A variety of signaling mechanisms are employed to maintain healthy levels of
glucose in the blood stream.
The hormone insulin is one of the primary regulators of glucose homeostasis.
Insulin, which activates glucose uptake, is released from pancreatic
beta-cells in a bi-phasic manner. The first phase is triggered by increased
ATP levels in the cell. The second release phase is triggered by the so-called
amplifying pathway, which has
not been fully characterized. Recent experimental evidence indicates that
pyruvate-recycling pathways are key components of the amplifying pathway. The
fuel intermediates from these pathways may be the signaling factors that couple
insulin-release to glucose availability. The co-factor nicotinamide adenine
dinucleotide phosphate (NADPH) has been identified as a putative coupling
factor. In this work we develop a kinetic model for the tricarboxylic acid cycle
and pyruvate recycling pathways, building on the previous modeling efforts of
Westermark et al. and Yugi and
Tomita. We
successfully validated the model against recent experimental observations.
Analysis of the model provides predictions of the flux distributions in the
pyruvate recycling pathways. Moreover, model simulations provides hypotheses to
guide further experimental investigation, and suggest potential drug targets for
treatment of type 2 diabetes.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OWTU.10012/7044 |
| Date | 17 September 2012 |
| Creators | Rahul, Rahul |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis or Dissertation |
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