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Mitochondrial protein patterns correlating with impaired insulin secretion from INS-1E cells exposed to elevated glucose concentrations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2006 (English)In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 6, no 19, 5193-5198 p.Article in journal (Refereed) Published
Abstract [en]

Extended hyperglycaemia leads to impaired glucose-stimulated insulin secretion (GSIS) and eventually P-cell apoptosis in individuals with type 2 diabetes mellitus. In an attempt to dissect mechanisms behind the detrimental effects of glucose, we focused on measuring changes in expression patterns of mitochondrial proteins. Impaired GSIS was observed from INS-1E cells cultured for 5 days at 20 or 27 mM glucose compared to cells cultured at 5.5 or 11 mM glucose. After culture, mitochondria were isolated from the INS-1E cells by differential centrifugation. Proteins of the mitochondrial fraction were bound to a strong anionic surface (SAX2) protein array and mass spectra generated by SELDI-TOF-MS. Analysis of the spectra revealed proteins with expression levels that correlated with the glucose concentration of the culture medium. Indeed, such differentially expressed proteins created patterns of protein changes, which correlated with impairment of GSIS. In conclusion, the study reveals the first glucose-induced differentially expressed patterns of P-cell mitochondrial proteins obtained by SELDI-TOF-MS.

Place, publisher, year, edition, pages
2006. Vol. 6, no 19, 5193-5198 p.
Keyword [en]
diabetes, glucose, insulin secretion, mitochondria, SELDI-TOF-MS
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96439DOI: 10.1002/pmic.200600137ISI: 000241249800011PubMedID: 16941568OAI: oai:DiVA.org:uu-96439DiVA: diva2:171012
Available from: 2007-11-14 Created: 2007-11-14 Last updated: 2017-12-14Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 291
Keyword
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
Identifiers
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
Opponent
Supervisors
Available from: 2007-11-14 Created: 2007-11-14Bibliographically approved

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Thorn, KristoferBergsten, Peter

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