Summary of Study ST000512

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 IDST000512
Study TitleInvestigating TCA concentrations in mice muscle tissue lacking insulin receptors and IGF-1 receptors
Study SummaryQuantitative measures of TCA cycle metabolites 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 Date2016-11-18
Analysis Type DetailGC-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:SU000534
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
SA026641Sample # 29CD Irlox Chow
SA026642Sample # 30CD Irlox Chow
SA026643Sample # 31CD Irlox Chow
SA026644Sample # 32CD Irlox Chow
SA026645Sample # 21Control IGFR lox Chow
SA026646Sample # 22Control IGFR lox Chow
SA026647Sample # 23Control IGFR lox Chow
SA026652Sample # 14Control Irlox Chow
SA026653Sample # 13Control Irlox Chow
SA026654Sample # 12Control Irlox Chow
SA026655Sample # 11Control Irlox Chow
SA026648Sample # 2Control IRlox IGFR lox Chow
SA026649Sample # 3Control IRlox IGFR lox Chow
SA026650Sample # 4Control IRlox IGFR lox Chow
SA026651Sample # 1Control IRlox IGFR lox Chow
SA026656Sample # 36HFD Irlox High Fat Diet
SA026657Sample # 37HFD Irlox High Fat Diet
SA026658Sample # 35HFD Irlox High Fat Diet
SA026659Sample # 34HFD Irlox High Fat Diet
SA026660Sample # 33HFD Irlox High Fat Diet
SA026661Sample # 25IGFRKO IGFR -/- Chow
SA026662Sample # 26IGFRKO IGFR -/- Chow
SA026663Sample # 28IGFRKO IGFR -/- Chow
SA026664Sample # 27IGFRKO IGFR -/- Chow
SA026665Sample # 24IGFRKO IGFR -/- Chow
SA026666Sample # 19IRKO IR -/- Chow
SA026667Sample # 20IRKO IR -/- Chow
SA026668Sample # 15IRKO IR -/- Chow
SA026669Sample # 16IRKO IR -/- Chow
SA026670Sample # 17IRKO IR -/- Chow
SA026671Sample # 18IRKO IR -/- Chow
SA026672Sample # 6MIGIRKO IR -/- IGFR -/- Chow
SA026673Sample # 5MIGIRKO IR -/- IGFR -/- Chow
SA026674Sample # 7MIGIRKO IR -/- IGFR -/- Chow
SA026675Sample # 10MIGIRKO IR -/- IGFR -/- Chow
SA026676Sample # 9MIGIRKO IR -/- IGFR -/- Chow
SA026677Sample # 8MIGIRKO IR -/- IGFR -/- Chow
Showing results 1 to 37 of 37

Collection:

Collection ID:CO000528
Collection Summary:mouse gastrocnemius muscle tissue
Sample Type:Muscle

Treatment:

Treatment ID:TR000548
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:SP000541
Sampleprep Summary:TCA concentrations in muscle tissue

Combined analysis:

Analysis ID AN000785
Analysis type MS
Chromatography type GC
Chromatography system Agilent 7890A
Column Agilent HP5-MS (30m × 0.25mm, 0.25 um)
MS Type EI
MS instrument type Single quadrupole
MS instrument name Agilent 5975
Ion Mode POSITIVE
Units nmol/mg tissue

Chromatography:

Chromatography ID:CH000562
Instrument Name:Agilent 7890A
Column Name:Agilent HP5-MS (30m × 0.25mm, 0.25 um)
Chromatography Type:GC

MS:

MS ID:MS000692
Analysis ID:AN000785
Instrument Name:Agilent 5975
Instrument Type:Single quadrupole
MS Type:EI
Ion Mode:POSITIVE
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