NSF Award
2401922
This research project is a collaboration between two Historically Black Universities, Howard University (HU) and North Carolina A&T State University (NCATSU). Type 2 diabetes (T2D) is a progressive disease of glucose homeostasis caused by various genetic and environmental factors. The most common pathway toward T2D is a failure of insulin-secreting pancreatic beta-cells to maintain normal blood glucose concentration as the body’s insulin demand increases due to obesity and aging. Clinical studies have shown that glucose concentration gradually increases before frank diabetes and then sharply rises at the onset of the disease, supporting the hypothesis that there exists a threshold for diabetes progression in terms of glucose concentration. Glucose concentration, however, cannot be used as the threshold for progression to diabetes. This project aims to identify mathematical structures for the mechanism underlying the sharp rise of glucose at the onset of diabetes. The project will also investigate the threshold behavior of diabetes and its dependence on genetic and environmental factors. The dynamics of the sharp rise of glucose will be identified by the diabetes progression feature of model. To reveal the dynamic structure of each patient’s diabetes intervention and therapy, the PIs also find personalized parameters by parameter estimation on short timescales and use those parameter estimates to inform progression on long timescales. Personalized treatment will be captured by the parameter estimation feature. The novelty of the current study lies in this approach of both revealing the dynamic structure of progression and estimating parameters with one model, which will potentially enable the implementation of personalized treatment. Diabetes educators will be able to use the theoretical threshold to motivate patients to keep lifestyle intervention. The project will provide STEM major graduate students in each institution with excellent research experience in mathematical biology. Workshop and conference presentations and manuscript preparations will lead these graduate students to a deeper understanding of the material while also cultivating their communication skills in interdisciplinary environments. Integration of research results and assets will facilitate outreach to local high school students and lead to additional avenues to recruit domestic students to STEM education.<br/><br/>To enhance understanding of the mechanisms underlying the threshold behavior of glucose concentration and blood glucose dynamics over the course of progression to T2D, the PIs use mathematical models, which incorporate secretory capacity of beta-cells to regulate beta-cell function and beta-mass, and insulin sensitivity to reflect body weight gain. The first part of this project is to construct a theoretical threshold that is identified by a slow manifold that plays a role of separatrix between diabetes and non-diabetes in the physiological model. The second part of the project is to validate the proposed models with a longitudinal clinical data from studies of Southwest Native Americans. Additionally, the project includes building of a data-derived slow manifold that will be used for personalized therapy. The theoretical threshold that is developed by mathematical tools and is validated with a historical clinical data set will give guidelines to design biological and clinical studies of diabetes. In particular, targeted metabolic parameters related to progression to T2D will be estimated by the theoretical threshold before implementing the experiments, so the degree of environment factor will be selected for precise experiments. This project has the potential for broad social and economic impacts and health benefits by facilitating new treatment methods for diabetes.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
