventricular wall thickness, cardiac hypertrophy and fibrosis, reduced cardiac function compared to normal chow control. In line with the HFD-STZ model in immunocompetent rats, the HFD-STZ treatment of athymic rats recapitulates key features of T2D, including aspects of established clinical diabetic cardiomyopathy and should be suitable for xenograft studies in the context of T2D.