Plasma Metabolomics Supports Non-Fasted Sampling for Early Detection of Impaired Glucose Tolerance in the Nile Rat Model of Type 2 Diabetes

Abstract Type 2 diabetes is a challenge in modern healthcare, and animal models are necessary to identify underlying mechanisms, where we can achieve much better environmental control than what is practical in human studies. The Nile rat (Arvicanthis niloticus) develops diet-induced diabetes rapidly on a conventional rodent chow diet without genetic or chemical manipulation. Unlike common laboratory models, the outbred Nile rat model is diurnal and can progress to advanced diabetic complications, better mimicking the human condition. Some human studies indicate that compared to fasting glucose, post-prandial blood glucose is more sensitive to the initial stages of diabetes, suggesting that we should capture the non-fasted state to study early diabetes. However, it is unknown if ad libitum feeding in the Nile rats leads to increased variance thus masking diabetes-related metabolic changes in the plasma. In this study, we compared the repeatability within triplicate non-fasted or fasted plasma samples and assessed prediction of impaired glucose tolerance in fasted and non-fasted plasma. We used liquid chromatography-mass spectrometry lipidomics and polar metabolomics to measure relative metabolite abundances in the plasma samples. Metabolite measurements in non-fasted plasma were less variable than measurements in fasted plasma. We detected 66 metabolites in non-fasted plasma associated with glucose tolerance in elastic net and individual metabolite linear regression models. Low metabolite replicate variance was reproduced in a cohort of mature 30-week male and female Nile rats. Our results support using non-fasted plasma metabolomics for early detection of impaired glucose tolerance in Nile rats.