MetaboLights

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3_019.lcdftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS11411/FILES/GCMS raw data files Technical2/240403_26_Control 3.qgdftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS11411/FILES/GCMS raw data files Technical2/240403_22_Control 1.qgdftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS11411/FILES/DERIVED_FILES/240403_07.qgdprimaryOK200ftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS11411Transition ions for each compound were as previously published (Heffernan et al., 2024), authentic reference standards serially diluted 15 times from 100 uM to 6 nM was used to quantify the detected peak areas. Concentrations were normalized using internal standards (AZT and succinate d6) by automated peak integration in LabSolutions Insight LCMS v4 sp2. Metabolomics statistical data analysis was performed using MetaboAnalyst 6.0 platform.MetaboLightsPublicLiquid Chromatography MS - alternating - reverse phaseGas Chromatography MS - positiveFor LC–MS analysis of central carbon metabolism, samples were analysed using a Shimadzu Nexera liquid chromatography system. Chromatographic separation was achieved using a Phenomenex Gemini NX C18 (150 × 2 mm, 3 µm) column (Part No. 00F-4453-B0), with a SecurityGuard guard column (Phenomenex Part No. AJ0-8367). The mobile phases consisted of 7.5 mM tributylamine (pH 4.95, adjusted with acetic acid) in water (solvent A) and acetonitrile with acetic acid (solvent B). In total 5 μL were injected. GC-MS analysis was performed on a Shimadzu GC/MS-TQ8050 NX system. In total, 1 µL of derivatized sample was injected into the GC inlet set at 280 °C in 1:10 split mode, and chromatographically separated using an Agilent DB-5 ms capillary column (30 m x 0.25 mm x 1 µm) using helium as carrier gas at 1 mL/min. The oven temperature program started at 100°C (4 min hold), ramped at 10 °C/min to 320 °C, and held for 11 min. Glycaemic variability identified as a critical determinant of myocyte dysfunction and risk for myocardial injury in preclinical models of diabetes.University of QueenslandYuanzhao Caoheartmass spectrometry assayApproximately 1 million cells were quenched with 1 mL ice cold 50% methanol added with internal standards (500 nM azidothymidine, U-13C-sorbitol (1.6 μM) and L-Valine 13C5,15N (8.3 μM)). Cells were homogenised using an OMNI Bead Ruptor Elite (NE486LL/A) prechilled to -1 °C. The extracts were aliquoted for analysis of central carbon metabolism (CCM) through Liquid Chromatography Mass Spectrometry (LC-MS) and Gas Chromatography Mass Spectrometry Human Metabolome Database (GC-MS HMDB) open profiling[1]. The aliquot for CCM analysis was purified by biphasic separation with chloroform. The aqueous layer was evaporated to dryness and resuspended in 100 µL 2% acetonitrile solution with 5 uM succinate d-6 as injection internal standard. For GC-MS, 60 μL of sample extracts were dried under vacuum (Eppendorf Concentrator Plus) in glass pulled point inserts. Samples were derivatized by methoxyamination by the addition of 25 μL methoxyamine hydrochloride (30 mg/mL in pyridine, 2 h, 37 °C, 900 rpm), followed by trimethylsilylation with 25 μL BSTFA + 1% TMCS (30 min, 37 °C, 900 rpm, followed by 1 h ambient temperature incubation. Ref:[1] Heffernan, J., Garcia Gonzalez, R.A., Mahamkali, V., McCubbin, T., Daygon, D., Liu, L., Palfreyman, R., Harris, A., Koepke, M., Valgepea, K. and Nielsen, L.K., 2024. Adaptive laboratory evolution of Clostridium autoethanogenum to metabolize CO2 and H2 enhances growth rates in chemostat and unravels proteome and metabolome alterations. Microbial Biotechnology, 17(4), p.e14452. doi:10.1111/1751-7915.14452.Homo sapienshttps://www.ebi.ac.uk/metabolights/MTBLS11411Nathan Palpant. The University of Queensland. n.palpant@uq.edu.au.Cao Yuanzhao. The University of Queensland. 306 Carmody Rd, St Lucia QLD 4067. y.cao@uq.edu.au.Concentrations were normalized using internal standards (AZT and succinate d6) by automated peak integration in LabSolutions Insight LCMS v4 sp2. A high-quality matrix was manually curated using the Shimadzu LabSolutions Insight GCMS program (v.3.7 SP3).Dosey.cao@uq.edu.auHuman iPSC-derived ventricular cardiomyocytes (hiPSC-CMs) were induced for disease modelling to generate constant glycaemia (cG) and variable glycaemia (vG) cell stress states, with vehicle-treated cells serving as controls. Differentiated cardiomyocytes on day 15 were harvested using 0.5% Trypsin (Dilute 2.5% Trypsin stock 1:5 in Versene with 10 µM ROCKi). 800,000 viable cells per well were plated on Vitronectin XF-coated 6-well plates for in vitro disease modelling, and cells were incubated at 37 °C, 5% CO2 overnight in replating medium (RPMI-1640+1X B27+5% FBS +10 µM ROCKi) and were refreshed with standard medium (RPMI-1640/B27/Insulin) for 48 h. After 48 h, standard medium was exchanged for maturation medium (DMEM+fatty acid (FA)) for 72 h. DMEM+FA is Dulbecco’s modified Eagle’s medium no glucose, 10 mM HEPES, 2 mM L-carnitine, 5 mM creatine, 5 mM taurine, 1 mM nonessential amino acids, 1× insulin-transferrin-selenium, and 1× linoleic-oleic acid. After 72 h, DMEM+FA was exchanged for cG (DMEM+FA plus 10 mM glucose, 10 nM endothelin-1, and 1 µM cortisol), vG (DMEM+FA plus 15 mM or 5 mM glucose, 10 nM endothelin-1, and 1 µM cortisol) or DMEM+FA vehicle control for a further 60 h. vG model was treated with variant diabetic media containing glucose at 15 mM or 5 mM every 12 h in cyclic episodes. Following induction, cells were harvested for intracellular metabolite extraction and downstream metabolomics analysis. Metabolomics analysis was performed in the Queensland Metabolomics and Proteomics Facility (Q-MAP, UQ). Metabolomicsstem cellCardiomyocytemyocardial infarctionCardiovascular DisordermortalityGeneticsmetabolismdiabetes mellitustargeted metabolitesdisease modelstem cellCardiomyocytemyocardial infarctionCardiovascular DisordermortalityGeneticsmetabolismdiabetes mellitustargeted metabolitesdisease modelFor LC–MS analysis of central carbon metabolism, samples were analysed using a Shimadzu 8060 triple-quadrupole mass spectrometer, operated in negative electrospray ionisation (ESI) mode with scheduled multiple reaction monitoring (sMRM). For GC–MS analysis, derivatised samples were analysed using a Shimadzu GC/MS-TQ8050 NX system. Compounds were ionised by electron impact ionisation and analysed in MRM mode. falseGlycaemic variability identified as a critical determinant of myocyte dysfunction and risk for myocardial injury in preclinical models of diabetesHeart disease is the leading cause of morbidity and mortality in individuals with diabetes, due largely to risks associated with ischaemic injuries such as myocardial infarction (MI). We use human population genetic data to demonstrate that current biomarkers of hyperglycaemia do not account for risk of post-MI mortality in diabetes patients. This study therefore systematically evaluates glycaemic stress underpinning cardiovascular risk in diabetes. Using in vivo and in vitro models, we demonstrate that glycaemic variability rather than hyperglycaemia alone is a dominant risk factor for heart muscle dysfunction and myocardial injury sensitivity in diabetes. These findings provide new preclinical models for mechanistic and drug discovery studies and inform strategies for managing cardiovascular outcomes in patients with diabetes.2026-02-062024-12-20MTBLS11411