Open AccessContinuous variable responses and signal gating form kinetic bases for pulsatile insulin signaling and emergence of resistance
Author(s) -
Namrata Shukla,
Shantanu Kadam,
Ranjith Padinhateeri,
Ullas KolthurSeetharam
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2102560118
Subject(s) - gating , insulin resistance , signal transduction , insulin , pulsatile flow , phosphorylation , biology , biological system , biophysics , medicine , microbiology and biotechnology , endocrinology
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.