Speaker
Description
Type 2 diabetes (T2D) diabetes disease progression is associated with genetic susceptibility coupled with risk factors like overweight/obesity and prior incidence of gestational diabetes. Impaired insulin sensitivity coupled with alpha and beta cell dysregulation is observed in the progression to T2D. What is unclear is why some individuals progress to T2D while others never transition. In our previous model of
disease progression~\cite{subramanian2025evaluating}, we showed that mild alpha cell dysregulation could be beneficial as it leads to robust compensatory insulin secretion in the milieu of impaired insulin sensitivity leading to long term glycemic stability. Here we analyze longitudinal data on at risk individuals from the DPP/DPPOS study~\cite{diabetes200910} using Machine Learning tools coupled with simulations of the previously developed physiological model. We generated fine-grained sub-phenotyping of individuals, based on the relative influence of the different underlying dysregulations in disease progression. We first performed multivariate dynamic time warping (DTW)-based hierarchical clustering of longitudinal trajectories using a composite dissimilarity measure that combined path-length-normalized dynamic time warping distance with penalties for differences in participants’ baseline levels at study entry and mean longitudinal levels over follow-up. The clustering revealed groups of individuals who showed not only long-term stability but also periods of improvement in glycemia. The simulations showed that mild alpha cell dysregulation is likely to develop and plateau in these individuals leading to this behavior. This work highlights the power of integrating physiological modeling with machine learning tools to deliver precision medicine.
Bibliography
@article{subramanian2025evaluating,
title={Evaluating the role of alpha cell dysregulation in the progression to type 2 diabetes using mathematical simulations},
author={Subramanian, Vijaya and Sherman, Arthur S and Holst, Jens J and Knop, Filip K and Vilsb{\o}ll, Tina and Bagger, Jonatan I},
journal={Diabetologia},
volume={68},
number={11},
pages={2595--2608},
year={2025},
publisher={Springer}
}
@article{diabetes200910,
title={10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study},
author={Diabetes Prevention Program Research Group and others},
journal={The Lancet},
volume={374},
number={9702},
pages={1677--1686},
year={2009},
publisher={Elsevier}
}
