Modeling the progression of Type 2 diabetes with underlying obesity

摘要

Environmentally induced or epigenetic-related beta-cell dysfunction and insulin resistance play a critical role in the progression to diabetes. We developed a mathematical modeling framework capable of studying the progression to diabetes incorporating various diabetogenic factors. Considering the heightened risk of beta-cell defects induced by obesity, we focused on the obesity-diabetes model to further investigate the influence of obesity on beta-cell function and glucose regulation. The model characterizes individualized glucose and insulin dynamics over the span of a lifetime. We then fit the model to the longitudinal data of the Pima Indian population, which captures both the fluctuations and long-term trends of glucose levels. As predicted, controlling or eradicating the obesity-related factor can alleviate, postpone, or even reverse diabetes. Furthermore, our results reveal that distinct abnormalities of beta-cell function and levels of insulin resistance among individuals contribute to different risks of diabetes. This study may encourage precise interventions to prevent diabetes and facilitate individualized patient treatment. Author summaryMathematical models depicting the progression of Type 2 diabetes can be used to study the durable effect of anti-diabetic agents at different disease stages. However, few existing models have been capable of depicting the long-term dynamics of diabetes progression. Mounting evidence has indicated that hyperinsulinemia aggravates insulin resistance no matter in which order they occur. We developed a generalized model which incorporates the effect of hyperinsulinemia on insulin resistance and enables the quantitative study of the impact of diverse diabetogenic factors on beta-cell dysfunction. Specifying the diabetogenic factor to be obesity-related in the modeling framework, we generated an obesity-related diabetes model to investigate the influence of obesity on the glucose regulatory system. The long-course glucose and insulin trajectories depicted by the obesity-diabetes model are consistent with clinical observations and capture the trend of the longitudinal glucose data of the Pima Indian tribe. This work may have the potential to help develop therapeutic strategies for diabetes.