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Improved mass and function in glucotoxic β-cells by AICAR is dose-dependent not affecting triglyceride content
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-96441OAI: oai:DiVA.org:uu-96441DiVA: diva2:171014
Available from: 2007-11-14 Created: 2007-11-14 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Glucotoxicity in Insulin-Producing β-Cells
Open this publication in new window or tab >>Glucotoxicity in Insulin-Producing β-Cells
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background and aims: Type 2 diabetes mellitus is connected with elevated glucose levels, which cause impaired glucose-stimulated insulin secretion (GSIS) and degeneration of β-cells. Mechanisms for such glucotoxic effects were explored in the present study.

Materials and methods: INS-1E cells were cultured for 5 days in 5.5, 11, 20 or 27 mM glucose in the presence or absence of AMPK-agonist AICAR. GSIS was determined from INS-1E cells and islets obtained from type 2 diabetes and control donors. Human islets and INS-1E cells were functionally characterized (GSIS) and protein profiled (SELDI-TOF MS). Glucose-induced de novo synthesis of fatty acyls (HR-MAS NMR spectroscopy), fatty acid composition (GC-MS), triglyceride content and specific proteins (Western blotting) were determined in INS-1E cells.

Results: Impaired GSIS was observed from INS-1E cells exposed to chronic hyperglycaemia and islets isolated from type 2 diabetics compared to INS-1E cells cultured at normal glucose levels and control islets, respectively. Several glucose-regulated proteins were found when type 2 diabetes and control islets or mitochondria from INS-1E cells cultured at different glucose concentrations were protein profiled. Glucose induced lipid de novo synthesis of both saturated and unsaturated fatty acids in specific proportions. Glucose-induced impairment of function and mass was reverted by inclusion of AICAR, which lowered levels of pro-apoptotic protein CHOP but left triglyceride content unaffected.

Conclusions: Impaired GSIS and increased apoptosis observed in β-cells after prolonged exposure to elevated glucose concentrations involved accumulation of lipid species in specific proportions, AMPK-inactivation, ER-stress activation and complex, coordinated changes in expression patterns of mitochondrial and human islet proteins.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 45 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 291
Cell biology, type 2 diabetes, SELDI-TOF MS, glucotoxicity, proteomics, insulin secretion, mitochondria, lipids, INS-1E cells, GC-MS, HR-MAS NMR, metabolomics, human islet, AMPK, AICAR, ER stress, apoptosis, Cellbiologi
urn:nbn:se:uu:diva-8309 (URN)978-91-554-7022-7 (ISBN)
Public defence
2007-12-08, B21, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2007-11-14 Created: 2007-11-14Bibliographically approved

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