Endothelial dysfunction due to selective insulin resistance in vascular endothelium: insights from mechanistic modeling
- 9 August 2020
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Endocrinology and Metabolism
- Vol. 319 (3), E629-E646
- https://doi.org/10.1152/ajpendo.00247.2020
Abstract
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.Funding Information
- Intramural Program, NIDDK
This publication has 99 references indexed in Scilit:
- Simplification of biochemical models: a general approach based on the analysis of the impact of individual species and reactions on the systems dynamicsBMC Systems Biology, 2012
- Green Tea Polyphenol Epigallocatechin Gallate Reduces Endothelin-1 Expression and Secretion in Vascular Endothelial Cells: Roles for AMP-Activated Protein Kinase, Akt, and FOXO1Endocrinology, 2010
- Hill coefficients, dose–response curves and allosteric mechanismsJournal of Chemical Biology, 2009
- eNOS, metabolic syndrome and cardiovascular diseaseTrends in Endocrinology & Metabolism, 2009
- Dehydroepiandrosterone Stimulates Phosphorylation of FoxO1 in Vascular Endothelial Cells via Phosphatidylinositol 3-Kinase- and Protein Kinase A-dependent Signaling Pathways to Regulate ET-1 Synthesis and SecretionPublished by Elsevier BV ,2008
- An Integrated View of Insulin Resistance and Endothelial DysfunctionEndocrinology and Metabolism Clinics of North America, 2008
- Dissection of the insulin signaling pathway via quantitative phosphoproteomicsProceedings of the National Academy of Sciences of the United States of America, 2008
- Inflammation and metabolic disordersNature, 2006
- Critical nodes in signalling pathways: insights into insulin actionNature Reviews Molecular Cell Biology, 2006
- Insulin signalling and the regulation of glucose and lipid metabolismNature, 2001