A steady state analysis indicates that negative feedback regulation of PTP1B by Akt elicits bistability in insulin-stimulated GLUT4 translocation.
BACKGROUND
The phenomenon of switch-like response to graded input signal is the theme involved in various signaling pathways in living systems. Positive feedback loops or double negative feedback loops embedded with nonlinearity exhibit these switch-like bistable responses. Such feedback regulations exist in insulin signaling pathway as well.


METHODS
In the current manuscript, a steady state analysis of the metabolic insulin-signaling pathway is presented. The threshold concentration of insulin required for glucose transporter GLUT4 translocation was studied with variation in system parameters and component concentrations. The dose response curves of GLUT4 translocation at various concentration of insulin obtained by steady state analysis were quantified in-terms of half saturation constant.


RESULTS
We show that, insulin-stimulated GLUT4 translocation can operate as a bistable switch, which ensures that GLUT4 settles between two discrete, but mutually exclusive stable steady states. The threshold concentration of insulin required for GLUT4 translocation changes with variation in system parameters and component concentrations, thus providing insights into possible pathological conditions.


CONCLUSIONS
A steady state analysis indicates that negative feedback regulation of phosphatase PTP1B by Akt elicits bistability in insulin-stimulated GLUT4 translocation. The threshold concentration of insulin required for GLUT4 translocation and the corresponding bistable response at different system parameters and component concentrations was compared with reported experimental observations on specific defects in regulation of the system.
Giri
Lopamudra
L
Department of Chemical Engineering and School of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai-400076, India. lopa@che.iitb.ac.in
Mutalik
Vivek K
VK
Venkatesh
K V
KV
D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D025461:Feedback, Physiological / Q000502:physiology*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D008954:Models, Biological; D009994:Osmolar Concentration; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D051275:Glucose Transporter Type 4; D007328:Insulin; D051057:Proto-Oncogene Proteins c-akt; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases