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Fatty acids stimulate insulin secretion from human pancreatic islets at fasting glucose concentrations via mitochondria-dependent and -independent mechanisms
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.
2016 (English)In: Nutrition & Metabolism, ISSN 1743-7075, E-ISSN 1743-7075, Vol. 13, article id 59Article in journal (Refereed) Published
Abstract [en]

Background: Free fatty acids (FFAs) acutely stimulate insulin secretion from pancreatic islets. Conflicting results have been presented regarding this effect at non-stimulatory glucose concentration, however. The aim of our study was to investigate how long-chain FFAs affect insulin secretion from isolated human pancreatic islets in the presence of physiologically fasting glucose concentrations and to explore the contribution of mitochondria to the effects on secretion. Methods: Insulin secretion from human pancreatic islets was measured from short-term static incubation or perfusion system at fasting glucose concentration (5.5 mM) with or without 4 different FFAs (palmitate, palmitoleate, stearate, and oleate). The contribution of mitochondrial metabolism to the effects of fatty acid-stimulated insulin secretion was explored. Results: The average increase in insulin secretion, measured from statically incubated and dynamically perifused human islets, was about 2-fold for saturated free fatty acids (SFAs) (palmitate and stearate) and 3-fold for mono-unsaturated free fatty acids (MUFAs) (palmitoleate and oleate) compared with 5.5 mmol/l glucose alone. Accordingly, MUFAs induced 50 % and SFAs 20 % higher levels of oxygen consumption compared with islets exposed to 5.5 mmol/l glucose alone. The effect was due to increased glycolysis. When glucose was omitted from the medium, addition of the FFAs did not affect oxygen consumption. However, the FFAs still stimulated insulin secretion from the islets although secretion was more than halved. The mitochondria-independent action was via fatty acid metabolism and FFAR1/GPR40 signaling. Conclusions: The findings suggest that long-chain FFAs acutely induce insulin secretion from human islets at physiologically fasting glucose concentrations, with MUFAs being more potent than SFAs, and that this effect is associated with increased glycolytic flux and mitochondrial respiration.

Place, publisher, year, edition, pages
2016. Vol. 13, article id 59
Keywords [en]
Insulin secretion, Human pancreatic islets, Saturated fatty acids, Monounsaturated fatty acids, Mitochondrial respiration
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-305932DOI: 10.1186/s12986-016-0119-5ISI: 000384583400001PubMedID: 27582778OAI: oai:DiVA.org:uu-305932DiVA, id: diva2:1046600
Available from: 2016-11-14 Created: 2016-10-24 Last updated: 2018-06-27Bibliographically 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)
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Supervisors
Available from: 2018-08-16 Created: 2018-06-27 Last updated: 2018-08-27Bibliographically approved

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