Summary of Study ST000349

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 PR000279. The data can be accessed directly via it's Project DOI: 10.21228/M8VC8G This work is supported by NIH grant, U2C- DK119886.

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Study IDST000349
Study TitleMetabolomic analysis on samples from rats expressing human amylin (hepatic tissue).
Study SummaryHuman amylin proteotoxicity impairs protein biosynthesis, and alters major cellular signaling pathways in the heart, brain and liver of humanized diabetic rat model in vivo. The 37 amino acid hormone Amylin is co­secreted with insulin from ß cells in the pancreas. In pre­diabetic and obese humans, chronic amylin hypersecretion parallels the course of disease and is involved in the pathophysiology of beta cell destruction in the pancreas. Recent studies in rats with transgenic expression of beta cell amylin (HIP), we have discovered that human amylin is prone to misfolding and has proteotoxic effects in vivo, resulting in the induction of cell death paralleling the pathophysiology of neurodegenerative disease. These misfolded proteotoxic amylin proteins are found to migrate to both the brain and heart to induce both neurologic deficits and cardiac dysfunction. In the present study, we use non­targeted GC­MS metabolomics analysis to investigate the metabolic consequences of amyloidogenic and cytotoxic amylin oligomers and diabetes in HIP heart, brain, liver, and plasma compared to wild type controls at 1 year of age. We identified that HIP hearts had 45 significantly altered metabolites by t­test (p<0.05) compared to wildtype control hearts (0.1­34.3 fold different,N=8/group). Similarly, we identified 30 metabolites significantly different in the HIP brain by t­test (p<0.05) compared to wildtype control brains (0.2­25.2 fold different (N=~10/group). HIP livers had 58 metabolites significantly altered by t­test (p<0.05) compared to wildtype livers (0.01­99.4 fold different,N=~10/group. Pathway enrichment analysis identified a systemic alteration in protein biosynthesis in the heart and brain of HIP rats compared to wild type controls. Alterations in phenylalanine metabolism and aminoacyl­tRNA biosynthesis were specifically affected in heart and plasma. Tyrosine metabolism is affected across organs, including decreased tyrosine (heart), phenylalanine (heart, liver, brain), and increased fumarate (heart, liver, brain). Increased urea and urea cycle were identified in heart and liver. As protein degradation is a major up­regulator of the urea cycle in human rat diabetic models, these findings suggest a broader connection between amylin, diabetes, protein catabolism, and effects on the urea cycle, which may contribute to the increased morbidity and mortality in diabetics at a multi­system level beyond the effects on glucose metabolism.
Institute
Duke University
DepartmentSarah W. Stedman Nutrition and Metabolism Center
LaboratoryMetabolomics lab
Last NameIlaiwy
First NameAmro
Address111 Mason Farm road, Chapel Hill, North Carolina, 27599-7126, USA
Emailamroilaiwy@gmail.com, monte_willis@med.unc.edu
Phone210-596-0171
Submit Date2016-02-18
Study CommentsHepatic tissue
Raw Data File Type(s)d
Analysis Type DetailGC-MS
Release Date2016-03-03
Release Version1
Amro Ilaiwy Amro Ilaiwy
https://dx.doi.org/10.21228/M8VC8G
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Combined analysis:

Analysis ID AN000565
Analysis type MS
Chromatography type GC
Chromatography system Agilent 6890N
Column Agilent DB5-MS (15m × 0.25mm, 0.25um)
MS Type EI
MS instrument type Single quadrupole
MS instrument name Agilent 5975
Ion Mode POSITIVE
Units Peak values (Log transformed)

MS:

MS ID:MS000501
Analysis ID:AN000565
Instrument Name:Agilent 5975
Instrument Type:Single quadrupole
MS Type:EI
Ion Mode:POSITIVE
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