Summary of Study ST000521
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.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Study ID | ST000521 |
| Study Title | Measuring NEFA concentrations in insulin resistant and insulin deficient mouse tissue models |
| Study Summary | To compare models of insulin resistance to a model of loss of insulin signaling, we will also determine nonesterified fatty acid metabolites in muscle, using control and streptozotocin (STZ) treated mice as a model of insulin deficient diabetes. |
| Institute | Mayo Clinic |
| Last Name | O'Neill |
| First Name | Brian |
| Address | One Joslin Place, Boston, MA 02215 |
| brian.o'neill@joslin.harvard.edu | |
| Phone | 617-309-2400 |
| Submit Date | 2016-12-07 |
| Analysis Type Detail | LC-MS |
| Release Date | 2018-12-11 |
| Release Version | 1 |
Select appropriate tab below to view additional metadata details:
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: | SU000543 |
| 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 |
|---|---|---|
| SA027249 | ms5691-4 | control |
| SA027250 | ms5691-38 | control |
| SA027251 | ms5691-2 | control |
| SA027252 | ms5691-36 | control |
| SA027253 | ms5691-3 | control |
| SA027254 | ms5691-6 | control |
| SA027255 | ms5691-31 | control |
| SA027256 | ms5691-1 | control |
| SA027257 | ms5691-34 | control |
| SA027258 | ms5691-5 | control |
| SA027220 | ms5691-8 | Fox0 TKO |
| SA027221 | ms5691-9 | Fox0 TKO |
| SA027222 | ms5691-12 | Fox0 TKO |
| SA027223 | ms5691-7 | Fox0 TKO |
| SA027224 | ms5691-10 | Fox0 TKO |
| SA027225 | ms5691-11 | Fox0 TKO |
| SA027226 | ms5691-33 | MIGIRKO |
| SA027227 | ms5691-39 | MIGIRKO |
| SA027228 | ms5691-32 | MIGIRKO |
| SA027229 | ms5691-35 | MIGIRKO |
| SA027230 | ms5691-37 | MIGIRKO |
| SA027231 | ms5691-17 | QKO |
| SA027232 | ms5691-18 | QKO |
| SA027233 | ms5691-16 | QKO |
| SA027234 | ms5691-15 | QKO |
| SA027235 | ms5691-14 | QKO |
| SA027236 | ms5691-13 | QKO |
| SA027237 | ms5691-25 | STZ |
| SA027238 | ms5691-26 | STZ |
| SA027239 | ms5691-24 | STZ |
| SA027240 | ms5691-27 | STZ |
| SA027241 | ms5691-20 | STZ |
| SA027242 | ms5691-23 | STZ |
| SA027243 | ms5691-21 | STZ |
| SA027244 | ms5691-19 | STZ |
| SA027245 | ms5691-22 | STZ |
| SA027246 | ms5691-30 | STZ FoxO TKO |
| SA027247 | ms5691-29 | STZ FoxO TKO |
| SA027248 | ms5691-28 | STZ FoxO TKO |
| Showing results 1 to 39 of 39 |
Collection:
| Collection ID: | CO000537 |
| 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: | TR000557 |
| 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: | SP000550 |
| Sampleprep Summary: | NEFA concentrations in muscle tissue |
Combined analysis:
| Analysis ID | AN000795 |
|---|---|
| Analysis type | MS |
| Chromatography type | Reversed phase |
| Chromatography system | Agilent 1290 Infinity |
| Column | Waters Acquity BEH C18 (150 x 2.1mm,1.7um) |
| MS Type | ESI |
| MS instrument type | Triple quadrupole |
| MS instrument name | Agilent 6460 QQQ |
| Ion Mode | POSITIVE |
| Units | ug/mg tissue |
Chromatography:
| Chromatography ID: | CH000571 |
| Instrument Name: | Agilent 1290 Infinity |
| Column Name: | Waters Acquity BEH C18 (150 x 2.1mm,1.7um) |
| Chromatography Type: | Reversed phase |
MS:
| MS ID: | MS000702 |
| Analysis ID: | AN000795 |
| Instrument Name: | Agilent 6460 QQQ |
| Instrument Type: | Triple quadrupole |
| MS Type: | ESI |
| Ion Mode: | POSITIVE |
