Search for molecular and metabolic mechanisms contributing to impaired β-cell function
Author
Summary, in English
In paper I, we showed that tight coupling between glycolysis and mitochondrial metabolism is required for robust insulin secretion from β-cells by comparing two insulin secreting β-cell lines with good and poor glucose responsiveness, respectably. The cell line with poor glucose responsiveness showed increased lactate production and glycolytic flux but decreased ATP production, suggesting a disturbed coupling between glycolytic flux and mitochondrial glucose metabolism. Several metabolic genes that differed between the cell lines were found to correlate with HbA1c in human islets, reflecting long term glucose control.
In paper II, a metabolic profiling analysis showed that a metabolic shift towards less glucose responsiveness and more anaerobic metabolism was characteristic for cells with poor glucosestimulated insulin secretion. Also, the hypoxia-induced transcription factor HIF-1α was found to be more stabilized in poorly responsive cells. A comparison between healthy and
T2D human islets showed that this mechanism may be occurring in T2D humans as well.
In paper III, we examined palmitate-induced lipotoxicity in β-cells and found that cellular stress introduced by lipotoxicity directs metabolism more towards metabolism of lipids than of glucose. Together with this, the cells exhibited poor glucose responsiveness in intracellular metabolic flux and insulin secretion. Changes in metabolic flux were accompanied by changes in gene expression and increased expression of genes in the pathways of steroid biosynthesis, cell cycle, fatty acid metabolism, DNA replication, and biosynthesis of unsaturated fatty acids. Histone-modifying enzyme activity and histone modifications on the genes Insig1, Lss, Peci, Idi1, Hmgcs1 and Casr were found to be altered in a manner consistent with gene expression. This suggests the involvement of epigenetic regulations.
In conclusion, this thesis suggests that the coupling between glycolytic and mitochondrial flux is essential for the glucose sensitivity of the β-cell. Alterations in transcription factors or gene expression could be underlying disturbances of this coupling. It also shows that a diabetogenic environment with increased concentrations of fatty acids affects metabolic flux in these cells, something that is paralleled by an altered expression of metabolic genes. Finally, it suggests that epigenetic mechanisms could be involved in the regulation of these alterations.
Department/s
Publishing year
2012
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2012:91
Full text
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Document type
Dissertation
Publisher
Units of Epigenetics and Diabetes and Molecular Metabolism, Department of Clinical Sciences, Malmö
Topic
- Endocrinology and Diabetes
Keywords
- HIF-1α
- oxygen consumption
- β-cell
- Insulin secretion
- Type 2 Diabetes
- mitochondrial metabolism
- metabolic profiling
- Lipotoxicity
- Histone acetylation
- Histone methylation
Status
Published
Research group
- Diabetes - Molecular Metabolism
- Diabetes - Epigenetics
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-87189-54-8
Defence date
30 November 2012
Defence time
13:15
Defence place
Jubileumsaulan, Jan Waldenströms gata 1, SUS i Malmö
Opponent
- Peter Bergsten (Professor)