Summary of Study ST000520

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench,, 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 IDST000520
Study TitleMeasuring TCA cycle 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 TCA cycle metabolites in muscle, using control and streptozotocin (STZ) treated mice as a model of insulin deficient diabetes.
Mayo Clinic
Last NameO'Neill
First NameBrian
AddressOne Joslin Place, Boston, MA 02215
Submit Date2016-12-07
Analysis Type DetailGC-MS
Release Date2018-12-11
Release Version1
Brian O'Neill Brian O'Neill application/zip

Select appropriate tab below to view additional metadata details:


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


Subject ID:SU000542
Subject Type:Mouse
Subject Species:Mus musculus
Taxonomy ID:10090
Species Group:Mammal


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

mb_sample_id local_sample_id group
SA027210Sample # 4control
SA027211Sample # 38control
SA027212Sample # 2control
SA027213Sample # 36control
SA027214Sample # 3control
SA027215Sample # 6control
SA027216Sample # 31control
SA027217Sample # 1control
SA027218Sample # 34control
SA027219Sample # 5control
SA027181Sample # 8Fox0 TKO
SA027182Sample # 9Fox0 TKO
SA027183Sample # 12Fox0 TKO
SA027184Sample # 7Fox0 TKO
SA027185Sample # 10Fox0 TKO
SA027186Sample # 11Fox0 TKO
SA027187Sample # 33MIGIRKO
SA027188Sample # 39MIGIRKO
SA027189Sample # 32MIGIRKO
SA027190Sample # 35MIGIRKO
SA027191Sample # 37MIGIRKO
SA027192Sample # 17QKO
SA027193Sample # 18QKO
SA027194Sample # 16QKO
SA027195Sample # 15QKO
SA027196Sample # 14QKO
SA027197Sample # 13QKO
SA027198Sample # 25STZ
SA027199Sample # 26STZ
SA027200Sample # 24STZ
SA027201Sample # 27STZ
SA027202Sample # 20STZ
SA027203Sample # 23STZ
SA027204Sample # 21STZ
SA027205Sample # 19STZ
SA027206Sample # 22STZ
SA027207Sample # 30STZ FoxO TKO
SA027208Sample # 29STZ FoxO TKO
SA027209Sample # 28STZ FoxO TKO
Showing results 1 to 39 of 39


Collection ID:CO000536
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 ID:TR000556
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 amino acid and TCA cycle 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:SP000549
Sampleprep Summary:TCA concentrations in muscle tissue

Combined analysis:

Analysis ID AN000794
Analysis type MS
Chromatography type GC
Chromatography system Agilent 7890B
Column Agilent HP5-MS (30m × 0.25mm, 0.25 um)
MS Type EI
MS instrument type Single quadrupole
MS instrument name Agilent 5977
Units nmol/mg


Chromatography ID:CH000570
Instrument Name:Agilent 7890B
Column Name:Agilent HP5-MS (30m × 0.25mm, 0.25 um)
Chromatography Type:GC


MS ID:MS000701
Analysis ID:AN000794
Instrument Name:Agilent 5977
Instrument Type:Single quadrupole
MS Type:EI