Summary of Study ST000350

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.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

Study ID	ST000350
Study Title	Metabolomic analysis on samples from rats expressing human amylin (plasma).
Study Summary	Human 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
Department	Sarah W. Stedman Nutrition and Metabolism Center
Laboratory	Metabolomics lab
Last Name	Ilaiwy
First Name	Amro
Address	111 Mason Farm road, Chapel Hill, North Carolina, 27599-7126, USA
Email	amroilaiwy@gmail.com, monte_willis@med.unc.edu
Phone	210-596-0171
Submit Date	2016-02-18
Study Comments	Blood plasma
Raw Data File Type(s)	d
Analysis Type Detail	GC-MS
Release Date	2016-03-03
Release Version	1

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Factors:

Subject type: Animal; Subject species: Rattus norvegicus (Factor headings shown in green)

mb_sample_id	local_sample_id	Genotype
SA015366	17	HIP
SA015367	25	HIP
SA015368	7	HIP
SA015369	26	HIP
SA015370	SRT14	HIP
SA015371	24	HIP
SA015372	43	HIP
SA015373	11	HIP
SA015374	36	HIP
SA015375	31	HIP
SA015376	2RT14	WT
SA015377	2RT13	WT
SA015378	SD2	WT
SA015379	41	WT
SA015380	2RT15	WT
SA015381	3RT25	WT
SA015382	SD1	WT
SA015383	STRL2	WT
SA015384	SD4	WT
SA015385	3RT39	WT

Showing results 1 to 20 of 20

Showing results 1 to 20 of 20