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 |
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Authors: | Amro Ilaiwy Miao Liu Traci L. Parry James R. Bain Christopher B. Newgard Jonathan C. Schisler Michael J. Muehlbauer Florin Despa Monte S. Willis |
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Affiliation: | 1.Faculty of Medicine,University of Damascus,Damascus,Syria;2.Department of Pharmacology and Nutritional Sciences,University of Kentucky,Lexington,USA;3.Department of Pharmacology,University of North Carolina,Chapel Hill,USA;4.McAllister Heart Institute,University of North Carolina,Chapel Hill,USA;5.Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute,Duke University Medical Center,Durham,USA;6.Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine,Duke University Medical Center,Durham,USA;7.Department of Pathology & Laboratory Medicine,University of North Carolina,Chapel Hill,USA |
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Abstract: | IntroductionChronic 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.ObjectivesIdentify systemic mechanisms/markers by which human amylin associated with cardiac and brain defects might be identified.MethodsWe 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).ResultsFour 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.ConclusionDECREASED 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. |
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