Kinetic modelling of β‐cell metabolism reveals control points in the insulin‐regulating pyruvate cycling pathways

Author:

Rahul Rahul1ORCID,Stinchcombe Adam R.2ORCID,Joseph Jamie W.3ORCID,Ingalls Brian1ORCID

Affiliation:

1. Department of Applied Mathematics University of Waterloo Waterloo Ontario Canada

2. Department of Mathematics University of Toronto Toronto Ontario Canada

3. School of Pharmacy University of Waterloo Waterloo Ontario Canada

Abstract

AbstractInsulin, a key hormone in the regulation of glucose homoeostasis, is secreted by pancreatic β‐cells in response to elevated glucose levels. Insulin is released in a biphasic manner in response to glucose metabolism in β‐cells. The first phase of insulin secretion is triggered by an increase in the ATP:ADP ratio; the second phase occurs in response to both a rise in ATP:ADP and other key metabolic signals, including a rise in the NADPH:NADP+ ratio. Experimental evidence indicates that pyruvate‐cycling pathways play an important role in the elevation of the NADPH:NADP+ ratio in response to glucose. The authors developed a kinetic model for the tricarboxylic acid cycle and pyruvate cycling pathways. The authors successfully validated the model against experimental observations and performed a sensitivity analysis to identify key regulatory interactions in the system. The model predicts that the dicarboxylate carrier and the pyruvate transporter are the most important regulators of pyruvate cycling and NADPH production. In contrast, the analysis showed that variation in the pyruvate carboxylase flux was compensated by a response in the activity of mitochondrial isocitrate dehydrogenase (ICDm) resulting in minimal effect on overall pyruvate cycling flux. The model predictions suggest starting points for further experimental investigation, as well as potential drug targets for the treatment of type 2 diabetes.

Funder

Natural Sciences and Engineering Research Council of Canada

Canadian Natural Resources Limited

Publisher

Institution of Engineering and Technology (IET)

Subject

Cell Biology,Genetics,Molecular Biology,Modeling and Simulation,Biotechnology

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