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Glucose, Palmitate and Apolipoprotein CIII-induced Effects on Insulin-Producing β-cells [Elektronisk resurs]

Sol, E-ri Maria (författare)
Bergsten, Peter (preses)
Morgan, Noel (opponent)
Uppsala universitet Medicinska och farmaceutiska vetenskapsområdet (utgivare)
Publicerad: Uppsala : Acta Universitatis Upsaliensis, 2009
Engelska 48
Serie: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 1651-6206
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  • E-bokAvhandling(Diss. (sammanfattning) Uppsala : Uppsala universitet, 2009)
Sammanfattning Ämnesord
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  • Background and aims: Type 2 diabetes mellitus results from complex interplay between genetic predisposition and environmental factors that together promote impairment of insulin-producing β-cells. Elevated levels of glucose, fatty acid palmitate and apolipoprotein CIII (apoCIII) are implicated in this process. To delineate effects of these factors, the role of enhanced carnitine palmitoyltransferase 1 (CPT1) expression in glucolipotoxic cells, glucose-dependency of the unfolded protein response (UPR) in palmitate-induced apoptosis and activation of mitogen activated protein kinases (MAPKs) in apoCIII-induced apoptosis were evaluated. In addition, protein profiles of β-cell exposed to elevated levels of glucose or palmitate were generated to identify proteins regulated by these nutrients. Methodology: INS-1E cells were cultured at different glucose concentrations in the absence or presence of palmitate or apoCIII for up to 48 hours. CPT1 was over-expressed with a Tet-ON regulated adenovirus. In cells exposed to apoCIII, inhibitors of MAPKs p38 or ERK1/2 were included during culture. After culture, apoptosis, insulin secretion, expression of UPR-markers and MAPKs and protein profiles were determined. Results: INS-1E cells exposed to elevated levels of glucose and palmitate showed deranged insulin secretion with increased insulin secretion at non-stimulatory glucose level, enhanced apoptosis and induced expression of UPR-markers. Over-expression of CPT1 reduced basal insulin secretion and attenuated apoptosis. Palmitate-induced apoptosis was accentuated by increasing the culture glucose concentration. Markers of UPR were not modulated by the glucose concentration in INS-1E cell exposed to palmitate, however. ApoCIII-induced apoptosis in INS-1E cells was accompanied by activation of p38 and ERK1/2. Protein profiling of INS-1E cells exposed to elevated levels of glucose or palmitate revealed changes in expression of multiple β-cell proteins implicated in glucose metabolism, defence against reactive oxygen species, protein translation/folding/degradation and insulin granular trafficking. Conclusions: Over-expression of CPT1 counteracts β-cell glucolipotoxicity. Activation of UPR is not a major determinant for palmitate-induced β-cell apoptosis. ApoCIII-induced β-cell apoptosis involves activation of MAPKs. The identified differentially expressed proteins indicate a central role of altered glucose metabolism and protein synthesis in gluco- and lipotoxic β-cells and may provide specific molecular mechanisms offering new ways of treating the disease.   

Ämnesord

Medical and Health Sciences  (hsv)
Basic Medicine  (hsv)
Cell and Molecular Biology  (hsv)
Medicin och hälsovetenskap  (hsv)
Medicinska och farmaceutiska grundvetenskaper  (hsv)
Cell- och molekylärbiologi  (hsv)
MEDICINE  (svep)
Morphology, cell biology, pathology  (svep)
Cell biology  (svep)
Medical cell biology  (svep)
MEDICIN  (svep)
Morfologi, cellbiologi, patologi  (svep)
Cellbiologi  (svep)
Medicinsk cellbiologi  (svep)
medicinsk cellbiologi  (uu)
Medical Cell Biology  (uu)

Genre

government publication  (marcgt)
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