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Siri Malmgren

Search for molecular and metabolic mechanisms contributing to impaired bet-cell function

Type 2 Diabetes (T2D) prevalence is growing to pandemic proportions worldwide. The link between genotype, environment and β-cell function is still being investigated. I have devoted the work presented in this thesis to attempt to elucidate the coupling of β-cell metabolism to insulin secretion and to look for casual mechanisms underlying metabolic alterations disturbing insulin secretion.

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.

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