Year: 2012
Type: dissertation
Abstract: A variety of signaling mechanisms are employed to maintain healthy levels of \nglucose in the blood stream. \nThe hormone insulin is one of the primary regulators of glucose homeostasis. \nInsulin, which activates glucose uptake, is released from pancreatic \nbeta-cells in a bi-phasic manner. The first phase is triggered by increased \nATP levels in the cell. The second release phase is triggered by the so-called \namplifying pathway, which has \nnot been fully characterized. Recent experimental evidence indicates that \npyruvate-recycling pathways are key components of the amplifying pathway. The \nfuel intermediates from these pathways may be the signaling factors that couple \ninsulin-release to glucose availability. The co-factor nicotinamide adenine \ndinucleotide phosphate (NADPH) has been identified as a putative coupling \nfactor. In this work we develop a kinetic model for the tricarboxylic acid cycle \nand pyruvate recycling pathways, building on the previous modeling efforts of \nWestermark et al. and Yugi and \nTomita. We \nsuccessfully validated the model against recent experimental observations. \nAnalysis of the model provides predictions of the flux distributions in the \npyruvate recycling pathways. Moreover, model simulations provides hypotheses to \nguide further experimental investigation, and suggest potential drug targets for \ntreatment of type 2 diabetes.
Source: UWSpace (University of Waterloo)
Author: Rahul Rahul
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1183338053