| 1. |
- Ahlqvist, Emma, et al.
(author)
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Novel subgroups of adult-onset diabetes and their association with outcomes : a data-driven cluster analysis of six variables
- 2018
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In: The Lancet Diabetes and Endocrinology. - 2213-8587 .- 2213-8595. ; 6:5, s. 361-369
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Journal article (peer-reviewed)abstract
- BackgroundDiabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis.MethodsWe did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations.FindingsWe identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes.InterpretationWe stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.
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| 2. |
- Fernandez, Celine, et al.
(author)
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Metabolomic and proteomic analysis of a clonal insulin-producing beta-cell line (INS-1 832/13).
- 2008
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 7:1, s. 400-411
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Journal article (peer-reviewed)abstract
- Metabolites generated from fuel metabolism in pancreatic beta-cells control exocytosis of insulin, a process which fails in type 2 diabetes. To identify and quantify these metabolites, global and unbiased analysis of cellular metabolism is required. To this end, polar metabolites, extracted from the clonal 832/13 beta-cell line cultured at 2.8 and 16.7 mM glucose for 48 h, were derivatized followed by identification and quantification, using gas chromatography (GC) and mass spectrometry (MS). After culture at 16.7 mM glucose for 48 h, 832/13 beta-cells exhibited a phenotype reminiscent of glucotoxicity with decreased content and secretion of insulin. The metabolomic analysis revealed alterations in the levels of 7 metabolites derived from glycolysis, the TCA cycle and pentose phosphate shunt, and 4 amino acids. Principal component analysis of the metabolite data showed two clusters, corresponding to the cells cultured at 2.8 and 16.7 mM glucose, respectively. Concurrent changes in protein expression were analyzed by 2-D gel electrophoresis followed by LC-MS/MS. The identities of 86 spots corresponding to 75 unique proteins that were significantly different in 832/13 beta-cells cultured at 16.7 mM glucose were established. Only 5 of these were found to be metabolic enzymes that could be involved in the metabolomic alterations observed. Anticipated changes in metabolite levels in cells exposed to increased glucose were observed, while changes in enzyme levels were much less profound. This suggests that substrate availability, allosteric regulation, and/or post-translational modifications are more important determinants of metabolite levels than enzyme expression at the protein level.
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| 3. |
- Jain, Ruchi, et al.
(author)
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Liver nucleotide biosynthesis is linked to protection from vascular complications in individuals with long-term type 1 diabetes
- 2020
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Journal article (peer-reviewed)abstract
- Identification of biomarkers associated with protection from developing diabetic complications is a prerequisite for an effective prevention and treatment. The aim of the present study was to identify clinical and plasma metabolite markers associated with freedom from vascular complications in people with very long duration of type 1 diabetes (T1D). Individuals with T1D, who despite having longer than 30 years of diabetes duration never developed major macro- or microvascular complications (non-progressors; NP) were compared with those who developed vascular complications within 25 years from diabetes onset (rapid progressors; RP) in the Scandinavian PROLONG (n = 385) and DIALONG (n = 71) cohorts. The DIALONG study also included 75 healthy controls. Plasma metabolites were measured using gas and/or liquid chromatography coupled to mass spectrometry. Lower hepatic fatty liver indices were significant common feature characterized NPs in both studies. Higher insulin sensitivity and residual beta-cell function (C-peptide) were also associated with NPs in PROLONG. Protection from diabetic complications was associated with lower levels of the glycolytic metabolite pyruvate and APOCIII in PROLONG, and with lower levels of thiamine monophosphate and erythritol, a cofactor and intermediate product in the pentose phosphate pathway as well as higher phenylalanine, glycine and serine in DIALONG. Furthermore, T1D individuals showed elevated levels of picolinic acid as compared to the healthy individuals. The present findings suggest a potential beneficial shunting of glycolytic substrates towards the pentose phosphate and one carbon metabolism pathways to promote nucleotide biosynthesis in the liver. These processes might be linked to higher insulin sensitivity and lower liver fat content, and might represent a mechanism for protection from vascular complications in individuals with long-term T1D.
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| 4. |
- Kamal, Nadia, et al.
(author)
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The mosaic oat genome gives insights into a uniquely healthy cereal crop
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 606:7912, s. 113-119
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Journal article (peer-reviewed)abstract
- Cultivated oat (Avena sativa L.) is an allohexaploid (AACCDD, 2n = 6x = 42) thought to have been domesticated more than 3,000 years ago while growing as a weed in wheat, emmer and barley fields in Anatolia1,2. Oat has a low carbon footprint, substantial health benefits and the potential to replace animal-based food products. However, the lack of a fully annotated reference genome has hampered efforts to deconvolute its complex evolutionary history and functional gene dynamics. Here we present a high-quality reference genome of A. sativa and close relatives of its diploid (Avena longiglumis, AA, 2n = 14) and tetraploid (Avena insularis, CCDD, 2n = 4x = 28) progenitors. We reveal the mosaic structure of the oat genome, trace large-scale genomic reorganizations in the polyploidization history of oat and illustrate a breeding barrier associated with the genome architecture of oat. We showcase detailed analyses of gene families implicated in human health and nutrition, which adds to the evidence supporting oat safety in gluten-free diets, and we perform mapping-by-sequencing of an agronomic trait related to water-use efficiency. This resource for the Avena genus will help to leverage knowledge from other cereal genomes, improve understanding of basic oat biology and accelerate genomics-assisted breeding and reanalysis of quantitative trait studies.
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| 5. |
- Lyssenko, Valeriya, et al.
(author)
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Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 82-88
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Journal article (peer-reviewed)abstract
- Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.
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| 6. |
- Malmström, David, et al.
(author)
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Continuous full filling capillary electrochromatography-electrospraying chromatographic nanoparticles
- 2011
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In: Electrophoresis. - : Wiley. - 0173-0835 .- 1522-2683. ; 32:2, s. 261-267
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Journal article (peer-reviewed)abstract
- The influence of instrumental parameters affecting the ionization in continuous full filling capillary electrochromatography/electrospray ionization mass spectrometry (CFF-CEC/ESI-MS) was investigated. The investigated parameters were the BGE and sheath liquid ion strength and organic modifier content, the nebulizer gas pressure, and the concentration of nanoparticles in the BGE. It was found that the nebulizer pressure had the largest influence on the separation efficiency and apparent retention. It was shown that even the lowest pressure investigated was sufficient to guide the nanoparticle flow away from the mass spectrometer inlet. A nebulizer pressure of 5 psi was found to be optimal; increasing the pressure significantly decreased the separation efficiency due to the generation of a hydrodynamic flow. Generally, the ion strength of both the BGE and the sheath liquid were found to have very moderate effects on the separation of a homologous series of dialkyl phthalates, whereas the ionization efficiency was found to be unaffected by the nanoparticles and the separation efficiency was found to increase with increasing concentrations up to 3.8 mg/mL, whereafter it was observed to drop. The optimized method was linear over a wide concentration range and presented LOD and LOQ more than threefold lower than those previously reported using CFF-CEC/ESI-MS.
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| 7. |
- Nilsson, Christian, et al.
(author)
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Nanoparticle-based continuous full filling capillary electrochromatography/electrospray ionization-mass spectrometry for separation of neutral compounds
- 2006
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In: Analytical Chemistry. - : American Chemical Society (ACS). - 1520-6882 .- 0003-2700. ; 78:17, s. 6088-6095
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Journal article (peer-reviewed)abstract
- Highly efficient reversed-phase capillary electrochromatography (CEC) separations (plate numbers up to 700 000/m), with electrospray ionization mass spectrometry detection were achieved utilizing novel dextran-coated polymer nanoparticles as a pseudostationary phase. A continuous full filling (CFF) technique in which nanoparticles are continuously introduced into the capillary was employed for separation of neutral analytes (dialkyl phthalates), utilizing an orthogonal electrospray interface to prevent nanoparticles from entering the mass spectrometer. CFF-CEC benefits from that an entirely fresh column is employed for every analysis, avoiding carryover effects associated with stationary-phase contamination. The highly efficient separations obtained were accomplished by optimizing the organic modifier concentration in the electrolyte and by using a high nanoparticle concentration (5 mg/mL), to improve interparticle mass transfer and gain sufficient retention. Nanoparticles, with an average diameter of 600 nm, were prepared by polymerization of methacrylic acid and trimethylolpropane trimethacrylate, which in turn were coated with dextran. These nanoparticles formed stable suspensions in electrolytes having broad ranges of polarities, enabling straightforward optimization of the reversed-phase conditions.
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| 8. |
- Santesson, Sabina, et al.
(author)
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Airborne Single Cell Chemistry
- 2002
-
In: European Biotechnology News. ; 1:1, s. 39-40
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Journal article (pop. science, debate, etc.)
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| 9. |
- Spégel, Peter, et al.
(author)
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Continuous full filling capillary electrochromatography: Nanoparticle synthesis and evaluation
- 2007
-
In: Journal of Chromatography A. - : Elsevier BV. - 0021-9673. ; 1154:1-2, s. 379-385
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Journal article (peer-reviewed)abstract
- Reversed phase continuous full filling capillary electrochromatography with electrospray ionisation mass spectrometric detection was performed with highly sulphated poly [styrene-co-(lauryl methacrylate)-co-(divinylbenzene)] nanoparticles. The nanoparticles that contained a hydrophobic core and a hydrophilic surface were prepared in a one step synthesis using soap free emulsion polymerisation. By changing the concentration of monomers, the polymerisation temperature, and the polarity of the dispersive phase, the size of the nanoparticles could be controlled. With the optimised conditions, nanoparticles with an average size of 157 nm were obtained. These nanoparticles were dispersed in the background electrolyte and used for reversed phase continuous full filling. An orthogonal electrospray ionisation interface was used to separate the eluting nanoparticles from the eluting analytes prior to mass spectrometry detection. Compared to previous studies on reversed phase continuous full filling, the retention, the separation efficiency, and the resolution of a homologous series of dialkyl phthalates were greatly improved.
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| 10. |
- Sun, Jiangming, et al.
(author)
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Discriminative prediction of A-To-I RNA editing events from DNA sequence
- 2016
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:10
-
Journal article (peer-reviewed)abstract
- RNA editing is a post-transcriptional alteration of RNA sequences that, via insertions, deletions or base substitutions, can affect protein structure as well as RNA and protein expression. Recently, it has been suggested that RNA editing may be more frequent than previously thought. A great impediment, however, to a deeper understanding of this process is the paramount sequencing effort that needs to be undertaken to identify RNA editing events. Here, we describe an in silico approach, based on machine learning, that ameliorates this problem. Using 41 nucleotide long DNA sequences, we show that novel A-to-I RNA editing events can be predicted from known A-to-I RNA editing events intra- and interspecies. The validity of the proposed method was verified in an independent experimental dataset. Using our approach, 203 202 putative A-to-I RNA editing events were predicted in the whole human genome. Out of these, 9% were previously reported. The remaining sites require further validation, e.g., by targeted deep sequencing. In conclusion, the approach described here is a useful tool to identify potential A-to-I RNA editing events without the requirement of extensive RNA sequencing.
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| 11. |
- Viberg, Peter, et al.
(author)
-
Continuous full filling capillary electrochromatography: Chromatographic performance and reproducibility
- 2007
-
In: Journal of Chromatography A. - : Elsevier BV. - 0021-9673. ; 1154:1-2, s. 386-389
-
Journal article (peer-reviewed)abstract
- Continuous full filling capillary electrochromatography with nanoparticles as pseudostationary phase interfaced with electrospray ionisation mass spectrometric detection was used for reversed phase separations with very high separation efficiency. Several batches of nanoparticles were synthesised and their electrochromatographic performance were evaluated. Different parameters, such as repeatability, reproducibility, limit of detection, and peak asymmetry, were investigated yielding excellent results. The stability of the system over wide pH ranges and over time was found to be excellent. Very high separation efficiencies with over 1.1 million theoretical plates per metre were obtained. The limit of detection for the investigated dialkyl phthalates was approximately 1.0 mu mol L-1, corresponding to 3-5 fmol injected. After preparation, nanoparticle suspensions could be used without further treatment for at least an entire working day with maintained chromatographic qualities. (c) 2007 Elsevier B.V. All rights reserved.
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| 12. |
- Viberg, Peter, et al.
(author)
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Nanoparticles as pseudo stationary phase in CEC/ESI-MS
- 2002
-
In: Proceedings 50th ASMS Conference on Mass Spectrmetry and Allied Topics. ; , s. 905-906
-
Conference paper (peer-reviewed)abstract
- A technique which uses polymer nanoparticles as interaction phase in capillary electrochromatography (CEC)-ESI-MS was described. A continuous full filling technique in which nanoparticles were suspended in the entire electrolyte volume as well as conventional partial filling technique were presented. The results verified that polymer nanoparticles suspended in electrolyte can be used as pseudo stationary phase in CEC with ESI-MS detection using continuous full filling and partial filling techniques. The sample molecules were separated from the nanoparticles in the orthogonal ESI-interface and MS-detection was performed despite the continuous flow of nanoparticles into the interface.
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| 13. |
- Viberg, Peter, et al.
(author)
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Nanoparticles as pseudostationary phase in capillary electrochrornatography/ESI-MS
- 2002
-
In: Analytical Chemistry. - : American Chemical Society (ACS). - 1520-6882 .- 0003-2700. ; 74:18, s. 4595-4601
-
Journal article (peer-reviewed)abstract
- A novel technique that uses polymer nanoparticles as pseudostationary phase in capillary electrochromatography with electrospray ionization mass spectrometry detection is described. A continuous full filling technique in which the nanoparticles were suspended in the entire electrolyte volume as well as a conventional partial filling technique is presented. No nanoparticles entered the mass spectrometer, which was fitted with an orthogonal electrospray interface, despite the continuous flow of nanoparticles into the interface. Nanoparticles (average diameter 160 nm) were prepared from methacrylic acid, methyl methacrylate, and trimethylolpropane trimethacrylate by utilizing a precipitation polymerization technique. Salbutamol, nortriptyline, and diphenhydramine were used as analytes. The interaction between analytes and nanoparticles was found to be predominantly ionic.
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| 14. |
- Viberg, Peter, et al.
(author)
-
Reversed phase continuous full filling CEC-ESI-MS
- 2007
-
In: Chromatographia. - : Springer Science and Business Media LLC. - 0009-5893 .- 1612-1112. ; 65:5-6, s. 291-297
-
Journal article (peer-reviewed)abstract
- Nanoparticles were used as a pseudostationary phase in capillary electrochromatography (CEC) electrospray ionisation-mass spectrometry (ESI-MS) for separation of both neutral analytes by a reversed phase mechanism, as well as for cationic analytes by a cation exchange mechanism. Nanoparticles suspended in electrolyte, were injected as a plug prior to the sample using a partial filling technique (PF), or used as electrolyte in a continuous full filling (CFF) technique. An orthogonal ESI probe was used to hinder the nanoparticles from entering the mass spectrometer and to allow detection of analytes co-eluting with concentrated nanoparticle slurries. Two types of nanoparticles were synthesised and used, both of them having a hydrophobic core and a hydrophilic surface. The hydrophobic core gave the nanoparticles reversed phase properties and the hydrophilic surface promoted the formation of stable slurries of nanoparticles in electrolytes with a low concentration of organic modifier. The surface of one of the nanoparticle types was covered with sulphate groups that, besides from enhancing slurry stability and thus enabling reversed phase CEC, also enabled ion exchange CEC. Both nanoparticle types showed reproducible and interpretable retention properties.
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| 15. |
- Adam, Julie, et al.
(author)
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Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes
- 2017
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 20:13, s. 3135-3148
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Journal article (peer-reviewed)abstract
- We explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic β cells (Fh1βKO mice) appear normal for 6–8 weeks but then develop progressive glucose intolerance and diabetes. Glucose tolerance is rescued by expression of mitochondrial or cytosolic FH but not by deletion of Hif1α or Nrf2. Progressive hyperglycemia in Fh1βKO mice led to dysregulated metabolism in β cells, a decrease in glucose-induced ATP production, electrical activity, cytoplasmic [Ca2+]i elevation, and GSIS. Fh1 loss resulted in elevated intracellular fumarate, promoting succination of critical cysteines in GAPDH, GMPR, and PARK 7/DJ-1 and cytoplasmic acidification. Intracellular fumarate levels were increased in islets exposed to high glucose and in islets from human donors with type 2 diabetes (T2D). The impaired GSIS in islets from diabetic Fh1βKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D. Adam et al. have shown that progressive diabetes develops if fumarate hydratase is deleted in mouse pancreatic β cells. Such β cells exhibit elevated fumarate and protein succination and show progressively reduced ATP production and insulin secretion. The depleted insulin response to glucose recovers when diabetic islets are cultured in reduced glucose.
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| 16. |
- Al Hamimi, Said, et al.
(author)
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Screening of stationary phase selectivities for global lipid profiling by ultrahigh performance supercritical fluid chromatography
- 2018
-
In: Journal of Chromatography A. - : Elsevier BV. - 0021-9673. ; 1548, s. 76-82
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Journal article (peer-reviewed)abstract
- The performance of seven sub-2-μm particle packed columns (2-picolylamine, 2-PIC; charged surface hybrid fluoro-phenyl, CSH-FP; high strength silica C18 SB, HSS-C18; diethylamine, DEA; 1-aminoanthracene, 1-AA; high density diol and ethylene bridged hybrid; BEH) was examined for lipid separation in ultra-high performance supercritical fluid chromatography (UHPSFC) coupled to quadrupole time-of-flight mass spectrometry. Based on the results of the column screening a method for profiling of multiple lipid species from the major lipid classes was developed. Stationary phases containing β-hydroxy amines, i.e. 1-AA, DEA and 2-PIC, yielded strong retention and poor peak shapes of zwitterionic lipids with primary amine groups, such as phosphatidylserines, phosphatidylethanolamines and its lyso forms. The BEH and HSS-C18 columns showed strong retention of polar and nonpolar lipids, respectively. The Diol column retained the majority of major lipid classes and also produced symmetric peaks. In addition, this column also produced the highest resolution within and between major lipid classes. An injection solvent composed of methanol:chloroform (1:2, v:v) and the addition of 20 mM ammonium formate in the mobile phase improved chromatographic separation and mass spectrometry detection in comparison to ammonium acetate or absence of additive. Finally, chromatographic and mass spectrometric parameters were optimized for the Diol column using a design of experiments approach. The separation mechanism on the Diol column depended on the lipid functionality and the length and degree of unsaturation of the acyl groups. The developed method could resolve 18 lipid classes and multiple lipids within each class, from blood serum and brain tissue in 11 min.
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| 17. |
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| 18. |
- Al-Majdoub, Mahmoud, et al.
(author)
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Metabolite profiling of LADA challenges the view of a metabolically distinct subtype
- 2017
-
In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:4, s. 806-814
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Journal article (peer-reviewed)abstract
- Latent autoimmune diabetes in adults (LADA) usually refers to GAD65 autoantibodies (GADAb)-positive diabetes with onset after 35 years of age and no insulin treatment within the first 6 months after diagnosis. However, it is not always easy to distinguish LADA fromtype 1 or type 2 diabetes. In this study, we examined whether metabolite profiling could help to distinguish LADA (n = 50) from type 1 diabetes (n = 50) and type 2 diabetes (n = 50). Of 123 identified metabolites, 99 differed between the diabetes types. However, no unique metabolite profile could be identified for any of the types. Instead, the metabolome varied along a C-peptide-driven continuum from type 1 diabetes via LADA to type 2 diabetes. LADA was more similar to type 2 diabetes than to type 1 diabetes. In a principal component analysis, LADA patients overlapping with type 1 diabetes progressed faster to insulin therapy than those overlapping with type 2 diabetes. In conclusion, we could not find any unique metabolite profile distinguishing LADA from type 1 and type 2 diabetes. Rather, LADA was metabolically an intermediate of type 1 and type 2 diabetes, with those patients closer to the former showing a faster progression to insulin therapy than those closer to the latter.
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| 19. |
- Al-Majdoub, Mahmoud, et al.
(author)
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Metabolite profiling paradoxically reveals favorable levels of lipids, markers of oxidative stress and unsaturated fatty acids in a diabetes susceptible group of Middle Eastern immigrants
- 2020
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In: Acta Diabetologica. - : Springer Science and Business Media LLC. - 0940-5429 .- 1432-5233. ; 57:5, s. 597-603
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Journal article (peer-reviewed)abstract
- Aims: The population of immigrants from the Middle East in Sweden show a higher prevalence of type 2 diabetes (T2D) compared to native Swedes. The exact reason for this is unknown. Here, we have performed metabolite profiling to investigate these differences. Methods: Metabolite profiling was conducted in Iraqi immigrants (n = 93) and native Swedes (n = 77) using two complementary mass spectrometry-based platforms. Differences in metabolite levels were compared after adjustment for confounding anthropometric, diet and clinical variables. Results: The Iraqi immigrant population were more obese (44.1 vs 24.7%, p < 0.05), but had a lower prevalence of hypertension (32.3 vs 54.8%, p < 0.01) than the native Swedish population. We detected 140 metabolites, 26 of which showed different levels between populations (q < 0.05,) after adjustment for age, sex, BMI, T2D and use of metformin. Twenty-two metabolites remained significant after further adjustment for HOMA-IR, HOMA-beta or insulin sensitivity index. Levels of polyunsaturated acylcarnitines (14:2 and 18:2) and fatty acid (18:2) were higher, whereas those of saturated and monounsaturated acylcarnitines (14:0, 18:1, and 8:1), fatty acids (12:0, 14:0, 16:0, and 18:1), uremic solutes (urate and quinate) and ketone bodies (beta-hydroxybutyrate) were lower in Iraqi immigrants. Further, levels of phospholipids were generally lower in the Iraqi immigrant population. Conclusions: Our result suggests an overall beneficial lipid profile in Iraqi immigrants, despite a higher risk to develop T2D. Higher levels of polyunsaturated fatty acids may suggest differences in dietary pattern, which in turn may reduce the risk of hypertension.
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| 20. |
- Al-Majdoub, Mahmoud, et al.
(author)
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Population-level analysis to determine parameters that drive variation in the plasma metabolite profiles
- 2018
-
In: Metabolites. - : MDPI AG. - 2218-1989. ; 8:4
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Journal article (peer-reviewed)abstract
- The plasma metabolome is associated with multiple phenotypes and diseases. However, a systematic study investigating clinical determinants that control the metabolome has not yet been conducted. In the present study, therefore, we aimed to identify the major determinants of the plasma metabolite profile. We used ultra-high performance liquid chromatography (UHPLC) coupled to quadrupole time of flight mass spectrometry (QTOF-MS) to determine 106 metabolites in plasma samples from 2503 subjects in a cross-sectional study. We investigated the correlation structure of the metabolite profiles and generated uncorrelated metabolite factors using principal component analysis (PCA) and varimax rotation. Finally, we investigated associations between these factors and 34 clinical covariates. Our results suggest that liver function, followed by kidney function and insulin resistance show the strongest associations with the plasma metabolite profile. The association of specific phenotypes with several components may suggest multiple independent metabolic mechanisms, which is further supported by the composition of the associated factors. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.
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| 21. |
- Al-Majdoub, Mahmoud, et al.
(author)
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Treatment of Swedish Patients with Graves' Hyperthyroidism Is Associated with Changes in Acylcarnitine Levels
- 2017
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In: Thyroid : official journal of the American Thyroid Association. - : Mary Ann Liebert Inc. - 1557-9077. ; 27:9, s. 1109-1117
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Journal article (peer-reviewed)abstract
- BACKGROUND: Hyperthyroidism is associated with alterations in metabolism that are currently only partially understood. The objective of the study was to investigate changes in metabolism associated with reinstatement of euthyroidism in Swedish patients.METHODS: Eighty metabolites in plasma were profiled from 10 subjects with Graves' disease (GD) at baseline and after 9 and 15 months of treatment to reinstate euthyroidism. Thyroid parameters, thyrotropin (TSH), TSH receptor antibodies, free triiodothyronine, and free thyroxine were followed. Main findings were validated in plasma from 20 subjects with GD at baseline and at three, six, and nine months. The study was conducted at the endocrinology clinic in Malmö, Sweden.RESULTS: Euthyroidism was reinstated at three months, and thyroid status did not change further during the 15-month follow-up. This was paralleled by altered levels of 9/19 detected acylcarnitines (p < 0.05 after adjustment for multiple testing). Levels of short-chain acylcarnitines were decreased, intermediate-chain acylcarnitines elevated, and long-chain acylcarnitines unaltered.CONCLUSIONS: GD and treatment of the disease is associated with pronounced acyl chain length-dependent alterations in acylcarnitine levels. These changes may be impacted by ethnicity and or dietary differences.
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| 22. |
- Alhamimi, Said, et al.
(author)
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Alterations in the plasma metabolite profile associated with improved hepatic function and glycemia in mice fed lingonberry supplemented high-fat diets
- 2017
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In: Molecular Nutrition and Food Research. - : Wiley. - 1613-4125. ; 61:3
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Journal article (peer-reviewed)abstract
- Scope: Lingonberries have been shown to reduce the detrimental effects of high-fat diet (HFD) on weight gain, plasma glucose, and inflammation. However, the extent of effects was recently shown to vary between different batches of berries. Here, we examine the metabolic response to two independent batches of lingonberries. Methods and results: Alterations in the phenotype and circulating metabolome elicited by three matched HFDs, two of which containing lingonberries (L1D and L2D) from different sources, were investigated. Glycemia was improved only in mice fed L1D, whereas liver function was improved and inflammation reduced in mice fed both L1D and L2D, compared to mice fed HFD. The unique improvement in glycemia elicited by L1D was associated with a 21% increase in circulating levels of fatty acids. Increased levels of phosphatidylcholines (62%) and lysophosphatidylcholines (28%) and decreased levels of serine (−13%) and sphingomyelins (−26%) were observed in mice fed L1D and L2D, as compared to HFD. Conclusion: The unique improvement in glycemia in mice fed L1D was associated with a normal metabolic control with an altered set point. Moreover, the batch-independent reduction in liver steatosis and inflammation, was associated with an altered sphingomyelin metabolism.
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| 23. |
- Andersson, Lotta, et al.
(author)
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Characterization of Stimulus-Secretion Coupling in the Human Pancreatic EndoC-βH1 Beta Cell Line.
- 2015
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Journal article (peer-reviewed)abstract
- Studies on beta cell metabolism are often conducted in rodent beta cell lines due to the lack of stable human beta cell lines. Recently, a human cell line, EndoC-βH1, was generated. Here we investigate stimulus-secretion coupling in this cell line, and compare it with that in the rat beta cell line, INS-1 832/13, and human islets.
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| 24. |
- Andersson, Lotta E., et al.
(author)
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Glutamine-elicited secretion of glucagon-like peptide 1 is governed by an activated glutamate dehydrogenase
- 2018
-
In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 67:3, s. 372-384
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Journal article (peer-reviewed)abstract
- Glucagon-like peptide 1 (GLP-1), secreted from intestinal L cells, glucose dependently stimulates insulin secretion from β-cells. This glucose dependence prevents hypoglycemia, rendering GLP-1 analogs a useful and safe treatment modality in type 2 diabetes. Although the amino acid glutamine is a potent elicitor of GLP-1 secretion, the responsible mechanism remains unclear. We investigated how GLP-1 secretion is metabolically coupled in L cells (GLUTag) and in vivo inmice using the insulin-secreting cell line INS-1 832/13 as reference. A membrane-permeable glutamate analog (dimethylglutamate [DMG]), acting downstream of electrogenic transporters, elicited similar alterations in metabolism as glutamine in both cell lines. Both DMG and glutamine alone elicited GLP-1 secretion in GLUTag cells and in vivo, whereas activation of glutamate dehydrogenase (GDH) was required to stimulate insulin secretion from INS-1 832/13 cells. Pharmacological inhibition in vivo of GDH blocked secretion of GLP-1 in response to DMG. In conclusion, our results suggest that nonelectrogenic nutrient uptake and metabolism play an important role in L cell stimulus-secretion coupling. Metabolism of glutamine and related analogs by GDH in the L cell may explain why GLP-1 secretion, but not that of insulin, is activated by these secretagogues in vivo.
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| 25. |
- Andersson, Lotta E., et al.
(author)
-
Glycogen metabolism in the glucose-sensing and supply-driven β-cell
- 2016
-
In: FEBS Letters. - : Wiley. - 0014-5793. ; 590:23, s. 4242-4251
-
Journal article (peer-reviewed)abstract
- Glycogen metabolism in β-cells may affect downstream metabolic pathways controlling insulin release. We examined glycogen metabolism in human islets and in the rodent-derived INS-1 832/13 β-cells and found them to express the same isoforms of key enzymes required for glycogen metabolism. Our findings indicate that glycogenesis is insulin-independent but influenced by extracellular glucose concentrations. Levels of glycogen synthase decrease with increasing glucose concentrations, paralleling accumulation of glycogen. We did not find cAMP-elicited glycogenolysis and insulin secretion to be causally related. In conclusion, our results reveal regulated glycogen metabolism in human islets and insulin-secreting cells. Whether glycogen metabolism affects insulin secretion under physiological conditions remains to be determined.
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| 26. |
- Andersson, Tilde, et al.
(author)
-
Biogeographical variation in antimicrobial resistance in rivers is influenced by agriculture and is spread through bacteriophages
- 2022
-
In: Environmental Microbiology. - : Wiley. - 1462-2912 .- 1462-2920. ; 24:10, s. 4869-4884
-
Journal article (peer-reviewed)abstract
- Antibiotic resistance is currently an extensive medical challenge worldwide, with global numbers increasing steadily. Recent data have highlighted wastewater treatment plants as a reservoir of resistance genes. The impact of these findings for human health can best be summarized using a One Health concept. However, the molecular mechanisms impacting resistance spread have not been carefully evaluated. Bacterial viruses, that is bacteriophages, have recently been shown to be important mediators of bacterial resistance genes in environmental milieus and are transferrable to human pathogens. Herein, we investigated the biogeographical impact on resistance spread through river-borne bacteriophages using amplicon deep sequencing of the microbiota, absolute quantification of resistance genes using ddPCR, and phage induction capacity within wastewater. Microbial biodiversity of the rivers is significantly affected by river site, surrounding milieu and time of sampling. Furthermore, areas of land associated with agriculture had a significantly higher ability to induce bacteriophages carrying antibiotic resistance genes, indicating their impact on resistance spread. It is imperative that we continue to analyse global antibiotic resistance problem from a One Health perspective to gain novel insights into mechanisms of resistance spread.
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| 27. |
- Awla, Darbaz, et al.
(author)
-
NFATc3 Regulates Trypsinogen Activation, Neutrophil Recruitment, and Tissue Damage in Acute Pancreatitis in Mice.
- 2012
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In: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 143:5, s. 1352-1352
-
Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: The signaling mechanisms that regulate trypsinogen activation and inflammation in acute pancreatitis (AP) are unclear. We explored the involvement of the calcium- and calcineurin-dependent transcription factor nuclear factor of activated T-cells (NFAT) in development of AP in mice. METHODS: We measured levels of myeloperoxidase and macrophage inflammatory protein-2 (CXCL2), trypsinogen activation, and tissue damage in the pancreas 24 h after induction of AP by retrograde infusion of taurocholate into the pancreatic ducts of wild-type, NFAT luciferase reporter (NFAT-luc), and NFATc3-deficient mice. We isolated acinar cells and measured NFAT nuclear accumulation, trypsin activity, and expression of NFAT-regulated genes. RESULTS: Infusion of taurocholate increased the transcriptional activity of NFAT in the pancreas, aorta, lung, and spleen of NFAT-luc mice. Inhibition of NFAT with A-285222 blocked taurocholate-induced activation of NFAT in all organs. A-285222 also reduced taurocholate-induced increases in levels of amylase, myeloperoxidase and CXCL2; activation of trypsinogen; necrosis of acinar cells; edema; leukocyte infiltration; and hemorrhage in the pancreas. NFATc3-deficient mice were protected from these effects of taurocholate. Similar results were obtained using an L-arginine-induced model of AP. Reverse transcriptase PCR and confocal immunofluorescence analyses showed that NFATc3 is expressed by acinar cells. NFATc3 expression was activated by stimuli that increase intracellular calcium; activation was prevented by the calcineurin blocker cyclosporine A or A-285222. Activation of trypsinogen by secretagogues in acinar cells was prevented by pharmacologic inhibition of NFAT signaling or lack of NFATc3. A-285222 also reduced expression of inflammatory cytokines such as CXCL2 in acinar cells. CONCLUSIONS: NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice, and might be a therapeutic target.
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| 28. |
- Bajramova, Azemina, et al.
(author)
-
A comparative study of the fatty acid profile of common fruits and fruits claimed to confer health benefits
- 2022
-
In: Journal of Food Composition and Analysis. - : Elsevier BV. - 0889-1575. ; 112
-
Journal article (peer-reviewed)abstract
- This study aims to verify the nutritional value of the fatty acid (FA) profile of three fruits claimed to confer health benefits (goji berry, white mulberry, and cranberry), often referred to as “superfruits”, over three common fruits (banana, apple, and strawberry). Nineteen different FAs, ranging in concentrations between 0.018 and 9.4 mg/g dry sample were detected. Levels of very long-chained FAs were highest in cranberries, oleic acid was most abundant in goji berries, alpha-linolenic acid showed high levels in strawberries and linoleic acid showed high levels in goji berries and white mulberries. The ratio of unsaturated to saturated FAs was highest in strawberries and goji berries, and the ratio of odd-carbon to even carbon saturated FAs was high in all common fruits, whereas among the superfruits both goji- and white mulberries showed very low ratios. Finally, the ratio of very long-chain to long-chain FAs showed the highest levels in cranberries and apples. A composite measure of the FA profile suggests apples and cranberries to show the most beneficial lipid profile. However, a common and beneficial lipid profile was not found in the superfruits as compared to more common fruits.
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| 29. |
- Balderas Arroyo, Claudia, et al.
(author)
-
A randomized trial involving a multifunctional diet reveals systematic lipid remodeling and improvements in cardiometabolic risk factors in middle aged to aged adults
- 2023
-
In: Frontiers in Nutrition. - 2296-861X. ; 10
-
Journal article (peer-reviewed)abstract
- BACKGROUND: A multifunctional diet (MFD) combining foods and ingredients with proven functional properties, such as fatty fish and fiber-rich foods, among others, was developed and shown to markedly reduce cardiometabolic risk-associated factors.OBJECTIVE: Here, we aim at examining metabolic physiological changes associated with these improvements.METHODS: Adult overweight individuals without other risk factors were enrolled in an 8-week randomized controlled intervention following a parallel design, with one group ( n = 23) following MFD and one group ( n = 24) adhering to a control diet (CD) that followed the caloric formula (E%) advised by the Nordic Nutritional Recommendations. Plasma metabolites and lipids were profiled by gas chromatography and ultrahigh performance liquid chromatography/mass spectrometry. RESULTS: Weight loss was similar between groups. The MFD and CD resulted in altered levels of 137 and 78 metabolites, respectively. Out of these, 83 were uniquely altered by the MFD and only 24 by the CD. The MFD-elicited alterations in lipid levels depended on carbon number and degree of unsaturation.CONCLUSION: An MFD elicits weight loss-independent systematic lipid remodeling, promoting increased circulating levels of long and highly unsaturated lipids.CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02148653?term=NCT02148653&draw=2&rank=1, NCT02148653.
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| 30. |
- Bearden, IG, et al.
(author)
-
Particle production in central Pb+Pb collisions at 158A GeV/c
- 2002
-
In: Physical Review C (Nuclear Physics). - 0556-2813. ; 66:4
-
Journal article (peer-reviewed)abstract
- The NA44 experiment has measured single-particle inclusive spectra for charged pions, kaons, and protons as a function of transverse mass near midrapidity in 158A GeV/c Pb+Pb collisions. From the particle mass dependence of the observed m(T) distributions, we are able to deduce a value of about 120 MeV for the temperature at thermal freeze-out. From the observed ratios of the rapidity densities, we find values of the chemical potentials for light and strange quarks and a chemical freeze-out temperature of approximately 140 MeV.
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| 31. |
- Bennet, Hedvig, et al.
(author)
-
Altered serotonin (5-HT) 1D and 2A receptor expression may contribute to defective insulin and glucagon secretion in human type 2 diabetes.
- 2015
-
In: Peptides. - : Elsevier BV. - 1873-5169 .- 0196-9781. ; 71, s. 113-120
-
Journal article (peer-reviewed)abstract
- Islet produced 5-hydroxy tryptamine (5-HT) is suggested to regulate islet hormone secretion in a paracrine and autocrine manner in rodents. Hitherto, no studies demonstrate a role for this amine in human islet function, nor is it known if 5-HT signaling is involved in the development of beta cell dysfunction in type 2 diabetes (T2D). To clarify this, we performed a complete transcriptional mapping of 5-HT receptors and processing enzymes in human islets and investigated differential expression of these genes in non-diabetic and T2D human islet donors. We show the expression of fourteen 5-HT receptors as well as processing enzymes involved in the biosynthesis of 5-HT at the mRNA level in human islets. Two 5-HT receptors (HTR1D and HTR2A) were over-expressed in T2D islet donors. Both receptors (5-HT1d and 5-HT2a) were localized to human alpha, beta and delta cells. 5-HT inhibited both insulin and glucagon secretion in non-diabetic islet donors. In islets isolated from T2D donors the amine significantly increased release of insulin in response to glucose. Our results suggest that 5-HT signaling participates in regulation of overall islet hormone secretion in non- diabetic individuals and over-expression of HTR1D and HTR2A may either contribute to islet dysfunction in T2D or arise as a consequence of an already dysfunctional islet.
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| 32. |
- Borgström, Celina, et al.
(author)
-
Using phosphoglucose isomerase-deficient (pgi1Δ) Saccharomyces cerevisiae to map the impact of sugar phosphate levels on d-glucose and d-xylose sensing
- 2022
-
In: Microbial Cell Factories. - : Springer Science and Business Media LLC. - 1475-2859. ; 21:1
-
Journal article (peer-reviewed)abstract
- Background: Despite decades of engineering efforts, recombinant Saccharomyces cerevisiae are still less efficient at converting d-xylose sugar to ethanol compared to the preferred sugar d-glucose. Using GFP-based biosensors reporting for the three main sugar sensing routes, we recently demonstrated that the sensing response to high concentrations of d-xylose is similar to the response seen on low concentrations of d-glucose. The formation of glycolytic intermediates was hypothesized to be a potential cause of this sensing response. In order to investigate this, glycolysis was disrupted via the deletion of the phosphoglucose isomerase gene (PGI1) while intracellular sugar phosphate levels were monitored using a targeted metabolomic approach. Furthermore, the sugar sensing of the PGI1 deletants was compared to the PGI1-wildtype strains in the presence of various types and combinations of sugars. Results: Metabolomic analysis revealed systemic changes in intracellular sugar phosphate levels after deletion of PGI1, with the expected accumulation of intermediates upstream of the Pgi1p reaction on d-glucose and downstream intermediates on d-xylose. Moreover, the analysis revealed a preferential formation of d-fructose-6-phosphate from d-xylose, as opposed to the accumulation of d-fructose-1,6-bisphosphate that is normally observed when PGI1 deletants are incubated on d-fructose. This may indicate a role of PFK27 in d-xylose sensing and utilization. Overall, the sensing response was different for the PGI1 deletants, and responses to sugars that enter the glycolysis upstream of Pgi1p (d-glucose and d-galactose) were more affected than the response to those entering downstream of the reaction (d-fructose and d-xylose). Furthermore, the simultaneous exposure to sugars that entered upstream and downstream of Pgi1p (d-glucose with d-fructose, or d-glucose with d-xylose) resulted in apparent synergetic activation and deactivation of the Snf3p/Rgt2p and cAMP/PKA pathways, respectively. Conclusions: Overall, the sensing assays indicated that the previously observed d-xylose response stems from the formation of downstream metabolic intermediates. Furthermore, our results indicate that the metabolic node around Pgi1p and the level of d-fructose-6-phosphate could represent attractive engineering targets for improved d-xylose utilization.
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| 33. |
- Cataldo, Luis Rodrigo, et al.
(author)
-
The human batokine EPDR1 regulates β-cell metabolism and function
- 2022
-
In: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 66
-
Journal article (peer-reviewed)abstract
- Objective: Ependymin-Related Protein 1 (EPDR1) was recently identified as a secreted human batokine regulating mitochondrial respiration linked to thermogenesis in brown fat. Despite that EPDR1 is expressed in human pancreatic β-cells and that glucose-stimulated mitochondrial metabolism is critical for stimulus-secretion coupling in β-cells, the role of EPDR1 in β-cell metabolism and function has not been investigated. Methods: EPDR1 mRNA levels in human pancreatic islets from non-diabetic (ND) and type 2 diabetes (T2D) subjects were assessed. Human islets, EndoC-βH1 and INS1 832/13 cells were transfected with scramble (control) and EPDR1 siRNAs (EPDR1-KD) or treated with human EPDR1 protein, and glucose-stimulated insulin secretion (GSIS) assessed by ELISA. Mitochondrial metabolism was investigated by extracellular flux analyzer, confocal microscopy and mass spectrometry-based metabolomics analysis. Results: EPDR1 mRNA expression was upregulated in human islets from T2D and obese donors and positively correlated to BMI of donors. In T2D donors, EPDR1 mRNA levels negatively correlated with HbA1c and positively correlated with GSIS. EPDR1 silencing in human islets and β-cell lines reduced GSIS whereas treatment with human EPDR1 protein increased GSIS. Epdr1 silencing in INS1 832/13 cells reduced glucose- and pyruvate- but not K+-stimulated insulin secretion. Metabolomics analysis in Epdr1-KD INS1 832/13 cells suggests diversion of glucose-derived pyruvate to lactate production and decreased malate-aspartate shuttle and the tricarboxylic acid (TCA) cycle activity. The glucose-stimulated rise in mitochondrial respiration and ATP/ADP-ratio was impaired in Epdr1-deficient cells. Conclusion: These results suggests that to maintain glucose homeostasis in obese people, upregulation of EPDR1 may improve β-cell function via channelling glycolysis-derived pyruvate to the mitochondrial TCA cycle.
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| 34. |
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| 35. |
- Danielsson, Anders, et al.
(author)
-
Development and optimization of a metabolomic method for analysis of adherent cell cultures
- 2010
-
In: Analytical Biochemistry. - : Elsevier BV. - 1096-0309 .- 0003-2697. ; 404:1, s. 30-39
-
Journal article (peer-reviewed)abstract
- In this investigation, a gas chromatography/mass spectrometry (GC/MS)-based metabolomic protocol for adherent cell cultures was developed using statistical design of experiments. Cell disruption, metabolite extraction, and the GC/MS settings were optimized aiming at a gentle, unbiased, sensitive, and high-throughput metabolomic protocol. Due to the heterogeneity of the metabolome and the inherent selectivity of all analytical techniques, development of unbiased protocols is highly complex. Changing one parameter of the protocol may change the response of many groups of metabolites. In this investigation, statistical design of experiments and multivariate analysis also allowed such interaction effects to be taken into account. The protocol was validated with respect to linear range, precision, and limit of detection in a clonal rat insulinoma cell line (INS-1 832/13). The protocol allowed high-throughput profiling of metabolites covering the major metabolic pathways. The majority of metabolites displayed a linear range from a single well in a 96-well plate up to a 10 cm culture dish. The method allowed a total of 47 analyses to be performed in 24 h. (C) 2010 Elsevier Inc. All rights reserved.
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| 36. |
- Danielsson, Anders, et al.
(author)
-
Development of a gas chromatography/mass spectrometry based metabolomics protocol by means of statistical experimental design
- 2012
-
In: Metabolomics. - : Springer Science and Business Media LLC. - 1573-3882 .- 1573-3890. ; 8:1, s. 50-63
-
Journal article (peer-reviewed)abstract
- Metabolomics is a growing research field where new protocols are rapidly developed and new applications discovered. Common applications include biomarker discovery and elucidation of drug metabolism. However, the development of such protocols rarely includes a systematic optimization followed by validation with real samples. Here a GC/MS-based protocol using methoximation followed by silylation with N-tert-butyldi-methylsilyl-N-methyltrifluoroacetamide (MTBSTFA) for analysis of blood plasma metabolites is thoroughly developed and optimized from derivatization to detection with statistical design of experiments (DOE). Validation was performed with blood plasma samples and proved the methodology to be efficient, rapid and reliable with a total of 51 analyses performed in 24 h, with linear responses, low detection limits and good precision. The obtained chromatograms were much cleaner, due to the absence of glucose overloading, and the data was found to drift less with MTBSTFA derivatisation than with MTBSTFA derivatisation.
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| 37. |
- Diamanti, Klev, 1987-
(author)
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Integrating multi-omics for type 2 diabetes : Data science and big data towards personalized medicine
- 2019
-
Doctoral thesis (other academic/artistic)abstract
- Type 2 diabetes (T2D) is a complex metabolic disease characterized by multi-tissue insulin resistance and failure of the pancreatic β-cells to secrete sufficient amounts of insulin. Cells recruit transcription factors (TF) to specific genomic loci to regulate gene expression that consequently affects the protein and metabolite abundancies. Here we investigated the interplay of transcriptional and translational regulation, and its impact on metabolome and phenome for several insulin-resistant tissues from T2D donors. We implemented computational tools and multi-omics integrative approaches that can facilitate the selection of candidate combinatorial markers for T2D.We developed a data-driven approach to identify putative regulatory regions and TF-interaction complexes. The cell-specific sets of regulatory regions were enriched for disease-related single nucleotide polymorphisms (SNPs), highlighting the importance of such loci towards the genomic stability and the regulation of gene expression. We employed a similar principle in a second study where we integrated single nucleus ribonucleic acid sequencing (snRNA-seq) with bulk targeted chromosome-conformation-capture (HiCap) and mass spectrometry (MS) proteomics from liver. We identified a putatively polymorphic site that may contribute to variation in the pharmacogenetics of fluoropyrimidines toxicity for the DPYD gene. Additionally, we found a complex regulatory network between a group of 16 enhancers and the SLC2A2 gene that has been linked to increased risk for hepatocellular carcinoma (HCC). Moreover, three enhancers harbored motif-breaking mutations located in regulatory regions of a cohort of 314 HCC cases, and were candidate contributors to malignancy.In a cohort of 43 multi-organ donors we explored the alternating pattern of metabolites among visceral adipose tissue (VAT), pancreatic islets, skeletal muscle, liver and blood serum samples. A large fraction of lysophosphatidylcholines (LPC) decreased in muscle and serum of T2D donors, while a large number of carnitines increased in liver and blood of T2D donors, confirming that changes in metabolites occur in primary tissues, while their alterations in serum consist a secondary event. Next, we associated metabolite abundancies from 42 subjects to glucose uptake, fat content and volume of various organs measured by positron emission tomography/magnetic resonance imaging (PET/MRI). The fat content of the liver was positively associated with the amino acid tyrosine, and negatively associated with LPC(P-16:0). The insulin sensitivity of VAT and subcutaneous adipose tissue was positively associated with several LPCs, while the opposite applied to branch-chained amino acids. Finally, we presented the network visualization of a rule-based machine learning model that predicted non-diabetes and T2D in an “unseen” dataset with 78% accuracy.
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| 38. |
- dos Santos, Klinsmann Carolo, et al.
(author)
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The impact of macronutrient composition on metabolic regulation : An Islet-Centric view
- 2022
-
In: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 236:4
-
Journal article (peer-reviewed)abstract
- Aim: The influence of dietary carbohydrates and fats on weight gain is inconclusively understood. We studied the acute impact of these nutrients on the overall metabolic state utilizing the insulin:glucagon ratio (IGR). Methods: Following in vitro glucose and palmitate treatment, insulin and glucagon secretion from islets isolated from C57Bl/6J mice was measured. Our human in vivo study included 21 normoglycaemia (mean age 51.9 ± 16.5 years, BMI 23.9 ± 3.5 kg/m2, and HbA1c 36.9 ± 3.3 mmol/mol) and 20 type 2 diabetes (T2D) diagnosed individuals (duration 12 ± 7 years, mean age 63.6 ± 4.5 years, BMI 29.1 ± 2.4 kg/m2, and HbA1c 52.3 ± 9.5 mmol/mol). Individuals consumed a carbohydrate-rich or fat-rich meal (600 kcal) in a cross-over design. Plasma insulin and glucagon levels were measured at −30, −5, and 0 min, and every 30 min until 240 min after meal ingestion. Results: The IGR measured from mouse islets was determined solely by glucose levels. The palmitate-stimulated hormone secretion was largely glucose independent in the analysed mouse islets. The acute meal tolerance test demonstrated that insulin and glucagon secretion is dependent on glycaemic status and meal composition, whereas the IGR was dependent upon meal composition. The relative reduction in IGR elicited by the fat-rich meal was more pronounced in obese individuals. This effect was blunted in T2D individuals with elevated HbA1c levels. Conclusion: The metabolic state in normoglycaemic individuals and T2D-diagnosed individuals is regulated by glucose. We demonstrate that consumption of a low carbohydrate diet, eliciting a catabolic state, may be beneficial for weight loss, particularly in obese individuals.
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| 39. |
- Fex, Malin, et al.
(author)
-
The pathogenetic role of β-cell mitochondria in type 2 diabetes
- 2018
-
In: Journal of Endocrinology. - 0022-0795. ; 236:3, s. 145-149
-
Research review (peer-reviewed)abstract
- Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.
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| 40. |
- Garcia-Serrano, Alba, et al.
(author)
-
Cognitive Impairment and Metabolite Profile Alterations in the Hippocampus and Cortex of Male and Female Mice Exposed to a Fat and Sugar-Rich Diet are Normalized by Diet Reversal
- 2022
-
In: Aging and Disease. - 2152-5250. ; 13:1, s. 267-283
-
Journal article (peer-reviewed)abstract
- Diabetes impacts on brain metabolism, structure and function. Alterations in brain metabolism have been observed in obesity and diabetes models induced by exposure to diets rich in saturated fat and/or sugar and have been linked to memory impairment. However, it remains to be determined whether brain dysfunction induced by obesogenic diets results from permanent brain alterations. We tested the hypothesis that an obesogenic diet (high-fat and high-sucrose diet; HFHSD) causes reversible changes in hippocampus and cortex metabolism and alterations in behavior. Mice were exposed to HFHSD for 24 weeks or for 16 weeks followed by 8 weeks of diet normalization. Development of the metabolic syndrome, changes in behavior, and brain metabolite profiles by magnetic resonance spectroscopy (MRS) were assessed longitudinally. Control mice were fed an ingredient-matched low-fat and low-sugar diet. Mice fed the HFHSD developed obesity, glucose intolerance and insulin resistance, with a more severe phenotype in male than female mice. Relative to controls, both male and female HFHSD-fed mice showed increased anxiety-like behavior, impaired memory in object recognition tasks, but preserved working spatial memory as evaluated by spontaneous alternation in a Y-maze. Alterations in the metabolite profiles were observed both in the hippocampus and cortex but were more distinct in the hippocampus. HFHSD-induced metabolic changes included altered levels of lactate, glutamate, GABA, glutathione, taurine, N-acetylaspartate, total creatine and total choline. Notably, HFHSD-induced metabolic syndrome, anxiety, memory impairment, and brain metabolic alterations recovered upon diet normalization for 8 weeks. In conclusion, cortical and hippocampal derangements induced by long-term HFHSD consumption are reversible rather than being the result of permanent tissue damage.
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| 41. |
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| 42. |
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| 43. |
- Gil-Ramírez, Alicia, et al.
(author)
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Pressurized carbon dioxide as a potential tool for decellularization of pulmonary arteries for transplant purposes
- 2020
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10
-
Journal article (peer-reviewed)abstract
- Vascular bio-scaffolds produced from decellularized tissue offer a promising material for treatment of several types of cardiovascular diseases. These materials have the potential to maintain the functional properties of the extracellular matrix (ECM), and allow for growth and remodeling in vivo. The most commonly used methods for decellularization are based on chemicals and enzymes combinations, which often damage the ECM and cause cytotoxic effects in vivo. Mild methods involving pressurized CO2-ethanol (EtOH)-based fluids, in a supercritical or near supercritical state, have been studied for decellularization of cardiovascular tissue, but results are controversial. Moreover, data are lacking on the amount and type of lipids remaining in the tissue. Here we show that pressurized CO2-EtOH-H2O fluids (average molar composition, ΧCO2 0.91) yielded close to complete removal of lipids from porcine pulmonary arteries, including a notably decrease of pro-inflammatory fatty acids. Pressurized CO2-limonene fluids (ΧCO2 0.88) and neat supercritical CO2 (scCO2) achieved the removal of 90% of triacylglycerides. Moreover, treatment of tissue with pressurized CO2-limonene followed by enzyme treatment, resulted in efficient DNA removal. The structure of elastic fibers was preserved after pressurized treatment, regardless solvent composition. In conclusion, pressurized CO2-ethanol fluids offer an efficient tool for delipidation in bio-scaffold production, while pressurized CO2-limonene fluids facilitate subsequent enzymatic removal of DNA.
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| 44. |
- Göhring, Isabel, et al.
(author)
-
Chronic high glucose and pyruvate levels differentially affect mitochondrial bioenergetics and fuel-stimulated insulin secretion from clonal INS-1 832/13 cells.
- 2014
-
In: Journal of Biological Chemistry. - 1083-351X. ; 289:6, s. 3786-3798
-
Journal article (peer-reviewed)abstract
- Glucotoxicity in pancreatic β-cells is a well-established pathogenetic process in Type 2 Diabetes. It has been suggested that metabolism-derived reactive oxygen species perturb the β-cell transcriptional machi-nery. Less is known about altered mitochondrial function in this condition. We used INS-1 832/13 cells cultured for 48 h in 2.8 mM glucose (low-G), 16.7 mM glucose (high-G) or 2.8 mM glucose plus 13.7 mM pyruvate (high-P) to identify metabolic perturbations. High-G cells showed decreased responsiveness, relative to low-G cells, with respect to mitochondrial membrane hyperpolarization, plasma membrane depolarization and insulin secretion, when stimulated acutely with 16.7 mM glucose or 10 mM pyruvate. In contrast, high-P cells were functionally unimpaired, eliminating chronic provision of saturating mitochondrial substrate as a cause of glucotoxicity. Although cellular insulin content was depleted in high-G cells, relative to low-G and high-P cells, cellular functions were largely recovered following a further 24 h culture in low-G medium. After 2 h at 2.8 mM glucose, high-G cells did not retain increased levels of glycolytic or TCA-cycle intermediates, but nevertheless displayed increased glycolysis, increased respiration and an increased mitochondrial proton leak relative to low-G and high-P cells. This notwithstanding, titration of low-G cells with low protonophore concen-trations, monitoring respiration and insulin secretion in parallel, showed that the perturbed insulin secretion of high-G cells could not be accounted for by increased proton leak. The present study supports the idea that glucose-induced disturbances of stimulus-secretion coupling by extra-mitochondrial metabolism upstream of pyruvate, rather than exhaustion from metabolic overload, underlie glucotoxicity in insulin-producing cells.
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| 45. |
- Herzog, Katharina, et al.
(author)
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Metabolic Effects of Gastric Bypass Surgery : Is It All About Calories?
- 2020
-
In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 69:9, s. 2027-2035
-
Journal article (peer-reviewed)abstract
- Bariatric surgery is an efficient method to induce weight loss and also, frequently, remission of type 2 diabetes (T2D). Unpaired studies have shown bariatric surgery and dietary interventions to differentially affect multiple hormonal and metabolic parameters, suggesting that bariatric surgery causes T2D remission at least partially via unique mechanisms. In the current study, plasma metabolite profiling was conducted in patients with (n = 10) and without T2D (n = 9) subjected to Roux-en-Y gastric bypass surgery (RYGB). Mixed-meal tests were conducted at baseline, after the presurgical very-low-calorie diet (VLCD) intervention, immediately after RYGB, and after a 6-week recovery period. Thereby, we could compare fasted and postprandial metabolic consequences of RYGB and VLCD in the same patients. VLCD yielded a pronounced increase in fasting acylcarnitine levels, whereas RYGB, both immediately and after a recovery period, resulted in a smaller but opposite effect. Furthermore, we observed profound changes in lipid metabolism following VLCD but not in response to RYGB. Most changes previously associated with RYGB were found to be consequences of the presurgical dietary intervention. Overall, our results question previous findings of unique metabolic effects of RYGB and suggest that the effect of RYGB on the metabolite profile is mainly attributed to caloric restriction.
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| 46. |
- Huang, Mi, et al.
(author)
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Identification of a weight loss-associated causal eQTL in MTIF3 and the effects of MTIF3 deficiency on human adipocyte function
- 2023
-
In: eLife. - 2050-084X.
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Journal article (peer-reviewed)abstract
- Genetic variation at the MTIF3 (Mitochondrial Translational Initiation Factor 3) locus has been robustly associated with obesity in humans, but the functional basis behind this association is not known. Here, we applied luciferase reporter assay to map potential functional variants in the haplotype block tagged by rs1885988 and used CRISPR-Cas9 to edit the potential functional variants to confirm the regulatory effects on MTIF3 expression. We further conducted functional studies on MTIF3-deficient differentiated human white adipocyte cell line (hWAs-iCas9), generated through inducible expression of CRISPR-Cas9 combined with delivery of synthetic MTIF3-targeting guide RNA. We demonstrate that rs67785913-centered DNA fragment (in LD with rs1885988, r2 > 0.8) enhances transcription in a luciferase reporter assay, and CRISPR-Cas9-edited rs67785913 CTCT cells show significantly higher MTIF3 expression than rs67785913 CT cells. Perturbed MTIF3 expression led to reduced mitochondrial respiration and endogenous fatty acid oxidation, as well as altered expression of mitochondrial DNA-encoded genes and proteins, and disturbed mitochondrial OXPHOS complex assembly. Furthermore, after glucose restriction, the MTIF3 knockout cells retained more triglycerides than control cells. This study demonstrates an adipocyte function-specific role of MTIF3, which originates in the maintenance of mitochondrial function, providing potential explanations for why MTIF3 genetic variation at rs67785913 is associated with body corpulence and response to weight loss interventions.
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| 47. |
- Huang, Peng, et al.
(author)
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Cryo-EM structure supports a role of AQP7 as a junction protein
- 2023
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14, s. 1-12
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Journal article (peer-reviewed)abstract
- Aquaglyceroporin 7 (AQP7) facilitates glycerol flux across the plasma membrane with a critical physiological role linked to metabolism, obesity, and associated diseases. Here, we present the single-particle cryo-EM structure of AQP7 determined at 2.55 Å resolution adopting two adhering tetramers, stabilized by extracellularly exposed loops, in a configuration like that of the well-characterized interaction of AQP0 tetramers. The central pore, in-between the four monomers, displays well-defined densities restricted by two leucine filters. Gas chromatography mass spectrometry (GC/MS) results show that the AQP7 sample contains glycerol 3-phosphate (Gro3P), which is compatible with the identified features in the central pore. AQP7 is shown to be highly expressed in human pancreatic α- and β- cells suggesting that the identified AQP7 octamer assembly, in addition to its function as glycerol channel, may serve as junction proteins within the endocrine pancreas.
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| 48. |
- Khataei, Mohammad Mahdi, et al.
(author)
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A review of green solvent extraction techniques and their use in antibiotic residue analysis
- 2022
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In: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085. ; 209
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Research review (peer-reviewed)abstract
- Antibiotic residues are being continuously recognized in the aquatic environment and in food. Though the concentration of antibiotic residues is typically low, adverse effects on the environment and human health have been observed. Hence, an efficient method to determine numerous antibiotic residues should be simple, inexpensive, selective, with high throughput and with low detection limits. Liquid-based extractions have been exceedingly used for clean-up and preconcentration of antibiotics prior to chromatographic analysis. In order to make methods more green and environmentally sustainable, conventional hazardous organic solvents can be replaced with green solvents. This review presents sampling strategies as well as comprehensive and up-to-date methods for chemical analysis of antibiotic residues in different sample matrices. Particularly, solvent-based sample preparation techniques using green solvents are discussed along with applications in antibiotic residue analysis.
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| 49. |
- Knudsen, J. G., et al.
(author)
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Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production
- 2019
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 29:2
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Journal article (peer-reviewed)abstract
- Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their beta cells (Fh1 beta KO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion. Protein succination, reflecting reduced activity of fumarase, is observed in alpha cells from hyperglycemic Fh1 beta KO and beta-V59M gain-of-function K-ATP channel mice, diabetic Goto-Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1 beta KO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.
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| 50. |
- Krus, Ulrika, et al.
(author)
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Pyruvate dehydrogenase kinase 1 controls mitochondrial metabolism and insulin secretion in INS-1 832/13 clonal beta-cells
- 2010
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In: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 429, s. 205-213
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Journal article (peer-reviewed)abstract
- Tight coupling between cytosolic and mitochondrial metabolism is key for GSIS (glucose-stimulated insulin secretion). In the present study we examined the regulatory contribution of PDH (pyruvate dehydrogenase) kinase 1, a negative regulator of PDH, to metabolic coupling in 832/13 clonal beta-cells. Knockdown of PDH kinase 1 with siRNA (small interfering RNA) reduced its mRNA (>80 %) and protein level (>40 %) after 72 h. PDH activity, glucose-stimulated cellular oxygen consumption and pyruvate-stimulated mitochondrial oxygen consumption increased 1.7- (P < 0.05), 1.6- (P < 0.05) and 1.6-fold (P < 0.05) respectively. Gas chromatography/MS revealed an altered metabolite profile upon silencing of PDH kinase 1, determined by increased levels of the tricarboxylic acid cycle intermediates malate, fumarate and alpha-ketoglutarate. These metabolic alterations were associated with exaggerated GSIS (5-fold compared with 3.1-fold in control cells; P < 0.01). Insulin secretion, provoked by leucine and dimethylsuccinate, which feed into the tricarboxylic acid cycle bypassing PDH, was unaffected. The oxygen consumption and metabolic data strongly suggest that knockdown of PDH kinase 1 in beta-cells permits increased metabolic flux of glucose-derived carbons into the tricarboxylic acid cycle via PDH. Enhanced insulin secretion is probably caused by increased generation of tricarboxylic acid cycle-derived reducing equivalents for mitochondrial electron transport to generate ATP and/or stimulatory metabolic intermediates. On the basis of these findings, we suggest that PDH kinase 1 is an important regulator of PDH in clonal beta-cells and that PDH kinase 1 and PDH are important for efficient metabolic coupling. Maintaining low PDH kinase I expression/activity, keeping PDH in a dephosphorylated and active state, may be important for beta-cells to achieve the metabolic flux rates necessary for maximal GSIS.
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