title: Investigation of the age-at-onset heterogeneity in type 1 diabetes through mathematical modeling.
abstract: The heterogeneity between young- and adult-onset type 1 diabetes (T1D) is well known, but not well understood. We approach this question through mathematical formulation and analysis of the dynamic interactions between the immune cells and the pancreatic islet beta-cells that lead to the beta-cell destruction. Utilizing the perturbation expansion method we investigate the dynamic stability of our system under fast and slow beta-cell turnover limits. We find that if autoimmunity is initiated when the turnover is slow (adult age), a stable steady state can exist with reduced number of beta-cells, where the beta-cell regeneration balances the ongoing autoimmune destruction. This implies that a slow disease process is possible. In contrast, if autoimmunity occurs when the beta-cell turnover is rapid (young age), such a stable state will never be attained and the destruction will progress unabated, leading to an acute disease onset. The major findings of our model are consistent with clinical observations, and it offers an explanation for the dynamic and phenotypic heterogeneity between young- and adult-onset T1D. More importantly, the model analyses point out that pathways regulating beta-cell turnover can be new targets to interfere with the disease process of T1D.
authors.affiliation: Max McGee National Research Center for Juvenile Diabetes and Human and Molecular Genetics Center, Medical College of Wisconsin and Children's Research Institute of the Children's Hospital of Wisconsin, Milwaukee, WI 53226, United States.
authors.forename: Xujing
authors.initials: X
authors.lastname: Wang
authors.forename: Zening
authors.initials: Z
authors.lastname: He
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D000328:Adult; D017668:Age of Onset; D017209:Apoptosis / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000276:immunology*; D018450:Disease Progression; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology*; D018448:Models, Immunological
chemical_list: D001324:Autoantigens