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Screening of inflammatory markers finds hepatocyte growth factor to be associated with weight gain in children and adolescents with obesity
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, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
University of Luxembourg.
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.
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(English)Manuscript (preprint) (Other academic)
National Category
Pediatrics
Identifiers
URN: urn:nbn:se:uu:diva-380315OAI: oai:DiVA.org:uu-380315DiVA, id: diva2:1299281
Available 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)
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Supervisors
Available from: 2019-04-26 Created: 2019-03-28 Last updated: 2019-06-18

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Manell, HannesShen, QiujinCiba, IrisDahlbom, MarieKamali-Moghaddam, MasoodBergsten, PeterForslund, Anders
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Department of Women's and Children's HealthDepartment of Medical Cell BiologyScience for Life Laboratory, SciLifeLabMolecular toolsDepartment of Medical SciencesPaediatric Inflammation Research
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