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GLP-1 recovers impaired insulin secretion from human islets treated with palmitate via down-regulation of SOCS2
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.
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-230839OAI: oai:DiVA.org:uu-230839DiVA: diva2:742078
Available from: 2014-08-30 Created: 2014-08-30 Last updated: 2015-01-23
In thesis
1. Role of Cell-cell Interactions and Palmitate on β-cells Function
Open this publication in new window or tab >>Role of Cell-cell Interactions and Palmitate on β-cells Function
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The islets of Langerhans secrets insulin in response to fluctuations of blood glucose level and efficient secretion requires extensive intra-islet communication. Secretory failure from islets is one of the hallmark in progression of type 2 diabetes.  Changes in islet structure and high levels of saturated free fatty acids may contribute to this failure. The aim of this thesis is to study the role of cell-cell interactions and palmitate on β-cells functions.

To address the role of cell-cell interactions on β-cells functions MIN6 cells were cultured as monolayers and as pseudoislets. Glucose stimulated insulin secretion was higher in pseudoislets compared to monolayers. Transcript levels of mitochondrial metabolism as well glucose oxidation rate was higher in pseudoislets. Insulin receptor substrate-1 (IRS-1) phosphorylation was altered when cells were grown as pseudoislets. Proteins expression levels related to glycolysis, cellular connections and translational regulations were up-regulated in pseudoislets. We propose the superior capacity of pseudoislets compared to monolayers depend on metabolism, cell coupling, gene translation, protein turnover and differential IRS-1 phosphorylation.

To address the role of palmitate on β-cells human islets were cultured in palmitate. Long term palmitate treatment decreased insulin secretion which is associated with up-regulation of suppressor of cytokine signaling-2 (SOCS2) and protein inhibitor of activated STAT-1 (PIAS1). Up-regulation of SOCS2 decreased phosphorylation of Akt at site T308, whereas PIAS1 decreased protein level of ATP- citrate lyase (ACLY) and ATP synthase subunit B (ATP5B). We propose long term palmitate treatment reduces phosphatidylinositol 3-kinase (PI3K) activity, attenuates formation of acetyl-CoA and decreases ATP synthesis which may aggravate β-cells dysfunction.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 42 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1025
Keyword
Metabolism, PI3K, Pseudoislets, Human islets, SOCS, PIAS
National Category
Cell and Molecular Biology
Research subject
Biology with specialization in Molecular Biology
Identifiers
urn:nbn:se:uu:diva-230841 (URN)978-91-554-9021-8 (ISBN)
Public defence
2014-10-17, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-09-25 Created: 2014-08-30 Last updated: 2015-01-23

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