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Effects of Free Fatty Acids on Insulin and Glucagon Secretion: – with special emphasis on the role of Free fatty acid receptor 1
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prevalence of type 2 diabetes mellitus (T2DM) is still rising and even so in the juvenile population. Obesity is highly associated with increased risk for developing T2DM. The development has been related to elevated fasting concentrations of the pancreatic islet hormones insulin and glucagon as well as to an increase in plasma lipids that occurs during obesity. Specifically, research has indicated that chronic exposure to high levels of saturated free fatty acids cause dysfunction in islet alpha- and beta-cells. Fatty acids can affect islet cells by various mechanisms one of which is the G-protein coupled receptor FFAR1/GPR40. The role of the receptor in the effects of fatty acids on pancreatic islet-cell function is not clear. The aim of this thesis was to clarify the role of FFAR1 in how fatty acids, and more specifically the long-chain saturated fatty acid palmitate, affect insulin and glucagon secretion.

In children and adolescents with obesity elevated fasting levels of insulin and glucagon were positively correlated with lipid parameters. Specifically, plasma triglycerides and free fatty acids were positively correlated with insulin and glucagon at fasting as well as with visceral adipose tissue volume. Elevated glucagon levels at fasting were associated with worsening of glucose tolerance in the same population. In in vitro studies of isolated human islets palmitate stimulated basal insulin and glucagon secretion as well as mitochondrial respiration at fasting glucose levels. The effect was mediated by FFAR1 and fatty acid beta-oxidation. At higher glucose concentrations the receptor was involved in the potentiation of insulin secretion from isolated human islets and insulin-secreting MIN6 cells. Furthermore, we found that the effects of palmitate on hormone secretion were associated with enhanced mitochondrial respiration mediated by FFAR1 Gαq signaling and PKC activity as well as increased intracellular metabolism induced by the fatty acid. When islets were exposed to palmitate for long time periods and in the presence of FFAR1 antagonist, normalized insulin and glucagon secretion during culture and insulin response to glucose after culture were observed. In MIN6 cells chronic palmitate treatment increased mitochondrial uncoupling irrespective of FFAR1 involvement. However, FFAR1 antagonism during palmitate exposure resulted in elevated respiration and reduced apoptosis.

In conclusion, children and adolescents with obesity have elevated fasting concentrations of insulin and glucagon that correlate with free fatty acids and fatty acid sources. High glucagon levels are linked to worsening of glucose tolerance in these subjects. In vitro the combination or synergy of FFAR1 activation and intracellular metabolism caused by palmitate is decisive for both the short-term enhancement effects and the negative chronic effects on insulin and glucagon secretion. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1320
Keyword [en]
FFAR1, GPR40, palmitate, lipotoxicity, islets of Langerhans, type 2 diabetes, obesity
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-316991ISBN: 978-91-554-9867-2 (print)OAI: oai:DiVA.org:uu-316991DiVA: diva2:1084190
Public defence
2017-05-19, B22, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2017-04-24 Created: 2017-03-23 Last updated: 2017-05-05
List of papers
1. FFAR1 is involved in both the acute and chronic effects of palmitate on insulin secretion
Open this publication in new window or tab >>FFAR1 is involved in both the acute and chronic effects of palmitate on insulin secretion
2013 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, S194-S194 p.Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-218006 (URN)000329196901122 ()
Conference
49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 23-27, 2013, Barcelona, SPAIN
Available from: 2014-02-07 Created: 2014-02-06 Last updated: 2017-03-23Bibliographically approved
2. Palmitate stimulates insulin secretion by enhancing mitochondrial respiration via intracellular metabolism and FFAR1 signalling
Open this publication in new window or tab >>Palmitate stimulates insulin secretion by enhancing mitochondrial respiration via intracellular metabolism and FFAR1 signalling
2015 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, S214-S214 p.Article in journal, Meeting abstract (Other academic) Published
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-264904 (URN)000359820901120 ()
Conference
51st Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 14-18, 2015, Stockholm, SWEDEN
Note

Meeting Abstract: 430

Available from: 2015-11-05 Created: 2015-10-19 Last updated: 2017-03-23Bibliographically approved
3. Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion
Open this publication in new window or tab >>Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion
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(English)Article in journal (Refereed) Submitted
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-317899 (URN)
Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2017-03-23
4. Fatty acids trigger glucagon secretion: a potential link to fasting hyperglucagonemia in children with obesity
Open this publication in new window or tab >>Fatty acids trigger glucagon secretion: a potential link to fasting hyperglucagonemia in children with obesity
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Endocrinology and Diabetes
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-317898 (URN)
Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2017-03-23

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