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Hyperglucagonemia in youth is associated with high plasma free fatty acids, visceral adiposity and impaired glucose tolerance
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. 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 Surgical Sciences, Radiology.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-5722-4908
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(English)In: Article in journal (Refereed) Submitted
Abstract [en]

Objective: To delineate mechanisms for fasting hyperglucagonemia in childhood obesity bystudying the associations between fasting plasma glucagon concentrations and plasmalipid parameters and fat compartments.

Methods: Cross-sectional study of children and adolescents with obesity (n=147) and leancontrols (n=43). Differences in free fatty acids (FFA), triglycerides, insulin and fatcompartments (quantified by magnetic resonance imaging) across quartiles of fastingplasma glucagon concentration were analysed. Differences in OGTT glucagonresponse was tested in high vs low FFAs, triglycerides and insulin. Human islets ofLangerhans were cultured at 5.5 mmol/l glucose and in the absence or presence of aFFA mixture with total FFA concentration of 0.5 mmol/l and glucagon secretionquantified.

Results: In children with obesity, the quartile with the highest fasting glucagon had higherinsulin (201±174 vs 83±39 pmol/l, p<0.01), FFAs (383±52 vs 338±109 μmol/l,p=0.02), triglycerides (1.5±0.9 vs 1.0±0.7 mmol/l, p<0.01), visceral adipose tissuevolume (1.9±0.8 vs 1.2±0.3 dm3, p<0.001) and a higher prevalence of impairedglucose tolerance (41% vs 8%, p=0.01) than the lowest quartile. During OGTT,children with obesity and high insulin had a worse suppression of glucagon during thefirst 10 minutes after glucose intake. Glucagon secretion was 2.6-fold higher in isletstreated with FFAs than in those not treated with FFAs.4

Conclusion: Hyperglucagonemia in childhood obesity is associated with hyperinsulinemia, highplasma FFAs, high plasma triglycerides, visceral adiposity and impaired glucosetolerance. The glucagonotropic effect of FFAs on isolated human islets provides apotential mechanism linking high fasting plasma FFAs and glucagon levels.

Keywords [en]
Childhood obesity, glucagon, free fatty acids, insulin, visceral adiposity, impaired glucose tolerance, type 2 diabetes
National Category
Pediatrics
Identifiers
URN: urn:nbn:se:uu:diva-380313OAI: oai:DiVA.org:uu-380313DiVA, id: diva2:1299157
Funder
EU, FP7, Seventh Framework Programme, 279153EXODIAB - Excellence of Diabetes Research in SwedenErnfors FoundationErik, Karin och Gösta Selanders FoundationSwedish Research Council, 2015-4870Swedish Diabetes AssociationAvailable from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-03-28
In thesis
1. Impaired Glucose Tolerance in Childhood Obesity: Contribution of Glucagon, GLP-1 and Inflammation
Open this publication in new window or tab >>Impaired Glucose Tolerance in Childhood Obesity: Contribution of Glucagon, GLP-1 and Inflammation
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the wake of increased obesity prevalence, impaired glucose tolerance (IGT) and type 2 diabetes (T2D) in childhood and adolescence is increasingly common. Given the negative impacts these conditions have on health over time, understanding the pathophysiology in those affected early in life is important. Both the proglucagon-derived peptides and low-grade inflammation have been implicated in the development of obesity-related complications. The aim of this thesis was to study across the glucose tolerance spectrum in children and adolescents with obesity 1) proglucagon-derived peptides glucagon, GLP-1 and glicentin, 2) dipeptidyl peptidase-4 (DPP-4) and its degradation of GLP-1 and 3) novel inflammatory markers. To this end, children and adolescents of the Uppsala Longitudinal Study of Childhood Obesity were studied.   

Children and adolescents with obesity had higher fasting plasma glucagon concentrations than lean controls. In particular visceral adiposity, hyperinsulinemia, triglycerides and free fatty acids (FFAs) were associated with high plasma glucagon concentrations. In isolated islets elevated FFAs caused hypersecretion of glucagon. In children and adolescents with IGT or T2D, fasting plasma glucagon was further elevated and the GLP-1 and glicentin response to an oral glucose tolerance test (OGTT) was decreased. In T2D plasma glucagon increased during the first 15 minutes of OGTT. Plasma DPP-4 concentrations were elevated in obesity and associated with lower proportion of intact GLP-1 but not with IGT. Several pro-inflammatory markers were elevated in children and adolescents with obesity but not further elevated in IGT or T2D with the exception of low plasma Tumor necrosis factor-related weak inducer of apoptosis (TWEAK) levels, which were associated with IGT, hyperinsulinemia and hyperglucagonemia. High plasma hepatocyte growth factor (HGF) concentration was associated with increased risk of further weight gain in children and adolescents with obesity.

In conclusion, elevated glucagon concentration at fasting, a hyperglucagonemic response to OGTT and reduced GLP-1 and glicentin are characteristics of IGT and T2D development in childhood obesity reflecting altered usage of the proglucagon gene. DPP-4 concentrations are elevated in childhood obesity but not associated with IGT. Reduced circulating TWEAK was identified as a novel marker of IGT early in life. Children with obesity and high HGF are less likely to respond well to lifestyle intervention.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 49
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1560
Keywords
Childhood obesity, impaired glucose tolerance, type 2 diabetes, glucagon, glucagon-like peptide-1, dipeptidyl peptidase-4, inflammation, free fatty acids, insulin, visceral adiposity
National Category
Pediatrics Endocrinology and Diabetes Cell and Molecular Biology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-380318 (URN)978-91-513-0618-6 (ISBN)
Public defence
2019-05-22, Room B21, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2019-04-26 Created: 2019-03-28 Last updated: 2019-06-18

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Manell, HannesKristinsson, HjaltiKullberg, JoelUbhayasekera, KumariStaaf, JohanSargsyan, ErnestAhlström, HåkanBergquist, JonasForslund, AndersBergsten, Peter

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Manell, HannesKristinsson, HjaltiKullberg, JoelUbhayasekera, KumariStaaf, JohanSargsyan, ErnestAhlström, HåkanBergquist, JonasForslund, AndersBergsten, Peter
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Department of Women's and Children's HealthDepartment of Medical Cell BiologyRadiologyAnalytical ChemistryScience for Life Laboratory, SciLifeLabDepartment of Medical SciencesPaediatric Inflammation Research
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