Models of the metabolism of the pancreatic beta-cell

• Main Author: Westermark, Pål
• Format: Doctoral Thesis
• Language: English
• Published: KTH, Numerisk Analys och Datalogi, NADA 2005
• Subjects: Computer science; Datalogi
• Online Access: http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-408; http://nbn-resolving.de/urn:isbn:91-7178-140-0

The pancreatic β-cell secretes insulin in response to a raised blood glucose level. Deficiencies in this control system are an important part of the etiology of diabetes. The biochemical basis of glucose-stimulated insulin secretion is incompletely understood, and a more complete understanding is an important component in the quest for better therapies against diabetes. In this thesis, mathematical modeling has been employed in order to increase our understanding of the biochemical principles that underlie glucosestimulated insulin secretion of the pancreatic β-cell. The modeling efforts include the glycolysis in theβ-cell with particular emphasis on glycolytic oscillations. The latter have earlier been hypothesized to be the cause of normal pulsatile insulin secretion. This model puts this hypothesis into quantitative form and predicts that the enzymes glucokinase and aldolase play important roles in setting the glucose concentration threshold governing oscillations. Also presented is a model of the mitochondrial metabolism in the β-cell, and of the mitochondrial shuttles that connect the mitochondrial metabolism to the glycolysis. This model gives sound explanations to what was earlier thought to be paradoxical behavior of the mitochondrial shuttles during certain conditions. Moreover, it predicts a strong signal from glucose towards cytosolic NADPH formation, a putative stimulant of insulin secretion. The model also identifies problems with earlier interpretations of experimental results regarding the β- cell mitochondrial metabolism. As an aside, an earlier proposed conceptual model of the generation of oscillations in the TCA cycle is critically analyzed. Further, metabolic control analysis has been employed in order to obtain mathematical expressions that describe the control by pyruvate dehydrogenase and fatty acid oxidation over different aspects of the mitochondrial metabolism and the mitochondrial shuttles. The theories developed explain recently observed behavior of these systems and provide readily testable predictions. The methodological aspects of the work presented in the thesis include the development of a new generic enzyme rate equation, the generalized reversible Hill equation, as well as a reversible version of the classical general modifier mechanism of enzyme action.