Evaluating the role of alpha cell dysregulation in the progression to type 2 diabetes using mathematical simulations – Published online 09/09/2025

Vijaya Subramanian, Arthur S. Sherman, Jens J. Holst, Filip K. Knop, Tina Vilsbøll, Jonatan I. Bagger

Alpha cell dysregulation is known to elevate fasting and postprandial glucose levels in the progression to type 2 diabetes but its role in beta cell functional mass regulation is still not fully understood. In this issue, Subramanian et al (https://doi.org/10.1007/s00125-025-06524-1) report, using simulations of a coupled fast (glucose, insulin, glucagon and incretins)–slow (beta cell functional mass) dynamical system, the impact of alpha cell dysregulation in addition to insulin resistance on type 2 diabetes disease progression. Model simulations predict that alpha cell dysregulation leading to mild elevations in fasting glucose significantly increase beta cell functional mass, which has a huge impact on maintaining postprandial glucose levels in the normal to prediabetic range for prolonged periods of time. The authors highlight that this masks the underlying dysregulations that are progressing simultaneously, eventually leading to a sharp transition to type 2 diabetes as failure in compensation sets in. The authors conclude that these simulations point to a pathophysiological mechanism that may be relevant from a disease prevention/management viewpoint in individuals with pre-existing risk factors.

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