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
- 183 Downloads
Chronic hypersecretion of the 37 amino acid amylin is common in type 2 diabetics (T2D). Recent studies implicate human amylin aggregates cause proteotoxicity (cell death induced by misfolded proteins) in both the brain and the heart.
Identify systemic mechanisms/markers by which human amylin associated with cardiac and brain defects might be identified.
We investigated the metabolic consequences of amyloidogenic and cytotoxic amylin oligomers in heart, brain, liver, and plasma using non-targeted metabolomics analysis in a rat model expressing pancreatic human amylin (HIP model).
Four metabolites were significantly different in three or more of the four compartments (heart, brain, liver, and plasma) in HIP rats. When compared to a T2D rat model, HIP hearts uniquely had significant DECREASES in five amino acids (lysine, alanine, tyrosine, phenylalanine, serine), with phenylalanine decreased across all four tissues investigated, including plasma. In contrast, significantly INCREASED circulating phenylalanine is reported in diabetics in multiple recent studies.
DECREASED phenylalanine may serve as a unique marker of cardiac and brain dysfunction due to hyperamylinemia that can be differentiated from alterations in T2D in the plasma. While the deficiency in phenylalanine was seen across tissues including plasma and could be monitored, reduced tyrosine was seen only in the brain. The 50 % reduction in phenylalanine and tyrosine in HIP brains is significant given their role in supporting brain chemistry as a precursor for catecholamines (dopamine, norepinephrine, epinephrine), which may contribute to the increased morbidity and mortality in diabetics at a multi-system level beyond the effects on glucose metabolism.
KeywordsAmylin Metabolomics Neurodegenerative disease Cardiomyopathy Diabetes Proteotoxicity
Amyloid beta protein precursor
Rat model expressing pancreatic human amylin
Human islet amyloid polypeptide
Principal component analysis
Partial least squares discriminant analysis
Variable importance in projection
This work was supported by the National Institutes of Health (R01HL104129 to M.W.; R01HL118474 to F.D.), a Jefferson-Pilot Corporation Fellowship (to M.W.), National Science Foundation (CBET 1357600 to F.D.), Alzheimer’s Association (VMF-15-363458 to FD) and the Leducq Foundation (to M.W.).
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- Kouzu, H., et al. (2015). Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart. Journal of Molecular and Cellular Cardiology, 80, 136–145. doi: 10.1016/j.yjmcc.2015.01.004.CrossRefPubMedGoogle Scholar
- Lambert, R., Srodulski, S., Peng, X., Margulies, K. B., Despa, F., & Despa, S. (2015). Intracellular Na+ concentration ([Na+]i) is elevated in diabetic hearts due to enhanced Na+—Glucose cotransport. Journal of the American Heart Association, 4, e002183. doi: 10.1161/JAHA.115.002183.CrossRefPubMedPubMedCentralGoogle Scholar
- Pasini, E., Aquilani, R., Corsetti, G., & Dioguardi, F. S. (2014). Biomarkers to identify protein metabolism impairment in chronic/acute diseases. Journal of Molecular Biomarkers & Diagnosis, 5, 176–179.Google Scholar
- Pietzsch, J., Bergmann, R., & Kopprasch, S. (2004). Analysis of non-protein amino acids as specific markers of low density lipoprotein apolipoprotein B-100 oxidation in human atherosclerotic lesions: The use of N(O)-ethoxycarbonyl trifluoroethyl ester derivatives and GC-MS. Spectroscopy, 18, 177–183.CrossRefGoogle Scholar
- Tillin, T., et al. (2015). Diabetes risk and amino acid profiles: Cross-sectional and prospective analyses of ethnicity, amino acids and diabetes in a South Asian and European cohort from the SABRE (Southall And Brent REvisited) Study. Diabetologia, 58, 968–979. doi: 10.1007/s00125-015-3517-8.CrossRefPubMedPubMedCentralGoogle Scholar