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Models of the metabolism of the pancreatic beta-cell
KTH, School of Computer Science and Communication (CSC), Numerical Analysis and Computer Science, NADA.
2005 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

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.

Place, publisher, year, edition, pages
2005.
Series
Trita-NA, ISSN 0348-2952 ; 0527
Keyword [en]
Computer science
National Category
Computer Sciences
Identifiers
URN: urn:nbn:se:kth:diva-408ISBN: 91-7178-140-0 (print)OAI: oai:DiVA.org:kth-408DiVA: diva2:10655
Public defence
2005-09-23, D2, KTH huvudbyggnad, Lindstedtsv. 5, Stockholm, 12:15
Opponent
Supervisors
Available from: 2005-09-07 Created: 2005-09-07 Last updated: 2018-01-13
List of papers
1. A model of phosphofructokinase and glycolytic oscillations in the pancreatic beta-cell
Open this publication in new window or tab >>A model of phosphofructokinase and glycolytic oscillations in the pancreatic beta-cell
2003 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 85, no 1, 126--139 p.Article in journal (Refereed) Published
Abstract [en]

We have constructed a model of the upper part of the glycolysis in the pancreatic beta-cell. The model comprises the enzymatic reactions from glucokinase to glyceralclehyde-3-phosphate dehydrogenase (GAPD). Our results show, for a substantial part of the parameter space, an oscillatory behavior of the glycolysis for a large range of glucose concentrations. We show how the occurrence of oscillations depends on glucokinase, aldolase and/or GAPD activities, and how the oscillation period depends on the phosphofructokinase activity. We propose that the ratio of glucokinase and aldolase and/or GAPD activities are adequate as characteristics of the glucose responsiveness, rather than only the glucokinase activity. We also propose that the rapid equilibrium between different oligomeric forms of phosphofructokinase may reduce the oscillation period sensitivity to phosphofructokinase activity. Methodologically, we show that a satisfying description of phosphofructokinase kinetics can be achieved using the irreversible Hill equation with allosteric modifiers. We emphasize the use of parameter ranges rather than fixed values, and the use of operationally well-defined parameters in order for this methodology to be feasible. The theoretical results presented in this study apply to the study of insulin secretion mechanisms, since glycolytic oscillations have been proposed as a cause of oscillations in the ATP/ADP ratio which is linked to insulin secretion.

Keyword
RABBIT MUSCLE PHOSPHOFRUCTOKINASE; PURINE NUCLEOTIDE CYCLE; INSULIN-SECRETION; SKELETAL-MUSCLE; FRUCTOSE 2, 6-BISPHOSPHATE; GLUCOSE-METABOLISM; DIABETES-MELLITUS; KINETIC-BEHAVIOR; ESCHERICHIA-COLI; ALDOLASE-C
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-6056 (URN)000183820600013 ()
Note
QC 20100824Available from: 2005-09-07 Created: 2005-09-07 Last updated: 2017-12-14Bibliographically approved
2. Derivation of a reversible Hill equation with modifiers affecting catalytic properties
Open this publication in new window or tab >>Derivation of a reversible Hill equation with modifiers affecting catalytic properties
2004 (English)In: WSEAS Transactions on Biology and Biomedicine, ISSN 1109-9518, E-ISSN 2224-2902, Vol. 1, 91-98 p.Article in journal (Refereed) Published
Abstract [en]

An existing generic enzyme rate equation, the reversible Hill equation, was generalized to account for modifiers affecting the catalytical properties of the enzyme as well as for the case of several substrates and products. The resulting generalized reversible Hill (GRH) equation has relatively few but operationally well-defined parameters. Its usefulness is demonstrated by fitting it to experimental data on mammalian muscle phosphofructokinase. The fit is superior to that of previous models to the same data. The rate equation derived is suitable for replacing more complicated rate equations when exact mechanisms are unknown and data is scarce or contradictory.

Keyword
Metabolic Modeling, Enzyme Kinetics, Reversible Hill Equation, Operationally Welldefined parameters, Phosphofructokinase
National Category
Computer and Information Sciences
Identifiers
urn:nbn:se:kth:diva-6057 (URN)
Note

QC 20111110

Available from: 2005-09-07 Created: 2005-09-07 Last updated: 2018-01-13Bibliographically approved
3. Glucose-stimulated insulin secretion - insights from modelling
Open this publication in new window or tab >>Glucose-stimulated insulin secretion - insights from modelling
2004 (English)In: Recent Research Developments in Biophysics, Vol. 3, 325-350 p.Article in journal (Refereed) Published
Abstract [en]

Insulin is secreted by the pancreatic β-cells in response to a raised blood glucose concentration. Glucose-stimulated insulin secretion (GSIS) is pulsatile and correlated with bursting electrical activity. We review the current understanding of pancreatic p-cell GSIS from a mathematical modelling perspective. We discuss the glycolysis and the mitochondrial metabolism and metabolic modelling thereof. In particular, we describe the theoretical basis for the hypothesis of an oscillatory glycolysis, which may be the cause of the pulsatile secretion. We also discuss the electrophysiology of the P-cell and present insights gained from mathematical modelling in this context. There are important causal connections between β-cell metabolism and electrophysiology. This brings about an unusual challenge for theoretical and computational biologists.

Keyword
Pancreatic hormone, Mathematical model, Electrophysiology, Review, Stimulation, Secretion, Insulin, Glucose
National Category
Computer and Information Sciences
Identifiers
urn:nbn:se:kth:diva-6058 (URN)
Note
QC 20111110Available from: 2005-09-07 Created: 2005-09-07 Last updated: 2018-01-13Bibliographically approved
4. A mathematical model of the mitochondrial NADH shuttles and anaplerosis in the pancreatic beta-cell
Open this publication in new window or tab >>A mathematical model of the mitochondrial NADH shuttles and anaplerosis in the pancreatic beta-cell
Show others...
2007 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 292, no 2, E373-E393 p.Article in journal (Refereed) Published
Abstract [en]

The pancreatic beta-cells respond to an increased glycolytic flux by secreting insulin. The signal propagation goes via mitochondrial metabolism, which relays the signal to different routes. One route is an increased ATP production that, via ATP-sensitive K+ (K-ATP) channels, modulates the cell membrane potential to allow calcium influx, which triggers insulin secretion. There is also at least one other "amplifying" route whose nature is debated; possible candidates are cytosolic NADPH production or malonyl-CoA production. We have used mathematical modeling to analyze this relay system. The model comprises the mitochondrial NADH shuttles and the mitochondrial metabolism. We found robust signaling toward ATP, malonyl-CoA, and NADPH production. The signal toward NADPH production was particularly strong. Furthermore, the model reproduced the experimental findings that blocking the NADH shuttles attenuates the signaling to ATP production while retaining the rate of glucose oxidation (Eto K, Tsubamoto Y, Terauchi Y, Sugiyama T, Kishimoto T, Takahashi N, Yamauchi N, Kubota N, Murayama S, Aizawa T, Akanuma Y, Aizawa S, Kasai H, Yazaki Y, Kadowaki T. Science 283: 981 - 985, 1999) and provides an explanation for this apparent paradox. The model also predicts that the mitochondrial malate dehydrogenase reaction may proceed backward, toward malate production, if the activity of malic enzyme is sufficiently high. An increased fatty acid oxidation rate was found to attenuate the signaling strengths. This theoretical study has implications for our understanding of both the healthy and the diabetic beta-cell.

Keyword
systems biology, potassium-dependent adenosine triphosphate channel-independent, pathway of insulin secretion, reduced nicotinamide adenine dinucleotide, diabetes, fatty acid oxidation
National Category
Computer and Information Sciences
Identifiers
urn:nbn:se:kth:diva-6059 (URN)10.1152/ajpendo.00589.2005 (DOI)000243997100002 ()16849626 (PubMedID)2-s2.0-33846882164 (Scopus ID)
Note
QC 20100823 Uppdaterad från manuskript till artikel (20100823)Available from: 2005-09-07 Created: 2005-09-07 Last updated: 2018-01-13Bibliographically approved
5. On the metabolic control of pyruvate dehydrogenase and pyruvate carboxylase in the pancreatic beta-cell
Open this publication in new window or tab >>On the metabolic control of pyruvate dehydrogenase and pyruvate carboxylase in the pancreatic beta-cell
(English)Manuscript (Other academic)
National Category
Computer and Information Sciences
Identifiers
urn:nbn:se:kth:diva-6060 (URN)
Note
QC 20111110Available from: 2005-09-07 Created: 2005-09-07 Last updated: 2018-01-13Bibliographically approved

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