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High DPP-4 concentrations in adolescents are associated with low intact GLP-1
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Pediatrisk inflammationsforskning.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Antaros Med, SE-43183 Molndal, Sweden.
Vise andre og tillknytning
2018 (engelsk)Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, nr 8, s. 2958-2966Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Endocrine Society , 2018. Vol. 103, nr 8, s. 2958-2966
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-354234DOI: 10.1210/jc.2018-00194ISI: 000442236900022PubMedID: 29850829OAI: oai:DiVA.org:uu-354234DiVA, id: diva2:1220949
Forskningsfinansiär
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 FoundationTilgjengelig fra: 2018-06-19 Laget: 2018-06-19 Sist oppdatert: 2019-03-28bibliografisk kontrollert
Inngår i avhandling
1. Impaired Glucose Tolerance in Childhood Obesity: Contribution of Glucagon, GLP-1 and Inflammation
Åpne denne publikasjonen i ny fane eller vindu >>Impaired Glucose Tolerance in Childhood Obesity: Contribution of Glucagon, GLP-1 and Inflammation
2019 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 49
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1560
Emneord
Childhood obesity, impaired glucose tolerance, type 2 diabetes, glucagon, glucagon-like peptide-1, dipeptidyl peptidase-4, inflammation, free fatty acids, insulin, visceral adiposity
HSV kategori
Forskningsprogram
Medicinsk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-380318 (URN)978-91-513-0618-6 (ISBN)
Disputas
2019-05-22, Room B21, BMC, Husargatan 3, Uppsala, 13:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2019-04-26 Laget: 2019-03-28 Sist oppdatert: 2019-06-18

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