Home
Deutsch
Advanced Search
Browse by ...
Publication overview
Contact persons
Help
DOI
PMC
 |
|
Open Access Green as soon as Postprint is submitted to ZB.
Positive feedback amplifies the response of mitochondrial membrane potential to glucose concentration in clonal pancreatic beta cells.
Biochim. Biophys. Acta 1863, 1054-1065 (2016)
Analysis of the cellular mechanisms of metabolic disorders, including type 2 diabetes mellitus, is complicated by the large number of reactions and interactions in metabolic networks. Metabolic control analysis with appropriate modularization is a powerful method for simplifying and analyzing these networks. To analyze control of cellular energy metabolism in adherent cell cultures of the INS-1 832/13 pancreatic β-cell model we adapted our microscopy assay of absolute mitochondrial membrane potential (δψM) to a fluorescence microplate reader format, and applied it in conjunction with cell respirometry. In these cells the sensitive response of δψM to extracellular glucose concentration drives glucose-stimulated insulin secretion. Using metabolic control analysis we identified the control properties that generate this sensitive response. Force-flux relationships between δψM and respiration were used to calculate kinetic responses to δψM of processes both upstream (glucose oxidation) and downstream (proton leak and ATP turnover) of δψM. The analysis revealed that glucose-evoked δψM hyperpolarization is amplified by increased glucose oxidation activity caused by factors downstream of δψM. At high glucose, the hyperpolarized δψM is stabilized almost completely by the action of glucose oxidation, whereas proton leak also contributes to the homeostatic control of δψM at low glucose. These findings suggest a strong positive feedback loop in the regulation of β-cell energetics, and a possible regulatory role of proton leak in the fasting state. Analysis of islet bioenergetics from published cases of type 2 diabetes suggests that disruption of this feedback can explain the damaged bioenergetic response of β-cells to glucose.
Altmetric
Additional Metrics?
Edit extra informations
Login
Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Cell Respiration ; Metabolic Control Analysis ; Metabolism Secretion Coupling ; Mitochondrial Membrane Potential ; Pancreatic Beta Cells ; Type 2 Diabetes; Stimulated Insulin-secretion; Metabolic Control-theory; Ins-1 832/13 Cells; Top-down Approach; Elasticity Analysis; Proton Leak; Oxidative-phosphorylation; Energy-metabolism; Rat Hepatocytes; Line Ins-1
ISSN (print) / ISBN
0006-3002
Journal
Biochimica et Biophysica Acta
Quellenangaben
Volume: 1863,
Issue: 5,
Pages: 1054-1065
Publisher
Elsevier
Publishing Place
Amsterdam
Non-patent literature
Publications
Institute(s)
Institute of Diabetes and Obesity (IDO)