Previously, we have used mathematical modeling to gain mechanistic insights into
insulin-stimulated
glucose uptake.
Phosphatidylinositol 3-kinase (PI3K)-dependent
insulin signaling required for metabolic actions of
insulin also regulates endothelium-dependent production of the
vasodilator nitric oxide (NO). Vasodilation increases blood flow that augments direct metabolic actions of
insulin in skeletal muscle. This is counterbalanced by
mitogen-activated protein kinase (MAPK)-dependent
insulin signaling in endothelium that promotes secretion of the
vasoconstrictor endothelin-1 (ET-1). In the present study, we extended our model of metabolic
insulin signaling into a dynamic model of
insulin signaling in vascular endothelium that explicitly represents opposing PI3K/NO and MAPK/ET-1 pathways. Novel NO and ET-1 subsystems were developed using published and new experimental data to generate model structures/parameters. The signal-response relationships of our model with respect to
insulin-stimulated NO production, ET-1 secretion, and resultant vascular tone, agree with published experimental data, independent of those used for model development. Simulations of pathological stimuli directly impairing only
insulin-stimulated PI3K/Akt activity predict altered dynamics of NO and ET-1 consistent with endothelial dysfunction in
insulin-resistant states. Indeed, modeling pathway-selective impairment of PI3K/Akt pathways consistent with
insulin resistance caused by glucotoxicity, lipotoxicity, or
inflammation predict diminished NO production and increased ET-1 secretion characteristic of diabetes and endothelial dysfunction. We conclude that our mathematical model of
insulin signaling in vascular endothelium supports the hypothesis that pathway-selective
insulin resistance accounts, in part, for relationships between
insulin resistance and endothelial dysfunction. This may be relevant for developing novel approaches for the treatment of diabetes and its cardiovascular complications.