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Childhood Obesity and Islet Function
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. (Peter Bergsten)
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The prevalence of childhood obesity and Type 2 Diabetes Mellitus (T2DM) has increased during recent decades. T2DM is accompanied with functional changes in the islets of Langerhans, which can be identified early in the pathogenesis. The aim of this thesis was to explore how metabolic changes caused by obesity early in life relate to islet function prior to overt T2DM.

To address this, Uppsala Longitudinal Study of Childhood Obesity (ULSCO) was established (paper I). Initially, the association between palmitate and insulin secretion was investigated using a translational approach with obese and lean normoglycemic juveniles and isolated human islets (paper II). Secondly, dynamics of islet-hormones insulin and glucagon, and gut-hormones glucagon like-peptide 1 (GLP-1) and glicentin (paper III) and magnetic resonance imaging of pancreatic fat fraction (PFF) (paper IV) were studied in association to glucose tolerance and beta-cell function. Finally, a novel method of analysing shape features of oral glucose tolerance test (OGTT) curves was introduced and evaluated (paper V).

Obese subjects had high prevalence of prediabetes and metabolic syndrome (MetS) (paper I). In obese pre-pubertal children with elevated palmitate levels, hyperinsulinemia was observed (paper II). In contrast, obese pubertal adolescents with similar palmitate levels showed moderate insulin levels during OGTT with delayed first phase insulin response. To explore mechanisms for these variations, isolated human islets were exposed to palmitate for different time periods in vitro. After 2 days accentuated insulin response was observed. Impaired beta-cell function and apoptosis were evident after 7 days, however. Hyperglucagonemia and disturbed GLP-1 and glicentin levels were associated with obesity and glycaemic status, with fasting glicentin being predictive of prediabetes (paper III). Furthermore, PFF was increased in obese subjects and associated to MetS and visceral adipose tissue, but not to beta-cell function (paper IV). OGTT curves were converted into geometric centres, centroids, which correlated with differences in glucose tolerance (paper V).

In conclusion, the islet function in obese children was associated with elevated levels of palmitate, but not pancreatic fat. Fasting palmitate and glicentin levels, as well as centroid analyses of OGTT curves, could potentially identify obese children at risk of prediabetes and subsequent T2DM.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1293
Keyword [en]
type 2 diabetes mellitus, Uppsala Longitudinal Study of Childhood Obesity, palmitate, glucose-stimulated insulin secretion, hyperinsulinemia, hyperglucagonemia, GLP-1, glicentin, magnetic resonance imaging, metabolic syndrome, oral glucose tolerance test, centroid
National Category
Medical and Health Sciences
Research subject
Pediatrics
Identifiers
URN: urn:nbn:se:uu:diva-313310ISBN: 978-91-554-9801-6 (print)OAI: oai:DiVA.org:uu-313310DiVA: diva2:1066721
Public defence
2017-03-10, C2:301, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Funder
EU, FP7, Seventh Framework Programme, 279153
Available from: 2017-02-15 Created: 2017-01-18 Last updated: 2017-02-27
List of papers
1. Uppsala Longitudinal Study of Childhood Obesity: Protocol Description
Open this publication in new window or tab >>Uppsala Longitudinal Study of Childhood Obesity: Protocol Description
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2014 (English)In: Pediatrics, ISSN 0031-4005, E-ISSN 1098-4275, Vol. 133, no 2, E386-E393 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND OBJECTIVE: The prevalence of childhood obesity has risen considerably on a global scale during the past decades, and the condition is associated with increased risk of morbidity. The objective is to describe the Uppsala Longitudinal Study of Childhood Obesity (ULSCO) cohort, including some baseline data, and outline addressed research areas that aim at identifying factors implicated in and contributing to development of obesity and obesity-related diseases, including type 2 diabetes. METHODS: Severely obese and lean control subjects are examined at enrollment and at subsequent annual visits by using detailed questionnaires, anthropometric measurements, indirect calorimetry, and functional tests such as oral glucose tolerance tests. Some subjects undergo additional characterization with MRI, subcutaneous fat biopsies, frequent blood sampling, and hyperglycemic clamps. Biological samples are obtained and stored in a biobank. RESULTS: Active recruitment started in 2010, and standard operating procedures have been established. A high participation rate and annual follow-ups have resulted in a cohort exceeding 200 subjects, including 45 lean controls (as of October 2013). Initial research focus has been on traits of the metabolic syndrome, hyperinsulinemia and identifying risk factors for type 2 diabetes. CONCLUSIONS: The ULSCO cohort serves as an important resource in defining and understanding factors contributing to childhood obesity and development of obesity-related diseases. Given the comprehensive characterization of the cohort, factors contributing to disease development and progression can be identified. Such factors are further evaluated for their mechanistic role and significance, and noncommunicable metabolic diseases are especially addressed and considered.

Keyword
childhood obesity, cohort, MRI, pediatric, type 2 diabetes mellitus, ULSCO
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-227577 (URN)10.1542/peds.2013-2143 (DOI)000333413600041 ()
Available from: 2014-06-30 Created: 2014-06-27 Last updated: 2017-12-05Bibliographically approved
2. Initial hyperinsulinemia and subsequent beta-cell dysfunction is associated with elevated palmitate levels
Open this publication in new window or tab >>Initial hyperinsulinemia and subsequent beta-cell dysfunction is associated with elevated palmitate levels
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2016 (English)In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 80, no 2, 267-274 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The prevalence of obesity-related diabetes in childhood is increasing and circulating levels of nonesterified fatty acids may constitute a link. Here, the association between palmitate and insulin secretion was investigated in vivo and in vitro.

METHODS: Obese and lean children and adolescents (n = 80) were included. Palmitate was measured at fasting; insulin and glucose during an oral glucose tolerance test (OGTT). Human islets were cultured for 0 to 7 d in presence of 0.5 mmol/l palmitate. Glucose-stimulated insulin secretion (GSIS), insulin content and apoptosis were measured.

RESULTS: Obese subjects had fasting palmitate levels between 0.10 and 0.33 mmol/l, with higher average levels compared to lean subjects. While obese children with elevated palmitate (>0.20 mmol/l) had accentuated insulin levels during OGTT, obese adolescents with high palmitate had delayed first-phase insulin response. In human islets exposed to palmitate for 2 d GSIS was twofold enhanced, but after 7 d attenuated. Intracellular insulin content decreased time-dependently in islets cultured in the presence of palmitate and cleaved caspase 3 increased.

CONCLUSION: The rapid accentuated and delayed insulin secretory responses observed in obese children and adolescents, respectively, with high palmitate levels may reflect changes in islet secretory activity and integrity induced by extended exposure to the fatty acid.

National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-312661 (URN)10.1038/pr.2016.80 (DOI)000386719200016 ()27064244 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 279153Swedish Diabetes Association, DIA 2013-043Swedish Research Council, SRC 621-2011-4423, 2015-4870
Available from: 2017-01-12 Created: 2017-01-12 Last updated: 2017-11-29Bibliographically approved
3. 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, 1181-1189 p.Article 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: 2017-11-30Bibliographically approved
4. Pancreatic Fat Is Associated With Metabolic Syndrome and Visceral Fat but Not Beta-Cell Function or Body Mass Index in Pediatric Obesity
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, 358-365 p.Article 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.

Keyword
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
5. Centroid analysis of OGTT-data for type 2 diabetes risk assessment
Open this publication in new window or tab >>Centroid analysis of OGTT-data for type 2 diabetes risk assessment
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-313309 (URN)
Available from: 2017-01-18 Created: 2017-01-18 Last updated: 2017-01-18

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