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Mechanisms of beneficial effects of metformin on fatty acid-treated human islets
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Peter Bergsten)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Molecular Neuroscience Group, Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.ORCID iD: 0000-0001-9109-4556
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 Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
2018 (English)In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 61, no 3, p. 91-99Article in journal (Refereed) Published
Abstract [en]

Elevated levels of palmitate accentuate glucose-stimulated insulin secretion (GSIS) after short-term and cause beta-cell dysfunction after prolonged exposure. We investigated whether metformin, the first-line oral drug for treatment of T2DM, has beneficial effects on FFA-treated human islets and the potential mechanisms behind the effects. Insulin secretion, oxygen consumption rate (OCR), AMPK activation, endoplasmic reticulum (ER) stress and apoptosis were examined in isolated human islets after exposure to elevated levels of palmitate in the absence or presence of metformin. Palmitate exposure doubled GSIS after 2 days but halved after 7 days compared with control. Inclusion of metformin during palmitate exposure normalized insulin secretion both after 2 and 7 days. After 2-day exposure to palmitate, OCR and the marker of the adaptive arm of ER stress response (sorcin) were significantly raised, whereas AMPK phosphorylation, markers of pro-apoptotic arm of ER stress response (p-EIF2α and CHOP) and apoptosis (cleaved caspase 3) were not affected. Presence of metformin during 2-day palmitate exposure normalized OCR and sorcin levels. After 7-day exposure to palmitate, OCR and sorcin were not significantly different from control level, p-AMPK was reduced and p-EIF2α, CHOP and cleaved caspase 3 were strongly upregulated. Presence of metformin during 7-day culture with palmitate normalized the level of p-AMPK, p-EIF2α, CHOP and cleaved caspase 3 but significantly increased the level of sorcin. Our study demonstrates that metformin prevents early insulin hypersecretion and later decrease in insulin secretion from palmitate-treated human islets by utilizing different mechanisms.

Place, publisher, year, edition, pages
2018. Vol. 61, no 3, p. 91-99
Keywords [en]
Metformin, palmitate, human islets, insulin secretion, mitochondrial respiration, ER stress
National Category
Endocrinology and Diabetes Pharmacology and Toxicology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-353691DOI: 10.1530/JME-17-0304ISI: 000452706400005PubMedID: 30307162OAI: oai:DiVA.org:uu-353691DiVA, id: diva2:1228045
Funder
Swedish Diabetes Association, DIA 2016-146EU, FP7, Seventh Framework Programme, 279 153Ernfors Foundation, 170504Available from: 2018-06-27 Created: 2018-06-27 Last updated: 2019-01-11Bibliographically approved
In thesis
1. Free fatty acids and insulin hypersecretion studied in human islets
Open this publication in new window or tab >>Free fatty acids and insulin hypersecretion studied in human islets
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Free fatty acid (FFA) levels are increased in many obese subjects. High FFA levels stimulate the pancreatic beta-cells but have negative long-term effects. In obese children with high FFA levels circulating insulin concentration is high early in life but decline with age precipitating the development of type 2 diabetes mellitus (T2DM). The present study aims at preventing this development of T2DM by defining underlying mechanisms of insulin hypersecretion. Such mechanisms will be identified by studying regulation of insulin secretion from human pancreatic islets and human EndoC-βH1 cells exposed to elevated FFA levels.

We found that elevated concentrations of FFAs acutely stimulate insulin from human pancreatic islets at fasting blood glucose level, with mono-unsatured being more potent than saturated fatty acids. Enhanced secretion was associated with increased glycolytic flux and mitochondrial respiration. Continued exposure to elevated palmitate levels for up to 2 days accentuated insulin secretion, whereas 7 days’ exposure caused secretory decline. Metformin prevented insulin hypersecretion from human islets treated with palmitate for 2 days by decreasing mitochondrial metabolism. In islets exposed to palmitate for 7 days metformin improved insulin secretion by enhancing calcium binding protein sorcin levels and thereby reducing ER stress and apoptosis. Downregulation of sorcin had negative effects on insulin secretion, mitochondrial metabolism and ER stress in human islets and EndoC-βH1 cells. Specific cellular pathways involved in insulin hypersecretion and secretory decline were identified by microarray expression analysis and subsequent bioinformatics in human islets cultured with palmitate for 0, 4, 12 hours, 1, 2, and 7 days.

In conclusion, beta-cells respond to elevated levels of FFAs by initially augmenting insulin release followed by declining secretory levels after prolonged exposure. Metformin normalizes these secretory aberrations. Specific signaling pathways and proteins including sorcin contribute to the secretory alterations induced by palmitate. When developing strategies for prevention of T2DM in obese children with elevated FFA levels, metformin should be considered as well as novel strategies involving sorcin and the identified specific pathways.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 43
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1476
Keywords
free fatty acids, palmitate, human islets, EndoC-βH1 cells, metformin, sorcin, insulin secretion, mitochondrial respiration, ER stress, human transcriptome array
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-355090 (URN)978-91-513-0380-2 (ISBN)
Public defence
2018-09-07, C4:301, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-08-16 Created: 2018-06-27 Last updated: 2018-08-27Bibliographically approved

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Cen, JingSargsyan, ErnestForslund, AndersBergsten, Peter

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