Search for molecular and metabolic mechanisms contributing to impaired β-cell function
作者： Siri Malmgren
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摘要: Type 2 Diabetes (T2D) prevalence is growing to pandemic proportions worldwide. The link between genotype, environment and β-cell function still being investigated. I have devoted the work presented in this thesis attempt elucidate coupling of metabolism insulin secretion look for casual mechanisms underlying metabolic alterations disturbing secretion. In paper I, we showed that tight glycolysis mitochondrial required robust from β-cells by comparing two secreting lines with good poor glucose responsiveness, respectably. cell line responsiveness increased lactate production glycolytic flux but decreased ATP production, suggesting a disturbed metabolism. Several genes differed were found correlate HbA1c human islets, reflecting long term control. In II, profiling analysis shift towards less more anaerobic was characteristic cells glucosestimulated secretion. Also, hypoxia-induced transcription factor HIF-1α be stabilized poorly responsive cells. A comparison healthy and T2D islets mechanism may occurring T2D humans as well. In III, examined palmitate-induced lipotoxicity cellular stress introduced directs lipids than glucose. Together this, exhibited intracellular Changes accompanied changes gene expression pathways steroid biosynthesis, cycle, fatty acid metabolism, DNA replication, biosynthesis unsaturated acids. Histone-modifying enzyme activity histone modifications on Insig1, Lss, Peci, Idi1, Hmgcs1 Casr altered manner consistent expression. This suggests involvement epigenetic regulations. In conclusion, essential sensitivity β-cell. Alterations factors or could disturbances coupling. It also shows diabetogenic concentrations acids affects these cells, something paralleled an genes. Finally, it involved regulation alterations.
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