Summary of Study ST000519

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 PR000383. The data can be accessed directly via it's Project DOI: 10.21228/M8JG7B This work is supported by NIH grant, U2C- DK119886.

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Study IDST000519
Study TitleInvestigating ceremide concentrations in mice muscle tissue lacking insulin receptors and IGF-1 receptors
Study SummaryQuantitative measures of ceramide metabolite concentrations in muscle from control, M-IR-/-, M-IGF1R-/- , and MIGIRKO mice. Also compare mice on a chow diet to mice on a high fat diet (HFD).
Institute
Mayo Clinic
Last NameO'Neill
First NameBrian
AddressOne Joslin Place, Boston, MA 02215
Emailbrian.o'neill@joslin.harvard.edu
Phone617-309-2400
Submit Date2016-12-07
Analysis Type DetailLC-MS
Release Date2018-12-11
Release Version1
Brian O'Neill Brian O'Neill
https://dx.doi.org/10.21228/M8JG7B
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000383
Project DOI:doi: 10.21228/M8JG7B
Project Title:Mayo Metabolomics Pilot and Feasibility Award: Role of muscle insulin and IGF-1 signaling on serum and muscle metabolite profiles
Project Summary:Skeletal muscle insulin resistance is a cardinal feature of the pathogenesis of type 2 diabetes. Insulin and IGF-1 signal through their highly related receptors to impact on many aspects of muscle physiology including glucose homeostasis, protein metabolism, and mitochondrial function. Early physiological studies, as well as recent large scale metabolomic studies, have shown that changes in specific pools of circulating amino acid metabolites, such as branched chain amino acids (BCAAs), are associated with insulin resistance and can predict future diabetes, but the source and impact of these changes in amino acids are not fully understood. We have recently generated mice which lack insulin receptors (IR) or IGF-1 receptors (IGF1R) or both in muscle using Cre lox recombination. We find that mice which lack only IR or only IGF1R in muscle show minimal changes in muscle mass, but do display increases in proteasomal activity and autophagy in muscle. On the other hand, mice with combined loss of both IR and IGF1R display markedly decreased muscle mass and enhanced degradation pathways, associated with increased protein synthesis, and display changes in mitochondrial gene regulation, indicating that both receptors can compensate to some extent for loss of the other. We hypothesize that IR and IGF1R signaling in muscle coordinate amino acid metabolite turnover and fuel substrate/mitochondrial metabolism, and that in insulin resistant states, changes in protein metabolism and mitochondrial function disrupt relative proportions of amino acid metabolites, which in turn contribute to diabetes risk and/or muscle pathology. We propose to test this hypothesis by performing large scale metabolomics on serum and muscle from mice lacking IR, IGF1R or both in muscle, and we will compare these changes to both insulin deficient streptozotocin-treated and insulin resistant diet-induced obese mouse models. To gain insight into which pathways are critical for metabolite changes, we will also treat mice with specific inhibitors of mTOR, a common protein synthesis pathway, as well as inhibitors of autophagy or proteasomal degradation and determine metabolite concentrations in muscle and serum. These studies will identify specific pathways that impact amino acid and mitochondrial metabolite flux which are perturbed in insulin resistant states, and potentially provide insights into how changes in amino acid metabolites contribute to diabetes risk.
Institute:Mayo Clinic
Last Name:O'Neill
First Name:Brian
Address:One Joslin Place, Boston, MA 02215
Email:brian.o'neill@joslin.harvard.edu
Phone:617-309-2400

Subject:

Subject ID:SU000541
Subject Type:Mouse
Subject Species:Mus musculus
Taxonomy ID:10090
Species Group:Mammal

Factors:

Subject type: Mouse; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Group Genotype Diet
SA027154ms5689-21CD Irlox Chow
SA027155ms5689-19CD Irlox Chow
SA027156ms5689-22CD Irlox Chow
SA027157ms5689-20CD Irlox Chow
SA027158ms5689-13Control IGFR lox Chow
SA027159ms5689-11Control IGFR lox Chow
SA027160ms5689-12Control IGFR lox Chow
SA027161ms5689-1Control Irlox Chow
SA027162ms5689-2Control Irlox Chow
SA027163ms5689-4Control Irlox Chow
SA027164ms5689-3Control Irlox Chow
SA027165ms5689-24HFD Irlox High Fat Diet
SA027166ms5689-27HFD Irlox High Fat Diet
SA027167ms5689-26HFD Irlox High Fat Diet
SA027168ms5689-25HFD Irlox High Fat Diet
SA027169ms5689-23HFD Irlox High Fat Diet
SA027170ms5689-14IGFRKO IGFR -/- Chow
SA027171ms5689-18IGFRKO IGFR -/- Chow
SA027172ms5689-16IGFRKO IGFR -/- Chow
SA027173ms5689-15IGFRKO IGFR -/- Chow
SA027174ms5689-17IGFRKO IGFR -/- Chow
SA027175ms5689-6IRKO IR -/- Chow
SA027176ms5689-5IRKO IR -/- Chow
SA027177ms5689-7IRKO IR -/- Chow
SA027178ms5689-10IRKO IR -/- Chow
SA027179ms5689-9IRKO IR -/- Chow
SA027180ms5689-8IRKO IR -/- Chow
Showing results 1 to 27 of 27

Collection:

Collection ID:CO000535
Collection Summary:mouse muscle tissue
Sample Type:Muscle

Treatment:

Treatment ID:TR000555
Treatment Summary:Mice lacking insulin receptors (IR -/- genotype), or IGF-1 receptors (ICF-1 -/- genotype), or both were generated using Cre lox recombination. Controls were IR lox/lox, IGF-1 lox/lox, or both. Additional, 10 mice were included that were fed different diets for 8 weeks, chow or high fat diet.

Sample Preparation:

Sampleprep ID:SP000548
Sampleprep Summary:ceramide concentrations in muscle tissue

Combined analysis:

Analysis ID AN000793
Analysis type MS
Chromatography type Reversed phase
Chromatography system Waters Acquity
Column Waters Acquity BEH C8 (150 x 2mm,1.7um)
MS Type ESI
MS instrument type Triple quadrupole
MS instrument name Thermo Quantiva QQQ
Ion Mode POSITIVE
Units ng/mg

Chromatography:

Chromatography ID:CH000569
Instrument Name:Waters Acquity
Column Name:Waters Acquity BEH C8 (150 x 2mm,1.7um)
Chromatography Type:Reversed phase

MS:

MS ID:MS000700
Analysis ID:AN000793
Instrument Name:Thermo Quantiva QQQ
Instrument Type:Triple quadrupole
MS Type:ESI
Ion Mode:POSITIVE
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