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  • 1.
    Ahmed, Meftun
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose-induced changes of multiple mouse islet proteins analysed by two-dimensional gel electrophoresis and mass spectrometry.2005In: Diabetologia, ISSN 0012-186X, Vol. 48, no 3, p. 477-85Article in journal (Refereed)
  • 2.
    Ahmed, Meftun
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Forsberg, Jens
    Department of Medical Biochemistry and Microbiology.
    Bergsten, Peter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Protein profiling of human pancreatic islets by two-dimensional gel electrophoresis and mass spectrometry.2005In: J Proteome Res, ISSN 1535-3893, Vol. 4, no 3, p. 931-40Article in journal (Refereed)
  • 3.
    Aoyagi, K
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Eriksson, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Ebendal, Ted
    Department of Neuroscience.
    Hellerstrom, Claes
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    In vitro regulation of insulin release and biosynthesis of fetal rat pancreatic cells explanted on pregnancy day 16.1997In: Biol Neonate, Vol. 71, p. 60-68Article in journal (Refereed)
  • 4.
    Bergsten, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Aoyagi, K.
    Persson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Eriksson, Ulf J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Appearance of glucose-induced insulin release in fetal rat β-cells1998In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 158, no 1, p. 115-120Article in journal (Refereed)
    Abstract [en]

    Fetal rat pancreatic cells were isolated from pancreatic primordia on days 12-14 of pregnancy and cultured for 48 h in the presence of 5 mmol/l glucose. Insulin accumulation in the medium over the next 24 h was measured. Cultured cells from day 12 fetuses secreted about 1 fmol insulin per pancreas in response to 5 or 15 mmol/l glucose irrespective of whether 1 mmol/l tolbutamide, 400 mumol/l diazoxide, 5 mmol/l theophylline or 10 mmol/l mannoheptulose was present. In contrast, insulin released from day 13 cultured cells increased significantly from 3.0 +/- 0.6 to 6.2 +/- 2.2 fmol per pancreas, when the glucose concentration was raised. Tolbutamide increased, diazoxide and mannoheptulose decreased and theophylline had no effect on insulin release. Even more pronounced effects were found on insulin release from day 14 cultured cells, in which theophylline also increased the release. In addition, insulin release from cells from pregnancy day 14 was 75 +/- 16 amol/min per pancreas when the cells were perifused for 15-20 min in the presence of 5 mmol/l glucose within 3 h of isolation. Increasing the glucose concentration to 15 mmol/l or adding tolbutamide increased, whereas diazoxide decreased, insulin release in the freshly isolated cells. The insulin content of rat pancreata from pregnancy day 13 was 0.06 +/- 0.01 pmol per pancreas and increased approximately 10-fold every second day up to 6.7 +/- 0.9 pmol on day 17 of pregnancy. Between day 17 and 19 the pancreatic insulin content increased about fivefold to 39 +/- 2 pmol. The present data suggest that critical components of the insulin-secretory machinery, including ATP-regulated K+ channels, glucokinase and adenylate cyclase activities, are present in the developing beta-cell earlier than hitherto thought.

  • 5.
    Cen, Jing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Fatty acids stimulate insulin secretion from human pancreatic islets at fasting glucose concentrations via mitochondria-dependent and -independent mechanisms2016In: Nutrition & Metabolism, ISSN 1743-7075, E-ISSN 1743-7075, Vol. 13, article id 59Article in journal (Refereed)
    Abstract [en]

    Background: Free fatty acids (FFAs) acutely stimulate insulin secretion from pancreatic islets. Conflicting results have been presented regarding this effect at non-stimulatory glucose concentration, however. The aim of our study was to investigate how long-chain FFAs affect insulin secretion from isolated human pancreatic islets in the presence of physiologically fasting glucose concentrations and to explore the contribution of mitochondria to the effects on secretion. Methods: Insulin secretion from human pancreatic islets was measured from short-term static incubation or perfusion system at fasting glucose concentration (5.5 mM) with or without 4 different FFAs (palmitate, palmitoleate, stearate, and oleate). The contribution of mitochondrial metabolism to the effects of fatty acid-stimulated insulin secretion was explored. Results: The average increase in insulin secretion, measured from statically incubated and dynamically perifused human islets, was about 2-fold for saturated free fatty acids (SFAs) (palmitate and stearate) and 3-fold for mono-unsaturated free fatty acids (MUFAs) (palmitoleate and oleate) compared with 5.5 mmol/l glucose alone. Accordingly, MUFAs induced 50 % and SFAs 20 % higher levels of oxygen consumption compared with islets exposed to 5.5 mmol/l glucose alone. The effect was due to increased glycolysis. When glucose was omitted from the medium, addition of the FFAs did not affect oxygen consumption. However, the FFAs still stimulated insulin secretion from the islets although secretion was more than halved. The mitochondria-independent action was via fatty acid metabolism and FFAR1/GPR40 signaling. Conclusions: The findings suggest that long-chain FFAs acutely induce insulin secretion from human islets at physiologically fasting glucose concentrations, with MUFAs being more potent than SFAs, and that this effect is associated with increased glycolytic flux and mitochondrial respiration.

  • 6.
    Cen, Jing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Metformin restores insulin secretion from palmitate-treated human islets by normalising mitochondrial metabolism and reducing ER stress and apoptosis2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, p. S47-S47Article in journal (Other academic)
  • 7.
    Cen, Jing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Molecular Neuroscience Group, Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia.
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Bergsten, Peter
    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, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Mechanisms of beneficial effects of metformin on fatty acid-treated human islets2018In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 61, no 3, p. 91-99Article in journal (Refereed)
    Abstract [en]

    Elevated levels of palmitate accentuate glucose-stimulated insulin secretion (GSIS) after short-term and cause beta-cell dysfunction after prolonged exposure. We investigated whether metformin, the first-line oral drug for treatment of T2DM, has beneficial effects on FFA-treated human islets and the potential mechanisms behind the effects. Insulin secretion, oxygen consumption rate (OCR), AMPK activation, endoplasmic reticulum (ER) stress and apoptosis were examined in isolated human islets after exposure to elevated levels of palmitate in the absence or presence of metformin. Palmitate exposure doubled GSIS after 2 days but halved after 7 days compared with control. Inclusion of metformin during palmitate exposure normalized insulin secretion both after 2 and 7 days. After 2-day exposure to palmitate, OCR and the marker of the adaptive arm of ER stress response (sorcin) were significantly raised, whereas AMPK phosphorylation, markers of pro-apoptotic arm of ER stress response (p-EIF2α and CHOP) and apoptosis (cleaved caspase 3) were not affected. Presence of metformin during 2-day palmitate exposure normalized OCR and sorcin levels. After 7-day exposure to palmitate, OCR and sorcin were not significantly different from control level, p-AMPK was reduced and p-EIF2α, CHOP and cleaved caspase 3 were strongly upregulated. Presence of metformin during 7-day culture with palmitate normalized the level of p-AMPK, p-EIF2α, CHOP and cleaved caspase 3 but significantly increased the level of sorcin. Our study demonstrates that metformin prevents early insulin hypersecretion and later decrease in insulin secretion from palmitate-treated human islets by utilizing different mechanisms.

  • 8.
    Censin, J. C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nowak, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cooper, Nicholas
    Univ Cambridge, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Dept Med Genet,Cambridge Inst Med Res, Natl Inst Hlth Res,Cambridge Biomed Res Ctr, Cambridge, England..
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Todd, John A.
    Univ Cambridge, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Dept Med Genet,Cambridge Inst Med Res, Natl Inst Hlth Res,Cambridge Biomed Res Ctr, Cambridge, England.;Univ Oxford, NIHR Oxford Biomed Res Ctr, Wellcome Trust Ctr Human Genet,Nuffield Dept Med, JDRF,Wellcome Trust Diabet & Inflammat Lab, Oxford, England..
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Childhood adiposity and risk of type 1 diabetes: A Mendelian randomization study2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 8, article id e1002362Article in journal (Refereed)
    Abstract [en]

    Background The incidence of type 1 diabetes (T1D) is increasing globally. One hypothesis is that increasing childhood obesity rates may explain part of this increase, but, as T1D is rare, intervention studies are challenging to perform. The aim of this study was to assess this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal associations. Methods and findings We created a genetic instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood adiposity in children aged 2-10 years. Summary-level association results for these 23 SNPs with childhood-onset (<17 years) T1D were extracted from a meta-analysis of genome-wide association study with 5,913 T1D cases and 8,828 reference samples. Using inverse-variance weighted Mendelian randomization analysis, we found support for an effect of childhood adiposity on T1D risk (odds ratio 1.32, 95% CI 1.06-1.64 per standard deviation score in body mass index [SDS-BMI]). A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We therefore applied Egger regression and multivariable Mendelian randomization methods to control for this type of bias and found evidence in support of a role of childhood adiposity in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40-5.44). Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the score are not known. Mendelian randomization requires large sample sizes, and power was limited to provide precise estimates. This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science Genetic Association Consortium (SSGAC), as well as meta-analysis results from a T1D genome-wide association study. Conclusions This study provides genetic support for a link between childhood adiposity and T1D risk. Together with evidence from observational studies, our findings further emphasize the importance of measures to reduce the global epidemic of childhood obesity and encourage mechanistic studies.

  • 9.
    Chowdhury, Azazul Islam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    GLP-1 analogue recovers impaired insulin secretion from human islets treated with palmitate via down-regulation of SOCS22017In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 439, no C, p. 194-202Article in journal (Refereed)
    Abstract [en]

    Elevated circulating palmitate levels have been connected with type 2 diabetes mellitus. GLP-1 has favorable effects on beta-cells function. The aim was to identify mechanisms for decreased GSIS after long-term palmitate exposure and restoration by GLP-1 by analyzing changes in G-protein coupled receptor (GPCR) pathway signaling. Insulin secretory response to 20 mM glucose was attenuated after 7 days in islets exposed to palmitate but inclusion of exendin-4 restored secretion. Palmitate treatment altered genes of several GPCR signaling pathways including inflammatory pathways with up-regulated IL-1B, SOCS1 and SOCS2 transcript levels. Protein level of SOCS2 was also up-regulated by palmitate and accompanied by down-regulation of pAkt(T308), which was restored by exendin-4 treatment. When SOCS2 was knocked down, palmitate-induced clown-regulation of IRS-1 and pAkt(T308) was prevented and GSIS, proinsulin to insulin ratio and apoptosis was restored. Long-term palmitate treatment up regulates SOCS2 and reduces PI3K activity, thereby impairing GSIS. GLP-1 reverts the palmitate-induced effects.

  • 10.
    Chowdhury, Azazul Islam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dyachok, Oleg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Functional differences between aggregated and dispersed insulin-producing cells2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 7, p. 1557-1568Article in journal (Refereed)
    Abstract [en]

    Beta cells situated in the islet of Langerhans respond more vigorously to glucose than do dissociated beta cells. Mechanisms for this discrepancy were studied by comparing insulin-producing MIN6 cells aggregated into pseudoislets with MIN6 monolayer cells and mouse and human islets. MIN6 monolayers, pseudoislets and mouse and human islets were exposed to glucose, alpha-ketoisocaproic acid (KIC), pyruvate, KIC plus glutamine and the phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 or wortmannin. Insulin secretion (ELISA), cytoplasmic Ca2+ concentration ([Ca2+](c); microfluorometry), glucose oxidation (radiolabelling), the expression of genes involved in mitochondrial metabolism (PCR) and the phosphorylation of insulin receptor signalling proteins (western blotting) were measured. Insulin secretory responses to glucose, pyruvate, KIC and glutamine were higher in pseudoislets than monolayers and comparable to those of human islets. Glucose oxidation and genes for mitochondrial metabolism were upregulated in pseudoislets compared with single cells and monolayers, respectively. Phosphorylation at the inhibitory S636/639 site of IRS-1 was significantly higher in monolayers and dispersed human and mouse cells than pseudoislets and intact human and mouse islets. PI3K inhibition only slightly attenuated glucose-stimulated insulin secretion from monolayers, but substantially reduced that from pseudoislets and human and mouse islets without suppressing the glucose-induced [Ca2+](c) response. We propose that islet architecture is critical for proper beta cell mitochondrial metabolism and IRS-1 signalling, and that PI3K regulates insulin secretion at a step distal to the elevation of [Ca2+](c).

  • 11.
    Chowdhury, Azazul Islam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hörnaeus, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala Univ, Med Cell Biol, Uppsala, Sweden..
    Role of PIAS1 in palmitate mediated beta cell dysfunction2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S230-S230Article in journal (Other academic)
  • 12.
    Chowdhury, Azazul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Satagopam, Venkata P.
    Manukyan, Levon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Artemenko, Konstantin A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fung, Yi Man Eva
    Schneider, Reinhard
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Signaling in Insulin-Secreting MIN6 Pseudoislets and Monolayer Cells2013In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 12, no 12, p. 5954-5962Article in journal (Refereed)
    Abstract [en]

    Cell cell interactions are of fundamental importance for cellular function. In islets of Langerhans, which control blood glucose levels by secreting insulin in response to the blood . glucose concentration, the secretory response of intact islets is c higher than that of insulin-producing beta-cells not arranged in the islet architecture. The objective was to define mechanisms by which cellular performance is enhanced when cells are arranged in a) three-dimensional space. The task was addressed by making a c comprehensive analysis based on protein expression patterns " generated from insulin-secreting MIN6 cells grown as islet-like c clusters, so-called pseudoislets, and in monolayers. After culture, glucose-stimulated insulin secretion (GSIS) was measured from monolayers and pseudoislets. GSIS rose 6-fold in pseudoislets but only 3-fold in monolayers when the glucose concentration was increased from 2 to 20 mmol/L. Proteins from pseudoislets and monolayers were extracted and analyzed by liquid-chromatography mass spectrometry, and differentially expressed proteins were mapped onto KEGG pathways. Protein profiling identified 1576 proteins, which were common to pseudoislets and monolayers. When mapped onto KEGG pathways, 11 highly enriched pathways were identified. On the basis of differences in expression of proteins belonging to the pathways in pseudoislets and monolayers, predictions of differential pathway activation were performed. Mechanisms enhancing insulin secretory capacity of the beta-cell, when situated in the islet, include pathways regulating glucose metabolism, cell interaction, and translational regulation.

  • 13.
    Ciba, Iris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Eriksson, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ardelt-Gattinger, E.
    Obes Acad Austria, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.;Salzburg Univ, Dept Psychol, A-5020 Salzburg, Austria..
    Hofmann, J.
    Obes Acad Austria, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.;Salzburg Univ, Dept Psychol, A-5020 Salzburg, Austria.;Paracelsus Med Univ, Dept Paediat, Salzburg, Austria..
    Weghuber, D.
    Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.;Paracelsus Med Univ, Dept Paediat, Salzburg, Austria..
    Dahlbom, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Eating Behavior In Swedish And Austrian Children And Adolescents With Obesity2016In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, p. 30-31Article in journal (Refereed)
  • 14.
    Ciba, Iris
    et al.
    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, Pediatrics.
    Weghuber, D.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria..
    Manell, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Staaf, Johan
    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, Pediatrics.
    Dahlbom, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Paulmichl, K.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria..
    Zsoldos, F.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria..
    Widhalm, K.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria.;Acad Inst Clin Nutr, Vienna, Austria..
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Forslund, Anders
    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, Pediatrics.
    Development of Glucose Intolerance in Obese Children Studied in the Beta-Judo Cohort2015In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 104, no S466, p. 12-12Article in journal (Other academic)
  • 15.
    Drzazga, Anna
    et al.
    Lodz Univ Technol, Fac Biotechnol & Food Sci, Inst Tech Biochem, B Stefanowskiego 4-10, PL-90924 Lodz, Poland.
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Salaga, Maciej
    Med Univ Lodz, Dept Biochem, Mazowiecka 6-8, PL-92215 Lodz, Poland.
    Zatorski, Hubert
    Med Univ Lodz, Dept Biochem, Mazowiecka 6-8, PL-92215 Lodz, Poland.
    Koziolkiewicz, Maria
    Lodz Univ Technol, Fac Biotechnol & Food Sci, Inst Tech Biochem, B Stefanowskiego 4-10, PL-90924 Lodz, Poland.
    Gendaszewska-Darmach, Edyta
    Lodz Univ Technol, Fac Biotechnol & Food Sci, Inst Tech Biochem, B Stefanowskiego 4-10, PL-90924 Lodz, Poland.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lysophosphatidylcholine and its phosphorothioate analogues potentiate insulin secretion via GPR40 (FFAR1), GPR55 and GPR119 receptors in a different manner2018In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 472, p. 117-125Article in journal (Refereed)
    Abstract [en]

    Lysophosphatidylcholine (LPC) is an endogenous ligand for GPR119 receptor, mediating glucose-stimulated insulin secretion (GSIS). We demonstrate that LPC facilitates GSIS in MINE pancreatic beta-cell line and murine islets of Langerhans by recognizing not only GPR119 but also GPR40 (free fatty acid receptor 1) and GPR55 activated by lysophosphatidylinositol. Natural LPCs are unstable when administered in vivo limiting their therapeutic value and therefore, we present phosphorothioate LPC analogues with increased stability. All the modified LPCs under study (12:0,14:0,16:0,18:0, and 18:1) significantly enhanced GSIS. The 16:0 sulfur analogue was the most potent, evoking 2-fold accentuated GSIS compared to the native counterpart. Interestingly, LPC analogues evoked GPR40-, GPR55-and GPR119 dependent [Ca2+](i), signaling, but did not stimulate cAMP accumulation as in the case of unmodified molecules. Thus, introduction of a phosphorothioate function not only increases LPC stability but also modulates affinity towards receptor targets and evokes different signaling pathways.

  • 16.
    Forslund, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Staaf, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ciba, Iris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Dahlbom, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Uppsala Longitudinal Study of Childhood Obesity: Protocol Description2014In: Pediatrics, ISSN 0031-4005, E-ISSN 1098-4275, Vol. 133, no 2, p. E386-E393Article in journal (Refereed)
    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.

  • 17.
    Forslund, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala Univ, Childrens Hosp, Uppsala, Sweden.
    Weghuber, D.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.
    Paulmichl, K.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.
    Zsoldos, F.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.
    Widhalm, K.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.
    Vheu, M. D.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.
    Lagler, F.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.
    Cadamuro, J.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.
    Brunner, S.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.
    Hofmann, J.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.
    Dahlbom, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala Univ, Childrens Hosp, Uppsala, Sweden.
    Lidström, M.
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden.
    Vilen, H.
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden.
    Ciba, Iris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala Univ, Childrens Hosp, Uppsala, Sweden.
    Manell, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Alderborn, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    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.
    Exenatide Once Weekly Reduces Weight, Liver Fat And 2-Hour Postprandial Glucose In Obese Adolescents2017In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, no 470, p. 14-15Article in journal (Other academic)
  • 18.
    Fred, Rikard G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kappe, Camilla
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cen, Jing
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ravassard, Phillippe
    Univ Paris 06, Univ Paris 04, Biotechnol & Biotherapy Lab,Inst Cerveau & Moelle, Inserm,U1127,CNRS UMR 7225,UMR S 1127,ICM,CHU Pit, Paris, France..
    Scharfmann, Raphael
    Univ Paris 05, Sorbonne Paris Cite, Fac Med, INSERM,U1016,Inst Cochin, F-75014 Paris, France..
    Welsh, Nils
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Role of the AMP kinase in cytokine-induced human EndoC-beta H1 cell death2015In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 414, no C, p. 53-63Article in journal (Refereed)
    Abstract [en]

    The aim of the present investigation was to delineate cytokine-induced signaling and death using the EndoC-beta H1 cells as a model for primary human beta-cells. The cytokines IL-1 beta and IFN-gamma induced a rapid and transient activation of NF-kappa B, STAT-1, ERK, JNK and eIF-2 alpha signaling. The EndoC-beta H1 cells died rapidly when exposed to IL-1 beta + IFN-gamma, and this occurred also in the presence of the actinomycin D. Inhibition of NF-kappa B and STAT-1 did not protect against cell death, nor did the cytokines activate iNOS expression. Instead, cytokines promoted a rapid decrease in EndoC-beta H1 cell respiration and ATP levels, and we observed protection by the AMPK activator AICAR against cytokine-induced cell death. It is concluded that EndoC-beta H1 cell death can be prevented by AMPK activation, which suggests a role for ATP depletion in cytokine-induced human beta-cell death.

  • 19.
    Groebe, Karlfried
    et al.
    Pivot Biomed Sci GmbH, D-54296 Trier, Germany.
    Cen, Jing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Schvartz, Domitille
    Univ Geneva, Ctr Med Univ, Human Prot Sci Dept, CH-1211 Geneva, Switzerland.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Chowdhury, Azazul Islam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Roomp, Kirsten
    Univ Luxembourg, Luxembourg Ctr Syst Biomed, L-4365 Esch Sur Alzette, Luxembourg.
    Schneider, Reinhard
    Univ Luxembourg, Luxembourg Ctr Syst Biomed, L-4365 Esch Sur Alzette, Luxembourg.
    Alderborn, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sanchez, Jean-Charles
    Univ Geneva, Ctr Med Univ, Human Prot Sci Dept, CH-1211 Geneva, Switzerland.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Palmitate-Induced Insulin Hypersecretion and Later Secretory Decline Associated with Changes in Protein Expression Patterns in Human Pancreatic Islets2018In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 17, no 11, p. 3824-3836Article in journal (Refereed)
    Abstract [en]

    In obese children with high circulating concentrations of free fatty acid palmitate, we have observed that insulin levels at fasting and in response to a glucose challenge were several times higher than in obese children with low concentrations of the fatty acid as well as in lean controls. Declining and even insufficient insulin levels were observed in obese adolescents with high levels of the fatty acid. In isolated human islets exposed to palmitate we have observed insulin hypersecretion after 2 days exposure. In contrast, insulin secretion from the islets was reduced after 7 days culture in the presence of the fatty acid. This study aims at identifying islet-related biological events potentially linked with the observed insulin hypersecretion and later secretory decline in these obese children and adolescents using the islet model. We analyzed protein expression data obtained from human islets exposed to elevated palmitate levels for 2 and 7 days by an improved methodology for statistical analysis of differentially expressed proteins. Protein profiling of islet samples by liquid chromatography-tandem mass spectrometry identified 115 differentially expressed proteins (DEPs). Several DEPs including sorcin were associated with increased glucose-stimulated insulin secretion in islets after 2 days of exposure to palmitate. Similarly, several metabolic pathways including altered protein degradation, increased autophagy, altered redox condition, and hampered insulin processing were coupled to the functional impairment of islets after 7 days of culture in the presence of palmitate. Such biological events, once validated in the islets, may give rise to novel treatment strategies aiming at normalizing insulin levels in obese children with high palmitate levels, which may reduce or even prevent obesity-related type 2 diabetes mellitus.

  • 20. Hernández-Fisac, Inés
    et al.
    Fernández-Pascual, Sergio
    Ortsäter, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pizarro-Delgado, Javier
    Martín del Rí­o, Rafael
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tamarit-Rodriguez, Jorge
    Oxo-4-methylpentanoic acid directs the metabolism of GABA into the Krebs cycle in rat pancreatic islets2006In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 400, no 1, p. 81-89Article in journal (Refereed)
    Abstract [en]

    OMP (oxo-4-methylpentanoic acid) stimulates by itself a biphasic secretion of insulin whereas L-leucine requires the presence of L-glutamine. L-Glutamine is predominantly converted into GABA (gamma-aminobutyric acid) in rat islets and L-leucine seems to promote its metabolism in the 'GABA shunt' [Fernandez-Pascual, Mukala-Nsengu-Tshibangu, Martin del Rio and Tamarit-Rodriguez (2004) Biochem. J. 379,721-729]. In the present study, we have investigated how 10mM OMP affects L-glutamine metabolism to uncover possible differences with L-leucine that might help to elucidate whether they share a common mechanism of stimulation of insulin secretion. In contrast with L-leucine, OMP alone stimulated a biphasic insulin secretion in rat perifused islets and decreased the islet content of GABA without modifying its extracellular release irrespective of the concentration of L-glutamine in the medium. GABA was transaminated to L-leucine whose intracellular concentration did not change because it was efficiently transported out of the islet cells. The L-[U-C-14]-Glutamine (at 0.5 and 10.0 mM) conversion to (CO2)-C-14 was enhanced by 10 mM OMP within 30% and 70% respectively. Gabaculine (250 mu M), a GABA transaminase inhibitor, suppressed OMP-induced oxygen consumption but not L-leucineor glucose-stimulated respiration. It also suppressed the OMP-induced decrease in islet GABA content and the OMP-induced increase in insulin release. These results support the view that OMP promotes islet metabolism in the 'GABA shunt' generating 2-oxo-glutarate, in the branched-chain a-amino acid transaminase reaction, which would in turn trigger GABA deamination by GABA transaminase. OMP, but not L-leucine, suppressed islet semialdehyde succinic acid reductase activity and this might shift the metabolic flux of the 'GABA shunt' from gamma-hydroxybutyrate to succinic acid production.

  • 21.
    Heu, Verena
    et al.
    PMU, Univ Klin Kinder & Jugendheilkunde, Salzburg, Austria..
    Aigner, Elmar
    PMU, Univ Klin Innere Med 1, Salzburg, Austria..
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Cadamuro, Janne
    PMU, Univ Inst Med Chem Lab Diagnost, Salzburg, Austria..
    Ciba, Iris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Endocrinology.
    Dahlbom, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Endocrinology.
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Endocrinology.
    Kedenko, Ludmilla
    PMU, Univ Klin Innere Med 1, Salzburg, Austria..
    Lang, Josef
    PMU, Univ Klin Innere Med 1, Salzburg, Austria..
    Manell, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Katharina, Paulmichl
    PMU, Univ Klin Kinder & Jugendheilkunde, Salzburg, Austria..
    Bernhard, Paulweber
    PMU, Univ Klin Innere Med 1, Salzburg, Austria..
    Kirsten, Roomp
    Univ Luxemburg, LCSB, Luxembourg, Luxembourg..
    Kurt, Widhalm
    PMU, Univ Klin Kinder & Jugendheilkunde, Salzburg, Austria..
    Fanni, Zsoldos
    PMU, Univ Klin Kinder & Jugendheilkunde, Salzburg, Austria..
    Daniel, Weghuber
    PMU, Univ Klin Kinder & Jugendheilkunde, Salzburg, Austria..
    Effect of Glucose Load on the Incretin Response (GLP-1) in obese Adolescents compared to the normal-weight Adolescents2017In: Wiener Klinische Wochenschrift, ISSN 0043-5325, E-ISSN 1613-7671, Vol. 129, no 19-20, p. 736-736Article in journal (Other academic)
  • 22.
    Kristinsson, Hjalti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Free fatty acid receptor 1 (FFAR1/GPR40) signaling affects insulin secretion by enhancing mitochondrial respiration during palmitate exposure2015In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1853, no 12, p. 3248-3257Article in journal (Refereed)
    Abstract [en]

    Fatty acids affect insulin secretion via metabolism and FFAR1-mediated signaling. Recent reports indicate that these two pathways act synergistically. Still it remains unclear how they interrelate. Taking into account the key role of mitochondria in insulin secretion, we attempted to dissect the metabolic and FFAR1-mediated effects of fatty acids on mitochondrial function. One-hour culture of MIN6 cells with palmitate significantly enhanced mitochondrial respiration. Antagonism or silencing of FFAR1 prevented the palmitate-induced rise in respiration. On the other hand, in the absence of extracellular palmitate FFAR1 agonists caused a modest increase in respiration. Using an agonist of the M3 muscarinic acetylcholine receptor and PKC inhibitor we found that in the presence of the fatty acid mitochondrial respiration is regulated via G alpha(q) protein-coupled receptor signaling. The increase in respiration in palmitate-treated cells was largely due to increased glucose utilization and oxidation. However, glucose utilization was not dependent on FFAR1 signaling. Collectively, these results indicate that mitochondrial respiration in palmitate-treated cells is enhanced via combined action of intracellular metabolism of the fatty acid and the G alpha(q)-coupled FFAR1 signaling. Long-term palmitate exposure reduced ATP-coupling efficiency of mitochondria and deteriorated insulin secretion. The presence of the FFAR1 antagonist during culture did not improve ATP-coupling efficiency, however, it resulted in enhanced mitochondrial respiration and improved insulin secretion after culture. Taken together, our study demonstrates that during palmitate exposure, integrated actions of fatty acid metabolism and fatty acid-induced FFAR1 signaling on mitochondrial respiration underlie the synergistic action of the two pathways on insulin secretion.

  • 23.
    Kristinsson, Hjalti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Palmitate stimulates insulin secretion by enhancing mitochondrial respiration via intracellular metabolism and FFAR1 signalling2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S214-S214Article in journal (Other academic)
  • 24.
    Kristinsson, Hjalti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Manell, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dahlbom, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Presto, J.
    Mercodia, Uppsala, Sweden.
    Garedal, C.
    Mercodia, Uppsala, Sweden.
    Ritzen, H.
    Mercodia, Uppsala, Sweden.
    Vilhelmsson, M.
    Mercodia, Uppsala, Sweden.
    Kilstedt, E.
    Mercodia, Uppsala, Sweden.
    Johnson, F.
    Mercodia, Uppsala, Sweden.
    Stenberg, H.
    Mercodia, Uppsala, Sweden.
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The initial rise in GIP secretion during OGTT correlates with the initial suppression of glucagon secretion in adolescents with obesity and type 2 diabetes2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, p. S247-S247Article in journal (Other academic)
  • 25.
    Kristinsson, Hjalti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Free fatty acids amplify basal secretion of both glucagon and insulin from isolated human islets at normoglycaemia via metabolic and FFAR1 dependent mechanism2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S257-S257Article in journal (Refereed)
  • 26.
    Kristinsson, Hjalti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Manell, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Smith, D. M.
    AstraZeneca, Discovery Sci Innovat Med & Early Dev Biotech Uni, Cambridge, England..
    Gopel, S. O.
    AstraZeneca R&D Gothenburg, CVMD Biosci, Gothenburg, Sweden..
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 4657Article in journal (Refereed)
    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.

  • 27.
    Kristinsson, Hjalti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Smith, D.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    FFAR1 is involved in both the acute and chronic effects of palmitate on insulin secretion2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, p. S194-S194Article in journal (Other academic)
  • 28.
    Kristinsson, Hjalti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Smith, David M.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    FFAR1 Is Involved in Both the Acute and Chronic Effects of Palmitate on Insulin Secretion2013In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 154, no 11, p. 4078-4088Article in journal (Refereed)
    Abstract [en]

    Free fatty acids (FFAs) have pleiotropic effects on the pancreatic beta-cell. Although acute exposure to FFAs stimulates glucose-stimulated insulin secretion (GSIS), prolonged exposure impairs GSIS and causes apoptosis. FFAs exert their effects both via intracellular metabolism and interaction with the FFA receptor 1 (FFAR1/GPR40). Here we studied the role of FFAR1 in acute and long-term effects of palmitate on GSIS and insulin content in isolated human islets by using the FFAR1 agonist TAK-875 and the antagonist ANT203. Acute palmitate exposure potentiated GSIS approximately 3-fold, whereas addition of the antagonist decreased this potentiation to approximately 2-fold. In the absence of palmitate, the agonist caused a 40% increase in GSIS. Treatment with palmitate for 7 days decreased GSIS to 70% and insulin content to 25% of control level. These negative effects of long-term exposure to palmitate were ameliorated by FFAR1 inhibition and further aggravated by additional stimulation of the receptor. In the absence of extracellularly applied palmitate, long-term treatment with the agonist caused a modest increase in GSIS. The protective effect of FFAR1 inhibition was verified by using FFAR1-deficient MIN6 cells. Improved beta-cell function by the antagonist was paralleled by the decreased apoptosis and lowered oxidation of palmitate, which may represent the potential mechanisms of protection. We conclude that FFAR1 in the pancreatic beta-cell plays a substantial role not only in acute potentiation of GSIS by palmitate but also in the negative long-term effects of palmitate on GSIS and insulin content.

  • 29.
    Krizhanovskii, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Elksnis, Andris
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Wang, Xuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gavali, Hamid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Scharfmann, Raphael
    Univ Paris 05, Sorbonne Paris Cite, Fac Med, Inst Cochin,INSERM,U1016, Paris, France..
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    EndoC-beta H1 cells display increased sensitivity to sodium palmitate when cultured in DMEM/F12 medium2017In: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 9, no 3, p. 43-48Article in journal (Refereed)
    Abstract [en]

    Aims - Human pancreatic islets are known to die in response to the free fatty acid of sodium palmitate when cultured in vitro. This is in contrast to EndoC-beta H1 cells, which in our hands are not sensitive to the cell death-inducing effects sodium palmitate, making these cells seemingly unsuitable for lipotoxicity studies. However, the EndoC-beta H1 cells are routinely cultured in a nutrient mixture based on Dulbecco's Modified Eagle Medium (DMEM), which may not be the optimal choice for studies dealing with lipotoxicity. The aim of the present investigation was to define culture conditions that render EndoC-beta H1 cells sensitive to toxic effects of sodium palmitate. Methods - EndoC-beta H1 cells were cultured at standard conditions in either DMEM or DMEM/F12 culture medium. Cell death was analyzed using propidium iodide staining and flow cytometry. Insulin release and content was quantified using a human insulin ELISA. Results - We presently observe that substitution of DMEM for a DMEM/Ham's F12 mixture (50%/50% vol/vol) renders the cells sensitive to the apoptotic effects of sodium palmitate and sodium palmitate + high glucose leading to an increased cell death. Supplementation of the DMEM culture medium with linoleic acid partially mimicked the effect of DMEM/F12. Culture of EndoC-beta H1 cells in DMEM/F12 resulted also in increased proliferation, ROS production and insulin contents, but markers for metabolic stress, autophagy or amyloid deposits were unaffected. Conclusions - The culture conditions for EndoC-beta H1 cells can be modified so these cells display signs of lipotoxicity in response to sodium palmitate.

  • 30.
    Langner, Taro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Hedström, Anders
    BioVenture Hub, Antaros Med, Molndal, Sweden.
    Mörwald, Katharina
    Paracelsus Med Univ, Dept Pediat, Salzburg, Austria; Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.
    Weghuber, Daniel
    Paracelsus Med Univ, Dept Pediat, Salzburg, Austria; Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Bergsten, Peter
    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, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. BioVenture Hub, Antaros Med, Mölndal, Sweden.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. BioVenture Hub, Antaros Med, Mölndal, Sweden.
    Fully convolutional networks for automated segmentation of abdominal adipose tissue depots in multicenter water–fat MRI2019In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 81, no 4, p. 2736-2745Article in journal (Refereed)
    Abstract [en]

    Purpose: An approach for the automated segmentation of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in multicenter water–fat MRI scans of the abdomen was investigated, using 2 different neural network architectures.

    Methods: The 2 fully convolutional network architectures U‐Net and V‐Net were trained, evaluated, and compared using the water–fat MRI data. Data of the study Tellus with 90 scans from a single center was used for a 10‐fold cross‐validation in which the most successful configuration for both networks was determined. These configurations were then tested on 20 scans of the multicenter study beta‐cell function in JUvenile Diabetes and Obesity (BetaJudo), which involved a different study population and scanning device.

    Results: The U‐Net outperformed the used implementation of the V‐Net in both cross‐validation and testing. In cross‐validation, the U‐Net reached average dice scores of 0.988 (VAT) and 0.992 (SAT). The average of the absolute quantification errors amount to 0.67% (VAT) and 0.39% (SAT). On the multicenter test data, the U‐Net performs only slightly worse, with average dice scores of 0.970 (VAT) and 0.987 (SAT) and quantification errors of 2.80% (VAT) and 1.65% (SAT).

    Conclusion: The segmentations generated by the U‐Net allow for reliable quantification and could therefore be viable for high‐quality automated measurements of VAT and SAT in large‐scale studies with minimal need for human intervention. The high performance on the multicenter test data furthermore shows the robustness of this approach for data of different patient demographics and imaging centers, as long as a consistent imaging protocol is used.

  • 31.
    Lin, Jian-Man
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Ortsäter, Henrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Fakhrai-Rad, H
    Galli, Joakim
    Luthman, Holger
    Bergsten, Peter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Phenotyping of individual pancreatic islets locates genetic defects instimulus secretion coupling to Niddm1i within the major diabetes locus inGK rats.2001In: Diabetes, Vol. 50, p. 2737-Article in journal (Refereed)
  • 32.
    Lundström, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Strand, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Weghuber, Daniel
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Medical, BioVenture Hub, Mölndal.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Medical, BioVenture Hub, Mölndal.
    Automated segmentation of human cervical-supraclavicular adipose tissue in magnetic resonance images2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3064Article in journal (Refereed)
    Abstract [en]

    Human brown adipose tissue (BAT), with a major site in the cervical-supraclavicular depot, is a promising anti-obesity target. This work presents an automated method for segmenting cervical-supraclavicular adipose tissue for enabling time-efficient and objective measurements in large cohort research studies of BAT. Fat fraction (FF) and R2* maps were reconstructed from water-fat magnetic resonance imaging (MRI) of 25 subjects. A multi-atlas approach, based on atlases from nine subjects, was chosen as automated segmentation strategy. A semi-automated reference method was used to validate the automated method in the remaining subjects. Automated segmentations were obtained from a pipeline of preprocessing, affine registration, elastic registration and postprocessing. The automated method was validated with respect to segmentation overlap (Dice similarity coefficient, Dice) and estimations of FF, R2* and segmented volume. Bias in measurement results was also evaluated. Segmentation overlaps of Dice = 0.93 +/- 0.03 (mean +/- standard deviation) and correlation coefficients of r > 0.99 (P < 0.0001) in FF, R2* and volume estimates, between the methods, were observed. Dice and BMI were positively correlated (r = 0.54, P = 0.03) but no other significant bias was obtained (P >= 0.07). The automated method compared well with the reference method and can therefore be suitable for time-efficient and objective measurements in large cohort research studies of BAT.

  • 33.
    Lundström, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Strand, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Magnetic resonance imaging cooling–reheating protocol indicates decreased fat fraction via lipid consumption in suspected brown adipose tissue2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4, article id e0126705Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To evaluate whether a water-fat magnetic resonance imaging (MRI) cooling-reheating protocol could be used to detect changes in lipid content and perfusion in the main human brown adipose tissue (BAT) depot after a three-hour long mild cold exposure.

    MATERIALS AND METHODS: Nine volunteers were investigated with chemical-shift-encoded water-fat MRI at baseline, after a three-hour long cold exposure and after subsequent short reheating. Changes in fat fraction (FF) and R2*, related to ambient temperature, were quantified within cervical-supraclavicular adipose tissue (considered as suspected BAT, denoted sBAT) after semi-automatic segmentation. In addition, FF and R2* were quantified fully automatically in subcutaneous adipose tissue (not considered as suspected BAT, denoted SAT) for comparison. By assuming different time scales for the regulation of lipid turnover and perfusion in BAT, the changes were determined as resulting from either altered absolute fat content (lipid-related) or altered absolute water content (perfusion-related).

    RESULTS: sBAT-FF decreased after cold exposure (mean change in percentage points = -1.94 pp, P = 0.021) whereas no change was observed in SAT-FF (mean = 0.23 pp, P = 0.314). sBAT-R2* tended to increase (mean = 0.65 s-1, P = 0.051) and SAT-R2* increased (mean = 0.40 s-1, P = 0.038) after cold exposure. sBAT-FF remained decreased after reheating (mean = -1.92 pp, P = 0.008, compared to baseline) whereas SAT-FF decreased (mean = -0.79 pp, P = 0.008, compared to after cold exposure).

    CONCLUSIONS: The sustained low sBAT-FF after reheating suggests lipid consumption, rather than altered perfusion, as the main cause to the decreased sBAT-FF. The results obtained demonstrate the use of the cooling-reheating protocol for detecting changes in the cervical-supraclavicular fat depot, being the main human brown adipose tissue depot, in terms of lipid content and perfusion.

  • 34.
    Manell, Hannes
    et al.
    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.
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Paulmichl, K.
    Paracelsus Med Univ, Pediat, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria..
    Cadamuro, J.
    Paracelsus Med Univ, Lab Med, Salzburg, Austria..
    Zsoldos, F.
    Paracelsus Med Univ, Pediat, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria..
    Staaf, Johan
    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, Pediatrics.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Weghuber, D.
    Paracelsus Med Univ, Pediat, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria..
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hyperglucagonaemia is associated with elevated plasma triglycerides and increased visceral fat in children and adolescents2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S267-S268Article in journal (Refereed)
  • 35.
    Manell, Hannes
    et al.
    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.
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Paulmichl, Katharina
    Paracelsus Med Privatuniv, Abt Kinder & Jugendheilkunde, Salzburg, Austria.;Paracelsus Med Privatuniv, Obes Res Unit, Salzburg, Austria..
    Staaf, Johan
    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, Pediatrics.
    Cadamuro, Janne
    Paracelsus Med Privatuniv, Abt Med Chem Labordiagnost, Salzburg, Austria..
    Zsoldos, Fanni
    Paracelsus Med Privatuniv, Abt Kinder & Jugendheilkunde, Salzburg, Austria.;Paracelsus Med Privatuniv, Obes Res Unit, Salzburg, Austria..
    Gopel, Sven
    AstraZeneca R&D, Molndal, Sweden..
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Weghuber, Daniel
    Paracelsus Med Privatuniv, Abt Kinder & Jugendheilkunde, Salzburg, Austria.;Paracelsus Med Privatuniv, Obes Res Unit, Salzburg, Austria..
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hyperglucagonemia is associated with a Increase of Plasma Triglycerides as well as visceral Fat Tissue in a pediatric Cohort2016In: Wiener Klinische Wochenschrift, ISSN 0043-5325, E-ISSN 1613-7671, Vol. 128, no 19-20, p. 747-747Article in journal (Other academic)
  • 36.
    Manell, Hannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ubhayasekera, Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mörwald, Katharina
    Paracelsus Medical University.
    Staaf, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Cadamuro, Janne
    Paracelsus Medical University.
    Zsoldos, Fanni
    Paracelsus Medical University.
    Göpel, Sven
    AstraZeneca.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Weghuber, Daniel
    Paracelsus Medical University.
    Forslund, Anders
    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 Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Hyperglucagonemia in youth is associated with high plasma free fatty acids, visceral adiposity and impaired glucose toleranceIn: Article in journal (Refereed)
    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.

  • 37.
    Manell, Hannes
    et al.
    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.
    Shen, Qiujin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Forslund, Anders
    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, Research group (Dept. of women´s and children´s health), Pediatric Endocrinology.
    Bergsten, Peter
    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, Research group (Dept. of women´s and children´s health), Pediatric Endocrinology.
    TNFSF14: a potential contributor to hyperinsulinaemia in childhood obesity2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, p. S168-S168Article in journal (Other academic)
  • 38.
    Manell, Hannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shen, Qiujin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Roomp, Kirsten
    University of Luxembourg.
    Ciba, Iris
    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.
    Dahlbom, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Weghuber, Daniel
    Paracelsus Medical University.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Forslund, Anders
    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 Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Screening of inflammatory markers finds hepatocyte growth factor to be associated with weight gain in children and adolescents with obesityManuscript (preprint) (Other academic)
  • 39.
    Manell, Hannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Staaf, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Manukyan, Levon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Cen, Jing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Stenlid, Rasmus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ciba, Iris
    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, Pediatrics.
    Forslund, Anders
    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, Pediatrics.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Altered Plasma Levels of Glucagon, GLP-1 and Glicentin During OGTT in Adolescents With Obesity and Type 2 Diabetes2016In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 3, p. 1181-1189Article in journal (Refereed)
    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.

  • 40.
    Mangge, Harald
    et al.
    Med Univ Graz, Clin Inst Med, Auenbruggerpl 15, A-8036 Graz, Austria.;Med Univ Graz, Chem Lab Diagnost, Auenbruggerpl 15, A-8036 Graz, Austria..
    Zelzer, Sieglinde
    Med Univ Graz, Clin Inst Med, Auenbruggerpl 15, A-8036 Graz, Austria.;Med Univ Graz, Chem Lab Diagnost, Auenbruggerpl 15, A-8036 Graz, Austria..
    Prueller, Florian
    Med Univ Graz, Clin Inst Med, Auenbruggerpl 15, A-8036 Graz, Austria.;Med Univ Graz, Chem Lab Diagnost, Auenbruggerpl 15, A-8036 Graz, Austria..
    Schnedl, Wolfgang J.
    General Practice Internal Med, Bruck An Der Mur, Austria..
    Weghuber, Daniel
    Paracelsus Med Univ, Dept Pediat, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria..
    Enko, Dietmar
    Gen Hosp Steyr, Inst Lab Med, Steyr, Austria..
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Haybaeck, Johannes
    Med Univ Graz, Dept Pathol, Graz, Austria..
    Meinitzer, Andreas
    Med Univ Graz, Clin Inst Med, Auenbruggerpl 15, A-8036 Graz, Austria.;Med Univ Graz, Chem Lab Diagnost, Auenbruggerpl 15, A-8036 Graz, Austria..
    Branched-chain amino acids are associated with cardiometabolic risk profiles found already in lean, overweight and obese young2016In: Journal of Nutritional Biochemistry, ISSN 0955-2863, E-ISSN 1873-4847, Vol. 32, p. 123-127Article in journal (Refereed)
    Abstract [en]

    Cardiovascular risk is increased in obese subjects. Nevertheless, some overweight and obese remain cardiometabolically healthy (CMH), and normal-weight persons develop cardiovascular disease (CVD). Herein, we investigate the potential of branched-chain amino acids (BCAAs) to identify an increased CVD risk in a cross-sectional study of 666 adults and juveniles (age 25.3 +/- 12.8 years), classified as lean, overweight or obese. Cardiometabolic groups were defined by cutoffs of systolic blood pressure <130 mmHg, diastolic blood pressure<85 mmHg, glucose <125 mg/dl, triglycerides <150 mg/dl, HDL-cholesterol>40 mg/dl (males), HDL-cholesterol>50 mg/dl (females) and HOMA-IR<5. CMH had <= 1 cutoff, and cardiometabolically abnormal (CMA) had >= 2 cutoffs. Amino acids were measured by high-pressure lipid chromatography after precipitation of serum with perchloric acid and derivatization with o-phthalaldehyde. Valine correlated with 5, leucine correlated with 3 and isoleucine correlated with 5 of the cardiac risk classification factors. Valine and leucine were significantly higher in the obese (P<.001, P=.015, respectively), overweight (P<.001, P=.015, respectively) and lean (P=.024, P=.012, respectively) CMA compared to CMH subjects. Isoleucine showed except of the lean group the same results. Taken together, BCAAs, especially valine and leucine, are proposed as a cardiometabolic risk marker independent of body mass index (BMI) category.

  • 41.
    Manukyan, Levon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dunder, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Bergsten, Peter
    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, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Developmental exposure to a very low dose of bisphenol A induces persistent islet insulin hypersecretion in Fischer 344 rat offspring2019In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 172, p. 127-136Article in journal (Refereed)
    Abstract [en]

    Background: In children with obesity, accentuated insulin secretion has been coupled with development of type 2 diabetes mellitus (T2DM). Bisphenol A (BPA) is a chemical with endocrine- and metabolism-disrupting properties which can be measured in a majority of the population. Exposure to BPA has been associated with the development of metabolic diseases including T2DM.

    Objective: The aim of this study was to investigate if exposure early in life to an environmentally relevant low dose of BPA causes insulin hypersecretion in rat offspring.

    Methods: Pregnant Fischer 344 rats were exposed to 0.5 (BPA0.5) or 50 (BPA50) jig BPA/kg BW/day via drinking water from gestational day 3.5 until postnatal day 22. Pancreata from dams and 5- and 52-week-old offspring were procured and islets were isolated by collagenase digestion. Glucose-stimulated insulin secretion and insulin content in the islets were determined by ELISA.

    Results: Basal (5.5 mM glucose) islet insulin secretion was not affected by BPA exposure. However, stimulated (11 mM glucose) insulin secretion was enhanced by about 50% in islets isolated from BPA0.5-exposed 5- and 52 week-old female and male offspring and by 80% in islets from dams, compared with control. In contrast, the higher dose, BPA50, reduced stimulated insulin secretion by 40% in both 5- and 52-week-old female and male offspring and dams, compared with control.

    Conclusion: A BPA intake 8 times lower than the European Food Safety Authority's (EFSA's) current tolerable daily intake (TDI) of 4 mu g/kg BW/day of BPA delivered via drinking water during gestation and early development causes islet insulin hypersecretion in rat offspring up to one year after exposure. The effects of BPA exposure on the endocrine pancreas may promote the development of metabolic disease including T2DM.

  • 42.
    Manukyan, Levon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ubhayasekera, Sarojini J.K.A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergquist,, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Palmitate-induced impairments of beta-cell function are linked with generation of specific ceramide species via acylation of sphingosine2015In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 156, no 3, p. 802-812Article in journal (Refereed)
    Abstract [en]

    Prolonged exposure to palmitate impairs beta-cell function and mass. One of the proposed mechanisms is alteration in ceramide generation. In the present study, exposure to palmitate induced the level of palmitoyl transferase and ceramide synthases, enzymes of the ceramide de novo and salvage pathways, and doubled total ceramide levels, which was associated with decreased insulin secretion and augmented apoptosis in MIN6 cells and human islets. By inhibiting enzymes of the pathways pharmacologically with ISP-1 or fumonisin B1 or by siRNA we showed that Cer(14:0), Cer(16:0), Cer(20:1) and Cer(24:0) species, generated by the salvage pathway, are linked to the harmful effect of palmitate on beta-cells. Oleate attenuates negative effects of palmitate on beta-cells. When oleate was included during culture of MIN6 cells with palmitate the palmitate-induced up-regulation of the enzymes of the de novo and salvage pathways was prevented resulting in normalized levels of all ceramide species except Cer(20:1). Our data suggest that enhanced ceramide generation in response to elevated palmitate levels involves both de novo and salvage pathways. However, the negative effects of palmitate on beta-cells are attributed to generation of ceramide species Cer(14:0), Cer(16:0) and Cer(24:0) via acylation of sphingosine.

  • 43.
    Norgren, A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ciba, Iris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Manell, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Stenlid, R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dahlbom, Marie
    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, Pediatrics.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Forslund, Anders
    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, Pediatrics.
    Early Adiposity Rebound and its Association with Obesity and Neuropsychiatric Disorders2015In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 104, no S466, p. 16-16Article in journal (Other academic)
  • 44.
    Ntika, Stelia
    et al.
    Sodertalje Hosp, Dept Res, STS Biovat, SE-15286 Sodertalje, Sweden;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Thombare, Ketan
    Sodertalje Hosp, Dept Res, STS Biovat, SE-15286 Sodertalje, Sweden.
    Aryapoor, Masood
    Sodertalje Hosp, Dept Res, STS Biovat, SE-15286 Sodertalje, Sweden.
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Krizhanovskii, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Sodertalje Hosp, Dept Res, STS Biovat, SE-15286 Sodertalje, Sweden;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Oleate increase neutral lipid accumulation, cellular respiration and rescues palmitate-exposed GLP-1 secreting cells by reducing ceramide-induced ROS2019In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 159, p. 23-35Article in journal (Refereed)
    Abstract [en]

    Background: Fatty acids (FAs), and especially monounsaturated FAs (MUFAs) stimulate GLP-1 release. However, lipotoxicity is indicated in GLP-1 secreting cells following long-term exposure to elevated levels of saturated FAs (SFAs) in vivo and in vitro, where in vitro studies indicate that cosupplementation with MUFAs confers lipoprotection. SFAs and MUFAs differentially affect the fate of cells in ways that depend on the cell type, concentration and ratio of the FAs. The present study was designed to further elucidate the mechanisms underlying the effects of SFAs/MUFAs on GLP-1-producing cells in terms of lipotoxicity/lipoprotection and GLP-1 secretion.

    Methods: Cultured GLP-1 secreting cells were exposed to hyperlipidemia simulated by SFA-albumin complexes where the molar ratio was 2:1. The cellular response to simulated hyperlipidemia was assessed in the presence/absence of MUFA cosupplementation by determining intracellular ceramide, ROS, neutral lipid accumulation, and cellular respiration. The role for cellular respiration in GLP-1 secretion in response to SFAs/MUFAs was assessed.

    Results: Generation of intracellular ceramide mediate a detrimental increased in ROS production following long term exposure to SFAs in GLP-1-secreting cells. Cosupplementation with MUFAs increases cellular respiration, triglyceride synthesis, and the expression of ceramide kinase, while reducing ceramide synthesis and attenuating ROS production, caspase-3 activity and DNA fragmentation. Further, acute secretory effects of unsaturated FAs are independent of FAO, but mediated by a FFAR1 induced increase in cellular respiration.

    Conclusion: This study demonstrates novel data supporting effects of MUFAs on the ceramide biosynthetic pathway, triglyceride storage respiration and secretion in GLP-1 secreting cells. These findings may be of value for nutritional interventions, as well as for identification of novel targets, to help preserve L-cell mass and potentiate GLP-1 secretion in diabesity.

  • 45.
    Nyblom, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Thorn, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahmed, Meftun
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mitochondrial protein patterns correlating with impaired insulin secretion from INS-1E cells exposed to elevated glucose concentrations2006In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 6, no 19, p. 5193-5198Article in journal (Refereed)
    Abstract [en]

    Extended hyperglycaemia leads to impaired glucose-stimulated insulin secretion (GSIS) and eventually P-cell apoptosis in individuals with type 2 diabetes mellitus. In an attempt to dissect mechanisms behind the detrimental effects of glucose, we focused on measuring changes in expression patterns of mitochondrial proteins. Impaired GSIS was observed from INS-1E cells cultured for 5 days at 20 or 27 mM glucose compared to cells cultured at 5.5 or 11 mM glucose. After culture, mitochondria were isolated from the INS-1E cells by differential centrifugation. Proteins of the mitochondrial fraction were bound to a strong anionic surface (SAX2) protein array and mass spectra generated by SELDI-TOF-MS. Analysis of the spectra revealed proteins with expression levels that correlated with the glucose concentration of the culture medium. Indeed, such differentially expressed proteins created patterns of protein changes, which correlated with impairment of GSIS. In conclusion, the study reveals the first glucose-induced differentially expressed patterns of P-cell mitochondrial proteins obtained by SELDI-TOF-MS.

  • 46.
    Ohlsson, H.
    et al.
    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.
    Staaf, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Manukyan, Levon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Cen, J.
    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.
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Active GLP-1 but not insulin, glicentin or glucagon predicts the 2-hour OGTT glucose value in obese children2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S276-S276Article in journal (Other academic)
  • 47.
    Ortsater, H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Alberts, P
    Warpman, U
    Engblom, LO
    Abrahmsen, L
    Bergsten, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Regulation of 11beta-hydroxysterioid dehydrogenase type 1 and glucose-stimulated insulin secretion in pancreatic islets of Langerhans2004In: Diabetes Metab Res RevArticle in journal (Refereed)
  • 48.
    Ortsäter, Henrik
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Alberts, Peteris
    Warpman, Ulrika
    Engblom, Lars O M
    Abrahmsén, Lars
    Bergsten, Peter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Regulation of 11beta-hydroxysteroid dehydrogenase type 1 and glucose-stimulated insulin secretion in pancreatic islets of Langerhans.2005In: Diabetes Metab Res Rev, ISSN 1520-7552, Vol. 21, no 4, p. 359-66Article in journal (Refereed)
  • 49.
    Ortsäter, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Protein profiling of pancreatic islets2006In: Expert review of proteomics, ISSN 1478-9450, Vol. 3, no 6, p. 665-675Article, review/survey (Refereed)
    Abstract [en]

    The insulin-producing beta cell in the islet of Langerhans is central in glucose homeostasis. Its dysfunction is part of the pathogenesis of both Type 1 and 2 diabetes mellitus. In both forms of the disease, there is a cytotoxic component either induced by cytokines, as in Type 1 diabetes, or by elevated levels of glucose and fatty acids, as in Type 2 diabetes. To find the mechanisms responsible for the cytotoxic effects of these compounds proteomic approaches with 2D gel electrophoresis and surface-enhanced laser desorption/ionization time-of-flight mass spectrometry have been undertaken. In this article, we describe these methods, and other methodological aspects of protein profiling of pancreatic islets, and summarize the results obtained with these methods.

  • 50.
    Ostman, Johnny R.
    et al.
    Swedish Univ Agr Sci, Dept Mol Sci, SE-75007 Uppsala, Sweden.
    Mullner, Elisabeth
    Swedish Univ Agr Sci, Dept Mol Sci, SE-75007 Uppsala, Sweden.
    Eriksson, Jan
    Swedish Univ Agr Sci, Dept Mol Sci, SE-75007 Uppsala, Sweden.
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Witthoft, Cornelia
    Linnaeus Univ, Dept Chem & Biomed Sci, SE-43032 Kalmar, Sweden.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Moazzami, Ali A.
    Swedish Univ Agr Sci, Dept Mol Sci, SE-75007 Uppsala, Sweden.
    Glucose Appearance Rate Rather than the Blood Glucose Concentrations Explains Differences in Postprandial Insulin Responses between Wholemeal Rye and Refined Wheat Breads-Results from A Cross-Over Meal Study2019In: Molecular Nutrition & Food Research, ISSN 1613-4125, E-ISSN 1613-4133, Vol. 63, no 7, article id 1800959Article in journal (Refereed)
    Abstract [en]

    Scope Ingestion of rye bread leads to lower postprandial plasma insulin concentrations than wheat bread ingestion, but most often not too different glucose profiles. The mechanism behind this discrepancy is still largely unknown. This study investigates whether glucose kinetics may explain the observed discrepancy. Methods and results Nine healthy men participated in a crossover study, eating 50 g of available carbohydrates as either refined wheat (WB) or traditional wholemeal rye bread (WMR) during d-[6,6-H-2(2)]glucose infusion. Labeled glucose enrichment is measured by an HPLC-TOF-MS method. The calculated rate of glucose appearance (RaE) is significantly lower after ingestion of WMR during the initial 15 min postprandial period. Additionally, the 0-90 min RaE area under the curve (AUC) is significantly lower after ingestion of WMR, as is plasma gastric inhibitory polypeptide (GIP) at 60 and 90 min. Postprandial glycemic responses do not differ between the breads. Postprandial insulin is lower after ingestion of WMR at 45 and 60 min, as is the 0-90 min AUC. Conclusion Ingestion of WMR elicits a lower rate of glucose appearance into the bloodstream compared with WB. This may explain the lower insulin response observed after rye bread ingestion, commonly known as the rye factor.

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