Is high insulin protective or detrimental? Mathematical modeling reveals the base of the iceberg

Type 2 diabetes (T2D) progression involves complex interactions over time, yet longitudinal human data remain limited. Mathematical modeling enables reconstruction of individualized disease trajectories and mechanistic insights from sparse clinical observations. We developed a series of obesity-diabetes progression models, incorporating proposed mechanisms of glucose-insulin regulation and identified the best-performing framework using individualized longitudinal data from Southwest Native Americans. This population, with high rates of hyperinsulinemia and T2D progression, offers a good opportunity to investigate whether hyperinsulinemia is a primary factor in T2D. The model captured heterogeneous trajectories of glucose, insulin, insulin sensitivity, and beta-cell function, under the assumption that hyperinsulinemia reflects compensation for insulin resistance rather than a primary defect. We extended the model to study a subset of the population carrying an ABCC8 loss-of-function variant linked to primary rather than compensatory hyperinsulinemia. The simulations reproduced the observed earlier diabetes onset in heterozygous carriers by incorporating chronic calcium stress, which accelerates beta-cell failure when combined with insulin resistance. In contrast, homozygous carriers exhibited severe early-onset diabetes even without insulin resistance. These findings suggest that high insulin secretion alone does not initiate diabetes unless it is extreme but may exacerbate progression in the presence of metabolic stress caused by insulin resistance. Importantly, the model predicts that Ca²⁺-reducing therapies in all the genotypes can mitigate beta-cell dysfunction if applied sufficiently early and at appropriate intensity. This study addresses controversial questions in diabetes pathogenesis and provides a platform for personalized disease stratification and therapeutic development.NEW & NOTEWORTHY This study presents the first obesity-diabetes model validated against four-dimensional, individualized longitudinal data, capturing heterogeneous disease trajectories and quantifying key mechanisms of progression. Uniquely, it investigates the transition from primary hyperinsulinemia to beta-cell failure in ABCC8 loss-of-function carriers and highlights the potential of early, appropriately dosed Ca²⁺-reducing therapies to delay disease progression, providing new genotype- and stage-specific insights.