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Staaf, Johan
Publications (10 of 13) Show all publications
Manell, H., Kristinsson, H., Kullberg, J., Ubhayasekera, S. J., Mörwald, K., Staaf, J., . . . Bergsten, P. (2019). Hyperglucagonemia in youth is associated with high plasma free fatty acids, visceral adiposity and impaired glucose tolerance. Pediatric Diabetes, 20(7), 880-891
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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2019 (English)In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 20, no 7, p. 880-891Article in journal (Refereed) Published
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 Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-380313 (URN)10.1111/pedi.12890 (DOI)000476081000001 ()31271247 (PubMedID)
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: 2019-12-06Bibliographically approved
Staaf, J. (2017). Childhood Obesity and Islet Function. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Childhood Obesity and Islet Function
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. p. 54
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1293
Keywords
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:nbn:se:uu:diva-313310 (URN)978-91-554-9801-6 (ISBN)
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
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
Manell, H., Staaf, J., Manukyan, L., Kristinsson, H., Cen, J., Stenlid, R., . . . Bergsten, P. (2016). Altered Plasma Levels of Glucagon, GLP-1 and Glicentin During OGTT in Adolescents With Obesity and Type 2 Diabetes. Journal of Clinical Endocrinology and Metabolism, 101(3), 1181-1189
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
Manell, H., Kristinsson, H., Kullberg, J., Paulmichl, K., Cadamuro, J., Zsoldos, F., . . . Bergsten, P. (2016). Hyperglucagonaemia is associated with elevated plasma triglycerides and increased visceral fat in children and adolescents. Paper presented at 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY. Diabetologia, 59, S267-S268
Open this publication in new window or tab >>Hyperglucagonaemia is associated with elevated plasma triglycerides and increased visceral fat in children and adolescents
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S267-S268Article in journal (Refereed) Published
Place, publisher, year, edition, pages
SPRINGER, 2016
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-322049 (URN)000398373701364 ()
Conference
52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2017-05-16Bibliographically approved
Manell, H., Kristinsson, H., Kullberg, J., Paulmichl, K., Staaf, J., Cadamuro, J., . . . Bergsten, P. (2016). Hyperglucagonemia is associated with a Increase of Plasma Triglycerides as well as visceral Fat Tissue in a pediatric Cohort. Wiener Klinische Wochenschrift, 128(19-20), 747-747
Open this publication in new window or tab >>Hyperglucagonemia is associated with a Increase of Plasma Triglycerides as well as visceral Fat Tissue in a pediatric Cohort
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2016 (English)In: Wiener Klinische Wochenschrift, ISSN 0043-5325, E-ISSN 1613-7671, Vol. 128, no 19-20, p. 747-747Article in journal, Meeting abstract (Other academic) Published
National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-309486 (URN)000385367100033 ()
Available from: 2016-12-05 Created: 2016-12-05 Last updated: 2018-01-13Bibliographically approved
Ohlsson, H., Staaf, J., Manukyan, L., Cen, J., Forslund, A. & Bergsten, P. (2015). Active GLP-1 but not insulin, glicentin or glucagon predicts the 2-hour OGTT glucose value in obese children. Paper presented at 51st Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 14-18, 2015, Stockholm, SWEDEN. Diabetologia, 58(Suppl. 1), S276-S276
Open this publication in new window or tab >>Active GLP-1 but not insulin, glicentin or glucagon predicts the 2-hour OGTT glucose value in obese children
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2015 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S276-S276Article in journal, Meeting abstract (Other academic) Published
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-264910 (URN)000359820901258 ()
Conference
51st Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 14-18, 2015, Stockholm, SWEDEN
Note

Meeting Abstract: 568

Available from: 2015-11-04 Created: 2015-10-19 Last updated: 2017-12-01Bibliographically approved
Paulmichl, K., Binder, S., Eidherr, A., Zsoldos, F., Widhalm, K., Bergsten, P., . . . Weghuber, D. (2015). Deep Subcutaneous Adipose Tissue Correlates with Accentuated Insulin Secretion and Poor Insulin Sensitivity in Obese Children and Adolescents. Acta Paediatrica, 104(S466), 2-3
Open this publication in new window or tab >>Deep Subcutaneous Adipose Tissue Correlates with Accentuated Insulin Secretion and Poor Insulin Sensitivity in Obese Children and Adolescents
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2015 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 104, no S466, p. 2-3Article in journal, Meeting abstract (Other academic) Published
Keywords
childhood, insulin secretion, MRI, obesity, subcutaneous adipose tissue
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-267487 (URN)000362512600003 ()
Note

Meeting Abstract: OP02

Available from: 2015-12-14 Created: 2015-11-24 Last updated: 2017-12-01Bibliographically approved
Ciba, I., Weghuber, D., Manell, H., Staaf, J., Dahlbom, M., Paulmichl, K., . . . Forslund, A. (2015). Development of Glucose Intolerance in Obese Children Studied in the Beta-Judo Cohort. Acta Paediatrica, 104(S466), 12-12
Open this publication in new window or tab >>Development of Glucose Intolerance in Obese Children Studied in the Beta-Judo Cohort
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2015 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 104, no S466, p. 12-12Article in journal, Meeting abstract (Other academic) Published
Keywords
diabetes, glucose tolerance, obesity, paediatric, BMI-SDS
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-267489 (URN)000362512600027 ()
Note

Meeting Abstract: CP08

Available from: 2015-12-14 Created: 2015-11-24 Last updated: 2017-12-01Bibliographically approved
Staaf, J., Labmayr, V., Paulmichl, K., Ohlsson, H., Cen, J., Ciba, I., . . . Kullberg, J. (2015). Pancreatic Fat is Associated with Metabolic Syndrome and Visceral Adipose Tissue but not Beta-Cell Function or Body Mass Index in Paediatric Obesity. Acta Paediatrica, 104(S466), 2-2
Open this publication in new window or tab >>Pancreatic Fat is Associated with Metabolic Syndrome and Visceral Adipose Tissue but not Beta-Cell Function or Body Mass Index in Paediatric Obesity
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2015 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 104, no S466, p. 2-2Article in journal, Meeting abstract (Other academic) Published
Keywords
childhood obesity, insulin sensitivity, metabolism, visceral fat
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-267488 (URN)000362512600002 ()
Note

Meeting Abstract: OP01

Available from: 2015-12-14 Created: 2015-11-24 Last updated: 2017-12-01Bibliographically approved
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