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- Ciba, Iris, et al.
(författare)
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Studies in children with obesity in two European treatment centres show a high prevalence of impaired glucose metabolism in the Swedish cohort
- 2024
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Ingår i: Acta Paediatrica. - : John Wiley & Sons. - 0803-5253 .- 1651-2227. ; 113:2, s. 286-295
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To investigate the prevalence and possible risk factors for the development of impaired glucose metabolism in children and adolescents with obesity.Methods: This was a cross-sectional retrospective cohort study, including 634 patients with obesity and 98 normal weight controls aged 4-18 years from the Beta-cell function in Juvenile Diabetes and Obesity (Beta-JUDO) cohort, a dual-centre study at Uppsala University Hospital (Sweden) and Paracelsus Medical University Hospital (Salzburg, Austria) conducted between 2012 and 2021. A longitudinal subgroup analysis, including 188 of these subjects was performed. Impaired glucose metabolism was diagnosed by oral glucose tolerance tests according to American Diabetes Association criteria.Results: The prevalence of impaired glucose metabolism was 72% in Uppsala patients, 24% in Salzburg patients, 30% in Uppsala controls and 13% in Salzburg controls. The prevalence was lower at the follow-up visits compared with baseline both in Uppsala and Salzburg patients. A family history of type 2 diabetes showed the strongest association with impaired glucose metabolism at the follow-up visits besides belonging to the Uppsala cohort.Conclusion: The prevalence of impaired glucose metabolism was extraordinarily high in Swedish children and adolescents with obesity, but decreased during the follow-up period.
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| 2. |
- Groebe, Karlfried, et al.
(författare)
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Palmitate-Induced Insulin Hypersecretion and Later Secretory Decline Associated with Changes in Protein Expression Patterns in Human Pancreatic Islets
- 2018
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 17:11, s. 3824-3836
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Mörwald, Katharina, et al.
(författare)
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Serum Ferritin Correlates With Liver Fat in Male Adolescents With Obesity.
- 2020
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) contributes essentially to the burden of obesity and can start in childhood. NAFLD can progress to cirrhosis and hepatocellular carcinoma. The early phase of NAFLD is crucial because during this time the disease is fully reversible. Pediatric NAFLD shows unique features of histology and pathophysiology compared to adults. Changes in serum iron parameters are common in adult NAFLD and have been termed dysmetabolic iron overload syndrome characterized by increased serum ferritin levels and normal transferrin saturation; however, the associations of serum ferritin, inflammation, and liver fat content have been incompletely investigated in children. As magnetic resonance imaging (MRI) is an excellent measure for the degree of liver steatosis, we applied this method herein to clarify the interaction between ferritin and fatty liver in male adolescents. For this study, one hundred fifty male pediatric patients with obesity and who are overweight were included. We studied a subgroup of male patients with (n = 44) and without (n = 18) NAFLD in whom we determined liver fat content, visceral adipose tissue, and subcutaneous adipose tissue extent with a 1.5T MRI (Philips NL). All patients underwent a standardized oral glucose tolerance test. We measured uric acid, triglycerides, HDL-, LDL-, total cholesterol, liver transaminases, high sensitive CRP (hsCRP), interleukin-6, HbA1c, and insulin. In univariate analysis, ferritin was associated with MRI liver fat, visceral adipose tissue content, hsCRP, AST, ALT, and GGT, while transferrin and soluble transferrin receptor were not associated with ferritin. Multivariate analysis identified hsCRP and liver fat content as independent predictors of serum ferritin in the pediatric male patients. Our data indicate that serum ferritin in male adolescents with obesity is mainly determined by liver fat content and inflammation but not by body iron status.
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| 6. |
- Roomp, Kirsten, et al.
(författare)
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Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Studies on the pathophysiology of type 2 diabetes mellitus (T2DM) have linked the accumulation of lipid metabolites to the development of beta-cell dysfunction and impaired insulin secretion. In most in vitro models of T2DM, rodent islets or beta-cell lines are used and typically focus is on specific cellular pathways or organs. Our aim was to, firstly, develop a combined lipidomics and proteomics approach for lipotoxicity in isolated human islets and, secondly, investigate if the approach could delineate novel and/or confirm reported mechanisms of lipotoxicity. To this end isolated human pancreatic islets, exposed to chronically elevated palmitate concentrations for 0, 2 and 7 days, were functionally characterized and their levels of multiple targeted lipid and untargeted protein species determined. Glucosestimulated insulin secretion from the islets increased on day 2 and decreased on day 7. At day 7 islet insulin content decreased and the proinsulin to insulin content ratio doubled. Amounts of cholesterol, stearic acid, C16 dihydroceramide and C24: 1 sphingomyelin, obtained from the lipidomic screen, increased time-dependently in the palmitate-exposed islets. The proteomic screen identified matching changes in proteins involved in lipid biosynthesis indicating up-regulated cholesterol and lipid biosynthesis in the islets. Furthermore, proteins associated with immature secretory granules were decreased when palmitate exposure time was increased despite their high affinity for cholesterol. Proteins associated with mature secretory granules remained unchanged. Pathway analysis based on the protein and lipid expression profiles implicated autocrine effects of insulin in lipotoxicity. Taken together the study demonstrates that combining different omics approaches has potential in mapping of multiple simultaneous cellular events. However, it also shows that challenges exist for effectively combining lipidomics and proteomics in primary cells. Our findings provide insight into how saturated fatty acids contribute to islet cell dysfunction by affecting the granule maturation process and confirmation in human islets of some previous findings from rodent islet and cell-line studies.
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| 7. |
- Sargsyan, Ernest, et al.
(författare)
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Identification of early biological changes in palmitate-treated isolated human islets.
- 2018
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Ingår i: BMC Genomics. - BioMed Central, UK : Springer Science and Business Media LLC. - 1471-2164. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long-term exposure to elevated levels of free fatty acids (FFAs) is deleterious for beta-cell function and may contribute to development of type 2 diabetes mellitus (T2DM). Whereas mechanisms of impaired glucose-stimulated insulin secretion (GSIS) in FFA-treated beta-cells have been intensively studied, biological events preceding the secretory failure, when GSIS is accentuated, are poorly investigated. To identify these early events, we performed genome-wide analysis of gene expression in isolated human islets exposed to fatty acid palmitate for different time periods.Results: Palmitate-treated human islets showed decline in beta-cell function starting from day two. Affymetrix Human Transcriptome Array 2.0 identified 903 differentially expressed genes (DEGs). Mapping of the genes onto pathways using KEGG pathway enrichment analysis predicted four islet biology-related pathways enriched prior but not after the decline of islet function and three pathways enriched both prior and after the decline of islet function. DEGs from these pathways were analyzed at the transcript level. The results propose that in palmitate-treated human islets, at early time points, protective events, including up-regulation of metallothioneins, tRNA synthetases and fatty acid-metabolising proteins, dominate over deleterious events, including inhibition of fatty acid detoxification enzymes, which contributes to the enhanced GSIS. After prolonged exposure of islets to palmitate, the protective events are outweighed by the deleterious events, which leads to impaired GSIS.Conclusions: The study identifies temporal order between different cellular events, which either promote or protect from beta-cell failure. The sequence of these events should be considered when developing strategies for prevention and treatment of the disease.
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| 8. |
- Staaf, Johan, et al.
(författare)
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Pancreatic Fat Is Associated With Metabolic Syndrome and Visceral Fat but Not Beta-Cell Function or Body Mass Index in Pediatric Obesity
- 2017
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 46:3, s. 358-365
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Adolescents with obesity have increased risk of type 2 diabetes and metabolic syndrome (MetS). Pancreatic fat has been related to these conditions; however, little is known about associations in pediatric obesity. The present study was designed to explore these associations further.METHODS: We examined 116 subjects, 90 with obesity. Anthropometry, MetS, blood samples, and oral glucose tolerance tests were assessed using standard techniques. Pancreatic fat fraction (PFF) and other fat depots were quantified using magnetic resonance imaging.RESULTS: The PFF was elevated in subjects with obesity. No association between PFF and body mass index-standard deviation score (BMI-SDS) was found in the obesity subcohort. Pancreatic fat fraction correlated to Insulin Secretion Sensitivity Index-2 and Homeostatic Model Assessment of Insulin Resistance in simple regression; however, when using adjusted regression and correcting for BMI-SDS and other fat compartments, PFF correlated only to visceral adipose tissue and fasting glucose. Highest levels of PFF were found in subjects with obesity and MetS.CONCLUSIONS: In adolescents with obesity, PFF is elevated and associatedto MetS, fasting glucose, and visceral adipose tissue but not to beta-cellfunction, glucose tolerance, or BMI-SDS. This study demonstrates thatconclusions regarding PFF and its associations depend on the body massfeatures of the cohort.
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