Summary of study ST000383

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000300. The data can be accessed directly via it's Project DOI: 10.21228/M88C86 This work is supported by NIH grant, U2C- DK119886.

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Study IDST000383
Study TitlePlasma Metabolomic Profiles Reflective of Glucose Homeostasis in Non-Diabetic and Type 2 Diabetic Obese African-American Women
Study SummaryInsulin resistance progressing to type 2 diabetes mellitus (T2DM) is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and should foster discovery of new biomarkers of disease risk and severity. We examined differences in plasma concentrations of >350 metabolites in fasted obese T2DM vs. obese non-diabetic African-American women, and utilized principal components analysis to identify 158 metabolite components that strongly correlated with fasting HbA1c over a broad range of the latter (r?=??0.631; p<0.0001). In addition to many unidentified small molecules, specific metabolites that were increased significantly in T2DM subjects included certain amino acids and their derivatives (i.e., leucine, 2-ketoisocaproate, valine, cystine, histidine), 2-hydroxybutanoate, long-chain fatty acids, and carbohydrate derivatives. Leucine and valine concentrations rose with increasing HbA1c, and significantly correlated with plasma acetylcarnitine concentrations. It is hypothesized that this reflects a close link between abnormalities in glucose homeostasis, amino acid catabolism, and efficiency of fuel combustion in the tricarboxylic acid (TCA) cycle. It is speculated that a mechanism for potential TCA cycle inefficiency concurrent with insulin resistance is “anaplerotic stress” emanating from reduced amino acid-derived carbon flux to TCA cycle intermediates, which if coupled to perturbation in cataplerosis would lead to net reduction in TCA cycle capacity relative to fuel delivery.
Institute
University of California, Davis
DepartmentGenome and Biomedical Sciences Facility
LaboratoryWCMC Metabolomics Core
Last NameFiehn
First NameOliver
Address1315 Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Davis, CA 95616
Emailofiehn@ucdavis.edu
Phone(530) 754-8258
Submit Date2016-04-11
Study CommentsG/g and g/a are polymorphisms in the promoter region of the UCP3 gene that leads to the gene being enhanced and an increased chance of obesity in those with this polymorphism.
PublicationsPlasma Metabolomic Profiles Reflective of Glucose Homeostasis in Non-Diabetic and Type 2 Diabetic Obese African-American Women
Raw Data AvailableYes
Raw Data File Type(s).peg
Analysis Type DetailGC-MS
Release Date2016-04-25
Release Version1
Oliver Fiehn Oliver Fiehn
https://dx.doi.org/10.21228/M88C86
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000300
Project DOI:doi: 10.21228/M88C86
Project Title:Plasma Metabolomic Profiles Reflective of Glucose Homeostasis in Non-Diabetic and Type 2 Diabetic Obese African-American Women
Project Summary:Insulin resistance progressing to type 2 diabetes mellitus (T2DM) is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and should foster discovery of new biomarkers of disease risk and severity. We examined differences in plasma concentrations of >350 metabolites in fasted obese T2DM vs. obese non-diabetic African-American women, and utilized principal components analysis to identify 158 metabolite components that strongly correlated with fasting HbA1c over a broad range of the latter (r?=??0.631; p<0.0001). In addition to many unidentified small molecules, specific metabolites that were increased significantly in T2DM subjects included certain amino acids and their derivatives (i.e., leucine, 2-ketoisocaproate, valine, cystine, histidine), 2-hydroxybutanoate, long-chain fatty acids, and carbohydrate derivatives. Leucine and valine concentrations rose with increasing HbA1c, and significantly correlated with plasma acetylcarnitine concentrations. It is hypothesized that this reflects a close link between abnormalities in glucose homeostasis, amino acid catabolism, and efficiency of fuel combustion in the tricarboxylic acid (TCA) cycle. It is speculated that a mechanism for potential TCA cycle inefficiency concurrent with insulin resistance is “anaplerotic stress” emanating from reduced amino acid-derived carbon flux to TCA cycle intermediates, which if coupled to perturbation in cataplerosis would lead to net reduction in TCA cycle capacity relative to fuel delivery.
Institute:University of California, Davis
Department:Genome and Biomedical Sciences Facility
Laboratory:WCMC Metabolomics Core
Last Name:Fiehn
First Name:Oliver
Address:1315 Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Davis, CA 95616
Email:ofiehn@ucdavis.edu
Phone:(530) 754-8258
Funding Source:NIH U24DK097154
Publications:Plasma Metabolomic Profiles Reflective of Glucose Homeostasis in Non-Diabetic and Type 2 Diabetic Obese African-American Women

Subject:

Subject ID:SU000404
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Genotype Strain:g/g vs. g/a
Age Or Age Range:19.3 - 87.1
Human Race:African American
Human Ethnicity:African American
Species Group:Human

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Health Status UCP-3 Polymorphism
SA017419090309bsesa59_1diabetic g/a
SA017420090309bsesa67_1diabetic g/a
SA017421090309bsesa61_1diabetic g/a
SA017422090309bsesa106_1diabetic g/a
SA017423090309bsesa100_1diabetic g/a
SA017424090309bsesa96_1diabetic g/a
SA017425090309bsesa65_1diabetic g/a
SA017426090309bsesa77_1diabetic g/a
SA017427090309bsesa60_1diabetic g/a
SA017428090309bsesa88_1diabetic g/a
SA017429090309bsesa99_1diabetic g/a
SA017430090309bsesa95_1diabetic g/a
SA017431090309bsesa98_1diabetic g/a
SA017432090309bsesa109_1diabetic g/a
SA017433090309bsesa92_2diabetic g/a
SA017434090309bsesa78_1diabetic g/a
SA017435090309bsesa68_1diabetic g/a
SA017436090309bsesa75_1diabetic g/a
SA017437090309bsesa110_1diabetic g/a
SA017438090309bsesa69_1diabetic g/a
SA017439090309bsesa89_2diabetic g/a
SA017440090309bsesa66_1diabetic g/a
SA017441090309bsesa80_2diabetic g/g
SA017442090309bsesa58_1diabetic g/g
SA017443090309bsesa79_1diabetic g/g
SA017444090309bsesa104_1diabetic g/g
SA017445090309bsesa84_1diabetic g/g
SA017446090309bsesa62_1diabetic g/g
SA017447090309bsesa64_1diabetic g/g
SA017448090309bsesa101_1diabetic g/g
SA017449090309bsesa90_2diabetic g/g
SA017450090309bsesa83_1diabetic g/g
SA017451090309bsesa108_1diabetic g/g
SA017452090309bsesa85_1diabetic g/g
SA017453090309bsesa70_1diabetic g/g
SA017454090309bsesa87_1diabetic g/g
SA017455090309bsesa72_1diabetic g/g
SA017456090309bsesa112_1diabetic g/g
SA017457090309bsesa63_1diabetic g/g
SA017458090309bsesa94_1diabetic g/g
SA017459090309bsesa82_1diabetic g/g
SA017460090309bsesa73_1diabetic g/g
SA017461090309bsesa97_1diabetic g/g
SA017462090309bsesa86_1diabetic g/g
SA017463090309bsesa91_1non-diabetic g/a
SA017464090309bsesa103_1non-diabetic g/a
SA017465090309bsesa76_1non-diabetic g/a
SA017466090309bsesa93_2non-diabetic g/a
SA017467090309bsesa102_1non-diabetic g/a
SA017468090309bsesa74_1non-diabetic g/a
SA017469090309bsesa105_1non-diabetic g/g
SA017470090309bsesa57_1non-diabetic g/g
SA017471090309bsesa71_1non-diabetic g/g
SA017472090309bsesa111_1non-diabetic g/g
SA017473090309bsesa107_1non-diabetic g/g
SA017474090309bsesa81_1non-diabetic g/g
Showing results 1 to 56 of 56

Collection:

Collection ID:CO000398
Collection Summary:Blood was collected by arm venipuncture between ?08:00–09:00 into EDTA-treated collection tubes after an overnight fast (no food or drink since 20:00 the night before). Plasma was frozen at ?20°C for 1–7 days before transport to ?80°C freezers for longer-term storage.
Collection Protocol Filename:Plasma_Metabolomic_Profiles_of_Type_2_Diabetic_Obese_Women.pdf
Sample Type:Blood
Collection Method:Venipuncture
Blood Serum Or Plasma:Plasma

Treatment:

Treatment ID:TR000418
Treatment Summary:Volunteers were asked to avoid unusual activity and intentional exercise in the 3 days leading up to the study, and were instructed to continue to eat their habitual diet without unusual deviations. Patients with T2DM did not take doses of oral agents on the evening before and on the morning of study. Patients treated with insulin could take regular or rapid acting insulin at dinner the night before the study but were instructed to withhold any intermediate- or long-acting insulin on the evening before, and to avoid insulin injections on the morning of the study.
Treatment Protocol Filename:Plasma_Metabolomic_Profiles_of_Type_2_Diabetic_Obese_Women.pdf
Human Fasting:12-13 hours

Sample Preparation:

Sampleprep ID:SP000411
Sampleprep Summary:1. Switch on bath to pre-cool at –20°C (±2°C validity temperature range) 2. Gently rotate or aspirate the blood samples for about 10s to obtain a homogenised sample. 3. Aliquot 30?l of plasma sample to a 1.0 mL extraction solution. The extraction solution has to be prechilled using the ThermoElectron Neslab RTE 740 cooling bath set to -20°C. 4. Vortex the sample for about 10s and shake for 5 min at 4°C using the Orbital Mixing Chilling/Heating Plate. If you are using more than one sample, keep the rest of the sample on ice (chilled at <0°C with sodium chloride). 5. Centrifuge samples for 2min at 14000 rcf using the centrifuge Eppendorf 5415 D. 6. Aliquot two 450?L portions of the supernatant. One for analysis and one for a backup sample. Store the backup aliquot in -20°C freezer. 7. Evaporate one 450?L aliquots of the sample in the Labconco Centrivap cold trap concentrator to complete dryness. 8. The dried aliquot is then re-suspended with 450 ?L 50% acetonitrile (degassed as given above). 9. Centrifuged for 2 min at 14000 rcf using the centrifuge Eppendorf 5415. 10. Remove supernatant to a new Eppendorf tube. 11. Evaporate the supernatant to dryness in the Labconco Centrivap cold trap concentrator. 12. Submit to derivatization.
Sampleprep Protocol Filename:PR_SP_SOP_blood-GCTOF-11082012.pdf

Combined analysis:

Analysis ID AN000618
Analysis type MS
Chromatography type GC
Chromatography system Agilent 6890N
Column Restek Corporation Rtx-5Sil MS
MS Type EI
MS instrument type GC-TOF
MS instrument name Leco Pegasus IV TOF
Ion Mode POSITIVE
Units counts

Chromatography:

Chromatography ID:CH000443
Methods Filename:GCTOF_MS_primary_metabolism_10-15-2013_general.pdf
Instrument Name:Agilent 6890N
Column Name:Restek Corporation Rtx-5Sil MS
Column Pressure:7.7 PSI
Column Temperature:50-330C
Flow Rate:1 ml/min
Injection Temperature:50 C ramped to 2580 C by 12C/s
Sample Injection:0.5 uL
Oven Temperature:50°C for 1 min, then ramped at 20°C/min to 330°C, held constant for 5 min
Transferline Temperature:230C
Washing Buffer:Ethyl Acetate
Sample Loop Size:30 m length x 0.25 mm internal diameter
Randomization Order:Excel generated
Chromatography Type:GC

MS:

MS ID:MS000551
Analysis ID:AN000618
Instrument Name:Leco Pegasus IV TOF
Instrument Type:GC-TOF
MS Type:EI
Ion Mode:POSITIVE
Ion Source Temperature:250 C
Ionization Energy:70 eV
Mass Accuracy:Nominal
Source Temperature:250 C
Scan Range Moverz:85-500 Da
Scanning Cycle:17 Hz
Scanning Range:85-500 Da
Skimmer Voltage:1850 V
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