title: Transepithelial glucose transport and Na+/K+ homeostasis in enterocytes: an integrative model.
abstract: The uptake of glucose and the nutrient coupled transcellular sodium traffic across epithelial cells in the small intestine has been an ongoing topic in physiological research for over half a century. Driving the uptake of nutrients like glucose, enterocytes must have regulatory mechanisms that respond to the considerable changes in the inflow of sodium during absorption. The Na-K-ATPase membrane protein plays a major role in this regulation. We propose the hypothesis that the amount of active Na-K-ATPase in enterocytes is directly regulated by the concentration of intracellular Na(+) and that this regulation together with a regulation of basolateral K permeability by intracellular ATP gives the enterocyte the ability to maintain ionic Na(+)/K(+) homeostasis. To explore these regulatory mechanisms, we present a mathematical model of the sodium coupled uptake of glucose in epithelial enterocytes. Our model integrates knowledge about individual transporter proteins including apical SGLT1, basolateral Na-K-ATPase, and GLUT2, together with diffusion and membrane potentials. The intracellular concentrations of glucose, sodium, potassium, and chloride are modeled by nonlinear differential equations, and molecular flows are calculated based on experimental kinetic data from the literature, including substrate saturation, product inhibition, and modulation by membrane potential. Simulation results of the model without the addition of regulatory mechanisms fit well with published short-term observations, including cell depolarization and increased concentration of intracellular glucose and sodium during increased concentration of luminal glucose/sodium. Adding regulatory mechanisms for regulation of Na-K-ATPase and K permeability to the model show that our hypothesis predicts observed long-term ionic homeostasis.
authors.affiliation: Department of Electrical Engineering and Computer Science, University of Stavanger, Stavanger, Norway; and kristian.thorsen@uis.no.
authors.forename: Kristian
authors.initials: K
authors.lastname: Thorsen
authors.affiliation: Department of Electrical Engineering and Computer Science, University of Stavanger, Stavanger, Norway; and.
authors.forename: Tormod
authors.initials: T
authors.lastname: Drengstig
authors.affiliation: Centre for Organelle Research, University of Stavanger, Stavanger, Norway.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruoff
mesh_terms: D000818:Animals; D001692:Biological Transport; D002463:Cell Membrane Permeability; D003198:Computer Simulation; D004058:Diffusion; D020895:Enterocytes / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D007700:Kinetics; D008564:Membrane Potentials; D008954:Models, Biological; D011188:Potassium / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D051273:Glucose Transporter Type 2; D051269:Sodium-Glucose Transporter 1; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose; D011188:Potassium
keywords: enterocytes; epithelial transport; homeostasis; ionic regulation; mathematical modeling