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Impaired Glucose Tolerance in Childhood Obesity: Contribution of Glucagon, GLP-1 and Inflammation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Peter Bergsten)
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 [en]
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: urn:nbn:se:uu:diva-380318ISBN: 978-91-513-0618-6 (print)OAI: oai:DiVA.org:uu-380318DiVA, id: diva2:1299767
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
List of papers
1. Altered Plasma Levels of Glucagon, GLP-1 and Glicentin During OGTT in Adolescents With Obesity and Type 2 Diabetes
Open this publication in new window or tab >>Altered Plasma Levels of Glucagon, GLP-1 and Glicentin During OGTT in Adolescents With Obesity and Type 2 Diabetes
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2016 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 3, p. 1181-1189Article in journal (Refereed) Published
Abstract [en]

CONTEXT: Proglucagon-derived hormones are important for glucose metabolism, but little is known about them in pediatric obesity and type 2 diabetes mellitus (T2DM).

OBJECTIVE: Fasting and postprandial levels of proglucagon-derived peptides glucagon, GLP-1, and glicentin in adolescents with obesity across the glucose tolerance spectrum were investigated.

DESIGN: This was a cross-sectional study with plasma hormone levels quantified at fasting and during an oral glucose tolerance test (OGTT).

SETTING: This study took place in a pediatric obesity clinic at Uppsala University Hospital, Sweden.

PATIENTS AND PARTICIPANTS: Adolescents with obesity, age 10-18 years, with normal glucose tolerance (NGT, n = 23), impaired glucose tolerance (IGT, n = 19), or T2DM (n = 4) and age-matched lean adolescents (n = 19) were included.

MAIN OUTCOME MEASURES: Outcome measures were fasting and OGTT plasma levels of insulin, glucagon, active GLP-1, and glicentin.

RESULTS: Adolescents with obesity and IGT had lower fasting GLP-1 and glicentin levels than those with NGT (0.25 vs 0.53 pM, P < .05; 18.2 vs 23.6 pM, P < .01) and adolescents with obesity and T2DM had higher fasting glucagon levels (18.1 vs 10.1 pM, P < .01) than those with NGT. During OGTT, glicentin/glucagon ratios were lower in adolescents with obesity and NGT than in lean adolescents (P < .01) and even lower in IGT (P < .05) and T2DM (P < .001).

CONCLUSIONS: Obese adolescents with IGT have lowered fasting GLP-1 and glicentin levels. In T2DM, fasting glucagon levels are elevated, whereas GLP-1 and glicentin levels are maintained low. During OGTT, adolescents with obesity have more products of pancreatically than intestinally cleaved proglucagon (ie, more glucagon and less GLP-1) in the plasma. This shift becomes more pronounced when glucose tolerance deteriorates.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-292749 (URN)10.1210/jc.2015-3885 (DOI)000378811300051 ()26745255 (PubMedID)
Funder
VINNOVAEU, FP7, Seventh Framework Programme, 279153Swedish Diabetes Association, DIA 2013-043
Available from: 2016-05-09 Created: 2016-05-09 Last updated: 2019-03-28Bibliographically approved
2. High DPP-4 concentrations in adolescents are associated with low intact GLP-1
Open this publication in new window or tab >>High DPP-4 concentrations in adolescents are associated with low intact GLP-1
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2018 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 8, p. 2958-2966Article in journal (Refereed) Published
Abstract [en]

Context: Dipeptidyl Peptidase-4 (DPP-4) metabolizes glucagon-like peptide-1 (GLP-1) and increased DPP4 levels are associated with obesity and visceral adiposity in adults.

Objective: Investigating DPP-4 levels in adolescents and association with, firstly, circulating intact GLP-1 levels and glucose tolerance, secondly, BMI, and, thirdly visceral, subcutaneous and liver fat compartments.

Design: Cross-sectional study, July 2012 to April 2015.

Setting: Pediatric obesity clinic, Uppsala University Hospital.

Patients and participants: Children and adolescents with obesity (n=59) and lean controls (n=21), age 8-18.

Main outcome measures: BMI SDS, fasting plasma concentrations of DPP-4, total and intact GLP-1, fasting and OGTT concentrations of glucose and visceral (VAT) and subcutaneous (SAT) adipose tissue volumes and liver fat fraction.

Results: Plasma DPP-4 decreased with age both in obese (41 ng/ml per year) and lean subjects (48 ng/ml per year). Plasma DPP-4 was higher in males both in the obesity and lean group. When adjusting for age and sex, plasma DPP-4 was negatively associated with intact GLP-1 at fasting, B=-12.3, 95% CI [-22.9, -1.8] and during OGTT, B=-12.1, 95% CI [-22.5, -1.7]. No associations were found between DPP-4 and plasma glucose measured at fasting or after a 2-hour OGTT. Plasma DPP-4 was 19% higher in the obese subjects. Among adipose tissue compartments the strongest association was with VAT, B=0.05, 95% CI [-0.02, 0.12].

Conclusions: In adolescents, high plasma DPP-4 concentrations are associated with low proportion of intact GLP-1, high BMI, young age and male sex. The observed associations are compatible with an increased metabolism of GLP-1 in childhood obesity.

Place, publisher, year, edition, pages
Endocrine Society, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-354234 (URN)10.1210/jc.2018-00194 (DOI)000442236900022 ()29850829 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 279153Swedish Diabetes Association, DIA 2016-146Ernfors Foundation, 160504Swedish Research Council, 2016-01040EXODIAB - Excellence of Diabetes Research in SwedenErik, Karin och Gösta Selanders Foundation
Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2019-03-28Bibliographically approved
3. Hyperglucagonemia in youth is associated with high plasma free fatty acids, visceral adiposity and impaired glucose tolerance
Open this publication in new window or tab >>Hyperglucagonemia in youth is associated with high plasma free fatty acids, visceral adiposity and impaired glucose tolerance
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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
Childhood obesity, glucagon, free fatty acids, insulin, visceral adiposity, impaired glucose tolerance, type 2 diabetes
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-380313 (URN)
Funder
EU, FP7, Seventh Framework Programme, 279153EXODIAB - Excellence of Diabetes Research in SwedenErnfors FoundationErik, Karin och Gösta Selanders FoundationSwedish Research Council, 2015-4870Swedish Diabetes Association
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-03-28
4. Screening of inflammatory markers finds hepatocyte growth factor to be associated with weight gain in children and adolescents with obesity
Open this publication in new window or tab >>Screening of inflammatory markers finds hepatocyte growth factor to be associated with weight gain in children and adolescents with obesity
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(English)Manuscript (preprint) (Other academic)
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-380315 (URN)
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-03-28

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