期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：41
DOI：10.1073/pnas.2102560118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Evolutionarily conserved insulin signaling is central to nutrient sensing, storage, and utilization across tissues. Dysfunctional insulin signaling is associated with metabolic disorders, cancer, and aging. Hence, the pathway components have emerged as key targets for pharmacological interventions in addition to insulin administration itself. Despite this, activation–inactivation dynamics of individual components, which exert regulatory control in a physiological context, is poorly understood. Now, with our systems-based approach, we reveal kinetic parameters, which define the flow of information through both metabolic and growth-factor arms and thus determine signaling architecture. We also provide a kinetic basis for 1) the advantage of pulsatile-fasted insulin signaling that enables fed-insulin response and 2) the detrimental impact of repeat fed-insulin inputs that causes resistance.
Understanding kinetic control of biological processes is as important as identifying components that constitute pathways. Insulin signaling is central for almost all metazoans, and its perturbations are associated with various developmental disorders, metabolic diseases, and aging. While temporal phosphorylation changes and kinetic constants have provided some insights, constant or variable parameters that establish and maintain signal topology are poorly understood. Here, we report kinetic parameters that encode insulin concentration and nutrient-dependent flow of information using iterative experimental and mathematical simulation-based approaches. Our results illustrate how dynamics of distinct phosphorylation events collectively contribute to selective kinetic gating of signals and maximum connectivity of the signaling cascade under normo-insulinemic but not hyper-insulinemic states. In addition to identifying parameters that provide predictive value for maintaining the balance between metabolic and growth-factor arms, we posit a kinetic basis for the emergence of insulin resistance. Given that pulsatile insulin secretion during a fasted state precedes a fed response, our findings reveal rewiring of insulin signaling akin to memory and anticipation, which was hitherto unknown. Striking disparate temporal behavior of key phosphorylation events that destroy the topology under hyper-insulinemic states underscores the importance of unraveling regulatory components that act as bandwidth filters. In conclusion, besides providing fundamental insights, our study will help in identifying therapeutic strategies that conserve coupling between metabolic and growth-factor arms, which is lost in diseases and conditions of hyper-insulinemia.
