title: A novel method for simulating insulin mediated GLUT4 translocation.
abstract: Glucose transport in humans is a vital process which is tightly regulated by the endocrine system. Specifically, the insulin hormone triggers a cascade of intracellular signals in target cells mediating the uptake of glucose. Insulin signaling triggers cellular relocalization of the glucose transporter protein GLUT4 to the cell surface, which is primarily responsible for regulated glucose import. Pathology associated with the disruption of this pathway can lead to metabolic disorders, such as type II diabetes mellitus, characterized by the failure of cells to appropriately uptake glucose from the blood. We describe a novel simulation tool of the insulin intracellular response, incorporating the latest findings regarding As160 and GEF interactions. The simulation tool differs from previous computational approaches which employ algebraic or differential equations; instead, the tool incorporates statistical variations of kinetic constants and initial molecular concentrations which more accurately mimic the intracellular environment. Using this approach, we successfully recapitulate observed in vitro insulin responses, plus the effects of Wortmannin-like inhibition of the pathway. The developed tool provides insight into transient changes in molecule concentrations throughout the insulin signaling pathway, and may be employed to identify or evaluate potentially critical components of this pathway, including those associated with insulin resistance. In the future, this highly tractable platform may be useful for simulating other complex cell signaling pathways. Biotechnol. Bioeng. 2014;111: 2454-2465. © 2014 Wiley Periodicals, Inc.
authors.affiliation: Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Jezewski
authors.affiliation: Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Larson
authors.affiliation: Department of Engineering, University of Nebraska-Lincoln, 6001 Dodge St, 200 Peter Kiewit Institute, Omaha, Nebraska 68182-0572; twysocki2@unl.edu.
authors.forename: Beata
authors.initials: B
authors.lastname: Wysocki
authors.affiliation: Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska.|Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Davis
authors.affiliation: Department of Engineering, University of Nebraska-Lincoln, 6001 Dodge St, 200 Peter Kiewit Institute, Omaha, Nebraska 68182-0572; twysocki2@unl.edu.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Wysocki
mesh_terms: D001692:Biological Transport / Q000502:physiology*; D003198:Computer Simulation; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin
keywords: GLUT4; computational modeling; insulin; metabolism; queuing theory