Summary of Study ST000947

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 PR000652. The data can be accessed directly via it's Project DOI: 10.21228/M8D38P This work is supported by NIH grant, U2C- DK119886.

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Study IDST000947
Study TitleMechanisms for Insulin Resistance in Polycystic Ovary Syndrome with metformin therapy: aminoadipic acid, lysine concentrations, and enrichment (part I)
Study SummaryTo determine whether altered lysine and α-aminoadipic acid (AAA) kinetics explain previous observations of increased lysine and AAA concentrations in PCOS compared to controls, as measured by baseline lysine and AAA flux in PCOS versus healthy controls using [α-15N]-lysine and [13C]-AAA stable isotope tracers as well as by comparing the conversion of [α-15N]-lysine to [15N]-AAA. To evaluate how hyperinsulinemia affects lysine and AAA kinetics. Changes in lysine and AAA flux during a hyperinsulinemic-euglycemic clamp will be evaluated in healthy controls and compared to the baseline changes in lysine and AAA flux in PCOS. PCOS cases at baseline and after 3 months of metformin therapy.
Institute
Mayo Clinic
Last NameChang
First NameAl
Address200 First St. SW, Rochester, Minnesota, 55905, USA
EmailChang.Alice1@mayo.edu
Phone507-286-0505
Submit Date2018-04-09
Analysis Type DetailLC-MS
Release Date2020-04-13
Release Version1
Al Chang Al Chang
https://dx.doi.org/10.21228/M8D38P
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000652
Project DOI:doi: 10.21228/M8D38P
Project Title:Mayo Pilot and Feasibility: Mechanisms for Insulin Resistance in Polycystic Ovary Syndrome
Project Summary:Polycystic Ovary Syndrome (PCOS), a condition of androgen excess, infrequent ovulation, and insulin resistance is the most common endocrine disorder among premenopausal women. Little is known about the exact mechanisms of insulin resistance in PCOS and how metformin can improve insulin sensitivity, increase the frequency of ovulation and lower androgens in PCOS. Preliminary data from metabolomic analyses of amino acids demonstrate increased concentrations of lysine and its metabolite, α-aminoadipic acid (AAA), in PCOS versus obese controls. Interestingly, greater AAA concentrations predicted the development of type 2 diabetes in the Framingham epidemiologic cohort, experimentally lowers glucose in animal models and increases insulin secretion in vitro. To date, the mechanism for increased circulating concentrations of lysine and AAA in insulin-resistant individuals is not known. Building upon these findings, we have initiated a project to simultaneously study lysine and AAA kinetics for the first time in insulin-resistant individuals using stable isotope tracer methodology. We will evaluate: 1) whether lysine and AAA kinetics are altered in PCOS versus healthy controls; 2) the effect of hyperinsulinemia on lysine and AAA kinetics in PCOS versus controls; 3) whether treatment to improve insulin sensitivity changes lysine and AAA kinetics in PCOS. The long-term goal is to target pathways for the treatment of PCOS and the prevention of type 2 diabetes in PCOS and other insulin-resistant individuals at greater risk for type 2 diabetes.
Institute:Mayo Clinic
Last Name:Chang
First Name:Alice
Address:200 First St. SW, Rochester, Minnesota, 55905, USA
Email:Chang.Alice1@mayo.edu
Phone:507-286-0505

Subject:

Subject ID:SU000986
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606

Factors:

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

mb_sample_id local_sample_id Time point Group
SA056607ms6188-7120 control
SA056608ms6102-7120 control
SA056609ms6182-7120 control
SA056610ms6036-7120 control
SA056611ms6034-7120 control
SA056612ms6032-7120 control
SA056613ms6185-7120 control
SA056614ms6243-7120 control
SA056615ms6035-7120 control
SA056616ms6184-7120 control
SA056617ms6183-7120 control
SA056594ms6099-7120 PCOS
SA056595ms6042-7120 PCOS
SA056596ms6098-7120 PCOS
SA056597ms6039-7120 PCOS
SA056598ms6187-7120 PCOS
SA056599ms6189-7120 PCOS
SA056600ms6186-7120 PCOS
SA056601ms6087-7120 PCOS
SA056602ms6091-7120 PCOS
SA056603ms6101-7120 PCOS
SA056604ms6100-7120 PCOS
SA056605ms6038-7120 PCOS
SA056606ms6275-7120 PCOS
SA056631ms6034-8135 control
SA056632ms6036-8135 control
SA056633ms6182-8135 control
SA056634ms6102-8135 control
SA056635ms6243-8135 control
SA056636ms6183-8135 control
SA056637ms6188-8135 control
SA056638ms6035-8135 control
SA056639ms6185-8135 control
SA056640ms6184-8135 control
SA056641ms6032-8135 control
SA056618ms6099-8135 PCOS
SA056619ms6100-8135 PCOS
SA056620ms6098-8135 PCOS
SA056621ms6187-8135 PCOS
SA056622ms6042-8135 PCOS
SA056623ms6087-8135 PCOS
SA056624ms6091-8135 PCOS
SA056625ms6275-8135 PCOS
SA056626ms6101-8135 PCOS
SA056627ms6186-8135 PCOS
SA056628ms6189-8135 PCOS
SA056629ms6038-8135 PCOS
SA056630ms6039-8135 PCOS
SA056655ms6183-9150 control
SA056656ms6035-9150 control
SA056657ms6032-9150 control
SA056658ms6182-9150 control
SA056659ms6243-9150 control
SA056660ms6185-9150 control
SA056661ms6102-9150 control
SA056662ms6036-9150 control
SA056663ms6188-9150 control
SA056664ms6184-9150 control
SA056665ms6034-9150 control
SA056642ms6101-9150 PCOS
SA056643ms6099-9150 PCOS
SA056644ms6039-9150 PCOS
SA056645ms6098-9150 PCOS
SA056646ms6038-9150 PCOS
SA056647ms6187-9150 PCOS
SA056648ms6087-9150 PCOS
SA056649ms6189-9150 PCOS
SA056650ms6091-9150 PCOS
SA056651ms6042-9150 PCOS
SA056652ms6275-9150 PCOS
SA056653ms6186-9150 PCOS
SA056654ms6100-9150 PCOS
SA056511ms6188-5-15 control
SA056512ms6102-5-15 control
SA056513ms6243-5-15 control
SA056514ms6185-5-15 control
SA056515ms6036-5-15 control
SA056516ms6182-5-15 control
SA056517ms6035-5-15 control
SA056518ms6184-5-15 control
SA056519ms6183-5-15 control
SA056520ms6034-5-15 control
SA056521ms6032-5-15 control
SA056498ms6039-5-15 PCOS
SA056499ms6275-5-15 PCOS
SA056500ms6187-5-15 PCOS
SA056501ms6098-5-15 PCOS
SA056502ms6091-5-15 PCOS
SA056503ms6087-5-15 PCOS
SA056504ms6038-5-15 PCOS
SA056505ms6186-5-15 PCOS
SA056506ms6042-5-15 PCOS
SA056507ms6099-5-15 PCOS
SA056508ms6100-5-15 PCOS
SA056509ms6101-5-15 PCOS
SA056510ms6189-5-15 PCOS
SA056679ms6185-10165 control
SA056680ms6032-10165 control
SA056681ms6035-10165 control
SA056682ms6184-10165 control
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Collection:

Collection ID:CO000980
Collection Summary:We will perform a hyperinsulinemic-euglycemic clamp as previously described except that in this current proposal we will perform the study for 3 hours.(36) The goal for this infusion is to assess the effect of hyperinsulinemia on lysine and AAA kinetics and whether metformin changes the effect of hyperinsulinemia. We will collect samples every 10 min for glucose. 40% dextrose will be infused at a variable rate during the clamp to maintain euglycemia.(36) During the last hour of the clamp, 5 blood samples will be drawn for measurement of stable isotope tracer enrichment and amino acid concentrations.
Sample Type:Blood (plasma)

Treatment:

Treatment ID:TR001000
Treatment Summary:Ten women with PCOS will receive metformin therapy, and ten women will be randomized to receive no therapy and undergo the same repeat visits after 3 months. Ten age-matched women without PCOS with a BMI < 25 will be recruited as the control group for the baseline visit. Aside from criteria that they do not have PCOS and have a BMI < 25, this control group will have the same inclusion and exclusion criteria below. They will not receive metformin and will not return for repeat visits after 3 months. Metformin therapy: Previous studies with metformin demonstrated improvement in insulin sensitivity as early as 3 months with 1000 mg daily.(5, 33, 34) Metformin will be initiated with 500 mg extended-release tablet daily for one week, 1000 mg daily for one week and then 1500 mg daily. Visits 4 and 5 will be conducted three months after full dose is achieved. Oral glucose tolerance test: After 2 baseline fasting samples, 75 g of oral dextrose will be ingested with blood samples will be drawn at 10’, 20’, 30’, 60’, 90’, 120’, 150’and 180’ for measurement of glucose, insulin, c-peptide. Insulin sensitivity will be calculated using the oral glucose minimal model. Stable isotope tracer infusions (Figure 5): Three days prior to the tracer study, the participants will be placed on a weight-maintaining diet consisting of 50% carbohydrates, 20% protein, and 30% fats. Fat free mass (FFM) measured by dual-energy x-ray absorptiometry will be used for dose calculations of the stable isotope tracers and insulin infusions for the hyperinsulinemic-euglycemic clamp. A priming bolus dose of L-[α-15N]-lysine, 3 to 5 μmol/kg FFM, will be given at the start of a 3 hour infusion of 3 to 5 μmol/kg FFM/hr to achieve a plateau as previously described.(29) At the same time, a priming bolus of 1 to 2 μmol/kg FFM L-[1-13C]-2-aminoadipic acid will be given followed by infusion of 1 to 2 μmol/kg/hr based on prior study.(30) A retrograde hand intravenous line will be placed with the hand placed in a warm box maintained at 140°F to obtain arterialized venous blood samples for measurement of lysine and AAA concentrations and stable isotopic enrichment at steady state and during the clamp. Hyperinsulinemic-euglycemic clamp: We will perform a hyperinsulinemic-euglycemic clamp as previously described except that in this current proposal we will perform the study for 3 hours.(36) The goal for this infusion is to assess the effect of hyperinsulinemia on lysine and AAA kinetics and whether metformin changes the effect of hyperinsulinemia. We will collect samples every 10 min for glucose. 40% dextrose will be infused at a variable rate during the clamp to maintain euglycemia.(36) During the last hour of the clamp, 5 blood samples will be drawn for measurement of stable isotope tracer enrichment and amino acid concentrations.

Sample Preparation:

Sampleprep ID:SP000993
Sampleprep Summary:Plasma lysine and AAA concentrations and isotopic enrichment will be analyzed as previous described via a Thermo Fisher Q Exactive plus mass spectrometer coupled with a Dionex UltiMate 3000 Binary RSLC liquid chromatograph.

Combined analysis:

Analysis ID AN001554 AN001555
Analysis type MS MS
Chromatography type Reversed phase Reversed phase
Chromatography system Thermo Dionex Ultimate 3000 Thermo Dionex Ultimate 3000
Column Zorbax Extended C18 Zorbax Extended C18
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive Plus Orbitrap Thermo Q Exactive Plus Orbitrap
Ion Mode POSITIVE POSITIVE
Units uM MPE

Chromatography:

Chromatography ID:CH001090
Instrument Name:Thermo Dionex Ultimate 3000
Column Name:Zorbax Extended C18
Chromatography Type:Reversed phase

MS:

MS ID:MS001432
Analysis ID:AN001554
Instrument Name:Thermo Q Exactive Plus Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:uM
Ion Mode:POSITIVE
  
MS ID:MS001433
Analysis ID:AN001555
Instrument Name:Thermo Q Exactive Plus Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:MPE (molar percent excess )
Ion Mode:POSITIVE
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