Longitudinal characterization of the gut microbiota in the ZDSD rat model of diabetes

Abstract

The complex development of type 2 diabetes (T2D) creates challenges for studying its progression in animal models, which often lack transition through the prediabetic state or fail to fully develop the multifaceted aspects of T2D. However, studying T2D development and progression in humans is costly with extensive limitations. A newly developed rat model of T2D, the Zucker Diabetic Sprague Dawley (ZDSD) rat, more closely parallels the progression of T2D in humans. Our goal was to examine T2D progression and the associated changes in the gut microbiota in the ZDSD model and test whether the model can be used to examine potential therapeutics targeting the gut microbiota. As physiological parameters like blood glucose and insulin levels can impact the gut microbiota and vice versa, we anticipate significant shifts in the gut microbiota as the ZDSD rats progress from a healthy to prediabetic to overt diabetic phenotype. Bodyweight, adiposity, and fed/fasting blood glucose and insulin were recorded throughout the progression of T2D in male ZDSD rats over 24 weeks. Glucose and insulin tolerance tests were performed, and feces collected for microbiota analysis using 16s rRNA gene sequencing at 8, 16, and 24 weeks. At the end of 24 weeks, half of the rats were supplemented with oligofructose (OFS) in their drinking water and tests repeated. Over the 24 weeks, we observed a transition from nondiabetic to prediabetic and overtly diabetic states, via worsened insulin and glucose tolerance and significant increases in fed/ fasted glucose values, followed by a significant decrease in circulating insulin. Microbiota analysis demonstrated alterations in the gut microbiota throughout the development of diabetes with shifts in alpha and beta diversity as well as alterations in specific bacterial genera in healthy compared to prediabetic and diabetic states. OFS treatment significantly increased body weight and adiposity, improved glucose tolerance, and shifted the cecal microbiota of the ZDSD rats during late-stage diabetes. These findings demonstrate the translational potential of ZDSD rats as a T2D model and highlight the potential for the gut microbiota to both impact the development of the disease, as well as serve as a biomarker for T2D. Additionally, OFS treatment was able to moderately improve glucose homeostasis in the ZDSD model. Arizona Biomedical Research Commission New Investigator Award (ADHS18-198857), National Institute of Food and Agriculture (67017-29252), and NIDDK (R01ES033993). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.