Summary of Study ST000948

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 IDST000948
Study TitleMechanisms for Insulin Resistance in Polycystic Ovary Syndrome: aminoadipic acid, lysine concentrations, and enrichment (part II)
Study SummaryTo determine how metformin therapy changes lysine and AAA kinetics in PCOS and whether this is associated with improvements in insulin sensitivity. Changes in lysine and AAA flux before and after three months of metformin therapy will be compared to women with PCOS randomized to no treatment for three months.
Institute
Mayo Clinic
Last NameChang
First NameAlice
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
Alice Chang Alice 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:SU000987
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
SA056882ms6443-7120 PCOS
SA056883ms6713-18120 PCOS
SA056884ms6712-18120 PCOS
SA056885ms6440-7120 PCOS
SA056886ms6437-18120 PCOS
SA056887ms6438-7120 PCOS
SA056888ms6440-18120 PCOS
SA056889ms6438-18120 PCOS
SA056890ms6715-7120 PCOS
SA056891ms6442-7120 PCOS
SA056892ms6718-7120 PCOS
SA056893ms6717-7120 PCOS
SA056894ms6712-7120 PCOS
SA056895ms6441-7120 PCOS
SA056896ms6439-18120 PCOS
SA056897ms6437-7120 PCOS
SA056898ms6442-18120 PCOS
SA056899ms6441-18120 PCOS
SA056900ms6715-18120 PCOS
SA056901ms6713-7120 PCOS
SA056902ms6718-18120 PCOS
SA056903ms6714-18120 PCOS
SA056904ms6443-18120 PCOS
SA056905ms6714-7120 PCOS
SA056906ms6716-18120 PCOS
SA056907ms6436-18120 PCOS
SA056908ms6439-7120 PCOS
SA056909ms6716-7120 PCOS
SA056910ms6436-7120 PCOS
SA056911ms6717-18120 PCOS
SA056912ms6712-8135 PCOS
SA056913ms6718-8135 PCOS
SA056914ms6443-8135 PCOS
SA056915ms6442-8135 PCOS
SA056916ms6713-8135 PCOS
SA056917ms6712-19135 PCOS
SA056918ms6440-19135 PCOS
SA056919ms6716-8135 PCOS
SA056920ms6436-8135 PCOS
SA056921ms6718-19135 PCOS
SA056922ms6437-8135 PCOS
SA056923ms6715-19135 PCOS
SA056924ms6713-19135 PCOS
SA056925ms6439-19135 PCOS
SA056926ms6716-19135 PCOS
SA056927ms6717-19135 PCOS
SA056928ms6436-19135 PCOS
SA056929ms6437-19135 PCOS
SA056930ms6717-8135 PCOS
SA056931ms6438-19135 PCOS
SA056932ms6439-8135 PCOS
SA056933ms6438-8135 PCOS
SA056934ms6442-19135 PCOS
SA056935ms6714-8135 PCOS
SA056936ms6440-8135 PCOS
SA056937ms6441-8135 PCOS
SA056938ms6714-19135 PCOS
SA056939ms6443-19135 PCOS
SA056940ms6441-19135 PCOS
SA056941ms6715-8135 PCOS
SA056942ms6717-9150 PCOS
SA056943ms6713-20150 PCOS
SA056944ms6714-9150 PCOS
SA056945ms6715-20150 PCOS
SA056946ms6712-20150 PCOS
SA056947ms6713-9150 PCOS
SA056948ms6714-20150 PCOS
SA056949ms6715-9150 PCOS
SA056950ms6716-20150 PCOS
SA056951ms6717-20150 PCOS
SA056952ms6716-9150 PCOS
SA056953ms6441-9150 PCOS
SA056954ms6441-20150 PCOS
SA056955ms6440-20150 PCOS
SA056956ms6443-20150 PCOS
SA056957ms6437-20150 PCOS
SA056958ms6440-9150 PCOS
SA056959ms6438-20150 PCOS
SA056960ms6439-9150 PCOS
SA056961ms6436-9150 PCOS
SA056962ms6718-20150 PCOS
SA056963ms6439-20150 PCOS
SA056964ms6437-9150 PCOS
SA056965ms6438-9150 PCOS
SA056966ms6442-9150 PCOS
SA056967ms6442-20150 PCOS
SA056968ms6712-9150 PCOS
SA056969ms6443-9150 PCOS
SA056970ms6436-20150 PCOS
SA056971ms6718-9150 PCOS
SA056762ms6718-5-15 PCOS
SA056763ms6443-16-15 PCOS
SA056764ms6437-5-15 PCOS
SA056765ms6716-5-15 PCOS
SA056766ms6441-16-15 PCOS
SA056767ms6436-5-15 PCOS
SA056768ms6714-5-15 PCOS
SA056769ms6440-5-15 PCOS
SA056770ms6439-16-15 PCOS
SA056771ms6716-16-15 PCOS
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Collection:

Collection ID:CO000981
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. Previous studies have established that the combination of metformin and pioglitazone decrease lysine and AAA concentrations in overweight and obese adults with impaired fasting glucose or untreated diabetes.(7) Aim 3 is designed to establish whether changes in lysine and AAA flux are associated with changes in insulin sensitivity. Measurement of lysine and AAA flux will be repeated in 10 women with PCOS after three months of metformin and 10 women with PCOS randomized to receive no treatment for three months. Insulin sensitivity and other measures of glucose metabolism will be calculated from an oral glucose tolerance test using the oral minimal model as described below.
Sample Type:Blood (plasma)

Treatment:

Treatment ID:TR001001
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:SP000994
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 AN001556 AN001557
Analysis type MS MS
Chromatography type Reversed phase Reversed phase
Chromatography system Thermo Dionex Ultimate 3000 Thermo Dionex Ultimate 3000
Column Unspecified Unspecified
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:CH001091
Instrument Name:Thermo Dionex Ultimate 3000
Column Name:Unspecified
Chromatography Type:Reversed phase

MS:

MS ID:MS001434
Analysis ID:AN001556
Instrument Name:Thermo Q Exactive Plus Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:uM
Ion Mode:POSITIVE
  
MS ID:MS001435
Analysis ID:AN001557
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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