Kinetic Modeling of Pyruvate Recycling Pathways in Pancreatic β-Cells.

Abstract

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.