Summary of Study ST000518

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 IDST000518
Study TitleMeasuring ceramide concentrations in insulin resistant and insulin deficient mouse tissue models
Study SummaryTo compare models of insulin resistance to a model of loss of insulin signaling, we will also determine ceramide concentration in muscle, using control and streptozotocin (STZ) treated mice as a model of insulin deficient diabetes.
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:SU000540
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
SA027148ms5632-4control
SA027149ms5632-2control
SA027150ms5632-1control
SA027151ms5632-5control
SA027152ms5632-6control
SA027153ms5632-3control
SA027118ms5632-14Fox0 TKO
SA027119ms5632-13Fox0 TKO
SA027120ms5632-15Fox0 TKO
SA027121ms5632-16Fox0 TKO
SA027122ms5632-18Fox0 TKO
SA027123ms5632-17Fox0 TKO
SA027124ms5632-12MIGIRKO
SA027125ms5632-11MIGIRKO
SA027126ms5632-9MIGIRKO
SA027127ms5632-10MIGIRKO
SA027128ms5632-8MIGIRKO
SA027129ms5632-7MIGIRKO
SA027130ms5632-24QKO
SA027131ms5632-23QKO
SA027132ms5632-22QKO
SA027133ms5632-21QKO
SA027134ms5632-20QKO
SA027135ms5632-19QKO
SA027136ms5632-26STZ
SA027137ms5632-27STZ
SA027138ms5632-29STZ
SA027139ms5632-30STZ
SA027140ms5632-25STZ
SA027141ms5632-28STZ
SA027142ms5632-33STZ FoxO TKO
SA027143ms5632-34STZ FoxO TKO
SA027144ms5632-35STZ FoxO TKO
SA027145ms5632-36STZ FoxO TKO
SA027146ms5632-32STZ FoxO TKO
SA027147ms5632-31STZ FoxO TKO
Showing results 1 to 36 of 36

Collection:

Collection ID:CO000534
Collection Summary:To determine the role of FoxO transcription factors in muscle atrophy and increased autophagy in MIGIRKO mice, we crossed MIGIRKO (lacking IR and IGF1R) mice with mice in which FoxO1, FoxO3, and FoxO4 genes were floxed to delete all the major isoforms of FoxO expressed in muscle. Mice in which 5 separate genes — IR, Igf1r, FoxO1, FoxO3, and FoxO4 — were specifically deleted in muscle (muscle quintuple-knockout mice, hereafter referred to as QKO mice); were born in normal Mendelian ratios, and appeared normal both on external inspection and following dissection compared with littermate controls and with muscle FoxO1/3/4 triple-knockout mice (FoxO TKO). Streptozotocin (STZ) treated mice were used as a model of insulin deficient diabetes.
Sample Type:Muscle

Treatment:

Treatment ID:TR000554
Treatment Summary:To determine the relevance of the changes in M-IR-/-, M-IGF1R-/- , and MIGIRKO mice to insulin resistant states, we will perform large scale metabolomics and determine ceramide concentrations metabolites in muscle and serum from 5 mice fed chow diet or 5 fed a high fat diet (HFD) for 8 weeks. Lastly, to compare models of insulin resistance to a model of loss of insulin signaling, we will also determine muscle and serum metabolites in 5 control and 5 streptozotocin (STZ) treated mice as a model of insulin deficient diabetes.

Sample Preparation:

Sampleprep ID:SP000547
Sampleprep Summary:ceramide concentrations in muscle tissue

Combined analysis:

Analysis ID AN000792
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:CH000568
Instrument Name:Waters Acquity
Column Name:Waters Acquity BEH C8 (150 x 2mm,1.7um)
Chromatography Type:Reversed phase

MS:

MS ID:MS000699
Analysis ID:AN000792
Instrument Name:Thermo Quantiva QQQ
Instrument Type:Triple quadrupole
MS Type:ESI
Ion Mode:POSITIVE
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