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Lundström, E., Ljungberg, J., Andersson, J., Manell, H., Strand, R., Forslund, A., . . . Kullberg, J. (2019). Brown adipose tissue estimated with the magnetic resonance imaging fat fraction is associated with glucose metabolism in adolescents. Pediatric Obesity, 14(9), Article ID e12531.
Open this publication in new window or tab >>Brown adipose tissue estimated with the magnetic resonance imaging fat fraction is associated with glucose metabolism in adolescents
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2019 (English)In: Pediatric Obesity, ISSN 2047-6302, E-ISSN 2047-6310, Vol. 14, no 9, article id e12531Article in journal (Refereed) Published
Abstract [en]

Background

Despite therapeutic potential against obesity and diabetes, the associations of brown adipose tissue (BAT) with glucose metabolism in young humans are relatively unexplored.

Objectives

To investigate possible associations between magnetic resonance imaging (MRI) estimates of BAT and glucose metabolism, whilst considering sex, age, and adiposity, in adolescents with normal and overweight/obese phenotypes.

Methods

In 143 subjects (10‐20 years), MRI estimates of BAT were assessed as cervical‐supraclavicular adipose tissue (sBAT) fat fraction (FF) and T*2 from water‐fat MRI. FF and T*2 of neighbouring subcutaneous adipose tissue (SAT) were also assessed. Adiposity was estimated with a standardized body mass index, the waist‐to‐height ratio, and abdominal visceral and subcutaneous adipose tissue volumes. Glucose metabolism was represented by the 2h plasma glucose concentration, the Matsuda index, the homeostatic model assessment of insulin resistance, and the oral disposition index; obtained from oral glucose tolerance tests.

Results

sBAT FF and T*2 correlated positively with adiposity before and after adjustment for sex and age. sBAT FF, but not T*2, correlated with 2h glucose and Matsuda index, also after adjustment for sex, age, and adiposity. The association with 2h glucose persisted after additional adjustment for SAT FF.

Conclusions

The association between sBAT FF and 2h glucose, observed independently of sex, age, adiposity, and SAT FF, indicates a role for BAT in glucose metabolism, which potentially could influence the risk of developing diabetes. The lacking association with sBAT T*2 might be due to FF being a superior biomarker for BAT and/or to methodological limitations in the T*2 quantification.

Keywords
adolescent, brown adipose tissue, glucose metabolism, magnetic resonance imaging
National Category
Pediatrics Medical Image Processing
Identifiers
urn:nbn:se:uu:diva-380052 (URN)10.1111/ijpo.12531 (DOI)000482155600007 ()31290284 (PubMedID)
Funder
Swedish Heart Lung Foundation, 2170492Swedish Research Council, 2016-01040EU, FP7, Seventh Framework Programme, 279153
Available from: 2019-07-09 Created: 2019-03-22 Last updated: 2019-10-23Bibliographically approved
Manell, H. (2019). Impaired Glucose Tolerance in Childhood Obesity: Contribution of Glucagon, GLP-1 and Inflammation. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
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
Stenlid, R., Manell, H., Halldin, M., Kullberg, J., Ahlström, H., Manukyan, L., . . . Forslund, A. (2018). High DPP-4 concentrations in adolescents are associated with low intact GLP-1. Journal of Clinical Endocrinology and Metabolism, 103(8), 2958-2966
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
Kristinsson, H., Manell, H., Dahlbom, M., Presto, J., Garedal, C., Ritzen, H., . . . Bergsten, P. (2018). The initial rise in GIP secretion during OGTT correlates with the initial suppression of glucagon secretion in adolescents with obesity and type 2 diabetes. Paper presented at 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), OCT 01-05, 2018, Berlin, GERMANY. Diabetologia, 61, S247-S247
Open this publication in new window or tab >>The initial rise in GIP secretion during OGTT correlates with the initial suppression of glucagon secretion in adolescents with obesity and type 2 diabetes
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2018 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, p. S247-S247Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-367127 (URN)000443556003095 ()
Conference
54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), OCT 01-05, 2018, Berlin, GERMANY
Available from: 2018-11-30 Created: 2018-11-30 Last updated: 2018-11-30Bibliographically approved
Paulmichl, K., Ahlström, H., Bergsten, P., Brunner, S., Cadamuro, J., Dahlbom, I., . . . Weghuber, D. (2017). Association Between Non-Alcoholic Fatty Liver Disease (NAFLD) and Iron Metabolism in Obese Children and Adolescents: Results of the Beta-JUDO Study. Acta Paediatrica, 106(S470), 13-13
Open this publication in new window or tab >>Association Between Non-Alcoholic Fatty Liver Disease (NAFLD) and Iron Metabolism in Obese Children and Adolescents: Results of the Beta-JUDO Study
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2017 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, no S470, p. 13-13Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
Childhood, Hyperferritinemia, NAFLD, Obesity, Steatosis
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-366465 (URN)10.1111/apa.14093 (DOI)000440296300021 ()
Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2018-11-22Bibliographically approved
Kristinsson, H., Sargsyan, E., Manell, H., Smith, D. M., Gopel, S. O. & Bergsten, P. (2017). Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion. Scientific Reports, 7, Article ID 4657.
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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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 4657Article in journal (Refereed) Published
Abstract [en]

In obesity fasting levels of both glucagon and insulin are elevated. In these subjects fasting levels of the free fatty acid palmitate are raised. We have demonstrated that palmitate enhances glucose-stimulated insulin secretion from isolated human islets via free fatty acid receptor 1 (FFAR1/GPR40). Since FFAR1 is also present on glucagon- secreting alpha-cells, we hypothesized that palmitate simultaneously stimulates secretion of glucagon and insulin at fasting glucose concentrations. In addition, we hypothesized that concomitant hypersecretion of glucagon and insulin was also contributed by reduced somatostatin secretion. We found basal glucagon, insulin and somatostatin secretion and respiration from human islets, to be enhanced during palmitate treatment at normoglycemia. Secretion of all hormones and mitochondrial respiration were lowered when FFAR1 or fatty acid beta-oxidation was inhibited. The findings were confirmed in the human beta-cell line EndoC-beta H1. We conclude that fatty acids enhance both glucagon and insulin secretion at fasting glucose concentrations and that FFAR1 and enhanced mitochondrial metabolism but not lowered somatostatin secretion are crucial in this effect. The ability of chronically elevated palmitate levels to simultaneously increase basal secretion of glucagon and insulin positions elevated levels of fatty acids as potential triggering factors for the development of obesity and impaired glucose control.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-329998 (URN)10.1038/s41598-017-04730-5 (DOI)000404846000030 ()
Funder
EU, FP7, Seventh Framework Programme, 279153VINNOVASwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2017-10-13 Created: 2017-10-13 Last updated: 2018-01-13Bibliographically approved
Roomp, K., Kristinsson, H., Schvartz, D., Ubhayasekera, K., Sargsyan, E., Manukyan, L., . . . Bergsten, P. (2017). Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism. PLoS ONE, 12(4), Article ID e0176391.
Open this publication in new window or tab >>Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0176391Article in journal (Refereed) Published
Abstract [en]

Studies on the pathophysiology of type 2 diabetes mellitus (T2DM) have linked the accumulation of lipid metabolites to the development of beta-cell dysfunction and impaired insulin secretion. In most in vitro models of T2DM, rodent islets or beta-cell lines are used and typically focus is on specific cellular pathways or organs. Our aim was to, firstly, develop a combined lipidomics and proteomics approach for lipotoxicity in isolated human islets and, secondly, investigate if the approach could delineate novel and/or confirm reported mechanisms of lipotoxicity. To this end isolated human pancreatic islets, exposed to chronically elevated palmitate concentrations for 0, 2 and 7 days, were functionally characterized and their levels of multiple targeted lipid and untargeted protein species determined. Glucosestimulated insulin secretion from the islets increased on day 2 and decreased on day 7. At day 7 islet insulin content decreased and the proinsulin to insulin content ratio doubled. Amounts of cholesterol, stearic acid, C16 dihydroceramide and C24: 1 sphingomyelin, obtained from the lipidomic screen, increased time-dependently in the palmitate-exposed islets. The proteomic screen identified matching changes in proteins involved in lipid biosynthesis indicating up-regulated cholesterol and lipid biosynthesis in the islets. Furthermore, proteins associated with immature secretory granules were decreased when palmitate exposure time was increased despite their high affinity for cholesterol. Proteins associated with mature secretory granules remained unchanged. Pathway analysis based on the protein and lipid expression profiles implicated autocrine effects of insulin in lipotoxicity. Taken together the study demonstrates that combining different omics approaches has potential in mapping of multiple simultaneous cellular events. However, it also shows that challenges exist for effectively combining lipidomics and proteomics in primary cells. Our findings provide insight into how saturated fatty acids contribute to islet cell dysfunction by affecting the granule maturation process and confirmation in human islets of some previous findings from rodent islet and cell-line studies.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-323459 (URN)10.1371/journal.pone.0176391 (DOI)000400383600072 ()28448538 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2017-06-07 Created: 2017-06-07 Last updated: 2017-11-29Bibliographically approved
Heu, V., Aigner, E., Bergsten, P., Cadamuro, J., Ciba, I., Dahlbom, M., . . . Daniel, W. (2017). Effect of Glucose Load on the Incretin Response (GLP-1) in obese Adolescents compared to the normal-weight Adolescents. Wiener Klinische Wochenschrift, 129(19-20), 736-736
Open this publication in new window or tab >>Effect of Glucose Load on the Incretin Response (GLP-1) in obese Adolescents compared to the normal-weight Adolescents
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2017 (English)In: Wiener Klinische Wochenschrift, ISSN 0043-5325, E-ISSN 1613-7671, Vol. 129, no 19-20, p. 736-736Article in journal, Meeting abstract (Other academic) Published
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-346838 (URN)000412462900028 ()
Available from: 2018-04-03 Created: 2018-04-03 Last updated: 2018-04-03Bibliographically approved
Forslund, A., Weghuber, D., Paulmichl, K., Zsoldos, F., Widhalm, K., Vheu, M. D., . . . Bergsten, P. (2017). Exenatide Once Weekly Reduces Weight, Liver Fat And 2-Hour Postprandial Glucose In Obese Adolescents. Acta Paediatrica, 106(470), 14-15
Open this publication in new window or tab >>Exenatide Once Weekly Reduces Weight, Liver Fat And 2-Hour Postprandial Glucose In Obese Adolescents
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2017 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, no 470, p. 14-15Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
Pediatric obesity, reduced glucose tolerance, NAFLD, GLP-1 analog, Exenatide
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-366467 (URN)10.1111/apa.14093 (DOI)000440296300025 ()
Available from: 2018-11-21 Created: 2018-11-21 Last updated: 2018-11-21Bibliographically approved
Staaf, J., Labmayr, V., Paulmichl, K., Manell, H., Cen, J., Ciba, I., . . . Kullberg, J. (2017). Pancreatic Fat Is Associated With Metabolic Syndrome and Visceral Fat but Not Beta-Cell Function or Body Mass Index in Pediatric Obesity. Pancreas, 46(3), 358-365
Open this publication in new window or tab >>Pancreatic Fat Is Associated With Metabolic Syndrome and Visceral Fat but Not Beta-Cell Function or Body Mass Index in Pediatric Obesity
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2017 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 46, no 3, p. 358-365Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Adolescents with obesity have increased risk of type 2 diabetes and metabolic syndrome (MetS). Pancreatic fat has been related to these conditions; however, little is known about associations in pediatric obesity. The present study was designed to explore these associations further.

METHODS: We examined 116 subjects, 90 with obesity. Anthropometry, MetS, blood samples, and oral glucose tolerance tests were assessed using standard techniques. Pancreatic fat fraction (PFF) and other fat depots were quantified using magnetic resonance imaging.

RESULTS: The PFF was elevated in subjects with obesity. No association between PFF and body mass index-standard deviation score (BMI-SDS) was found in the obesity subcohort. Pancreatic fat fraction correlated to Insulin Secretion Sensitivity Index-2 and Homeostatic Model Assessment of Insulin Resistance in simple regression; however, when using adjusted regression and correcting for BMI-SDS and other fat compartments, PFF correlated only to visceral adipose tissue and fasting glucose. Highest levels of PFF were found in subjects with obesity and MetS.

CONCLUSIONS: In adolescents with obesity, PFF is elevated and associatedto MetS, fasting glucose, and visceral adipose tissue but not to beta-cellfunction, glucose tolerance, or BMI-SDS. This study demonstrates thatconclusions regarding PFF and its associations depend on the body massfeatures of the cohort.

Keywords
pancreatic fat, pediatric obesity, beta-cell function, metabolic syndrome, body mass index-standard deviation score
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-311308 (URN)10.1097/MPA.0000000000000771 (DOI)000394448600018 ()27941426 (PubMedID)
Funder
Swedish Research Council, 72X-14019 2012-2330 2011-4423Swedish Diabetes AssociationEU, FP7, Seventh Framework Programme, 279153
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2017-04-26Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-5209-4841

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