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

Amro Ilaiwy, Miao Liu, Traci L. Parry, James R. Bain, Christopher B. Newgard, Jonathan C. Schisler, Michael J. Muehlbauer, Florin Despa, Monte S. Willis

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Introduction: 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. Objectives: Identify systemic mechanisms/markers by which human amylin associated with cardiac and brain defects might be identified. Methods: 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). Results: 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. Conclusion: 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.

Original languageEnglish (US)
Article number95
JournalMetabolomics
Volume12
Issue number5
DOIs
StatePublished - May 1 2016
Externally publishedYes

Fingerprint

Islet Amyloid Polypeptide
Cell signaling
Biosynthesis
Protein Biosynthesis
Liver
Rats
Phenylalanine
Brain
Hot isostatic pressing
Plasmas
Proteins
Tyrosine
Brain Chemistry
Amino Acids
Tissue
Metabolomics
Alanine
Cell death
Serine
Epinephrine

Keywords

  • Amylin
  • Cardiomyopathy
  • Diabetes
  • Metabolomics
  • Neurodegenerative disease
  • Proteotoxicity

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Ilaiwy, Amro; Liu, Miao; Parry, Traci L.; Bain, James R.; Newgard, Christopher B.; Schisler, Jonathan C.; Muehlbauer, Michael J.; Despa, Florin; Willis, Monte S.

In: Metabolomics, Vol. 12, No. 5, 95, 01.05.2016.

Research output: Contribution to journalArticle

Ilaiwy, Amro ; Liu, Miao ; Parry, Traci L. ; Bain, James R. ; Newgard, Christopher B. ; Schisler, Jonathan C. ; Muehlbauer, Michael J. ; Despa, Florin ; Willis, Monte S. / 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. In: Metabolomics. 2016 ; Vol. 12, No. 5.
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abstract = "Introduction: 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. Objectives: Identify systemic mechanisms/markers by which human amylin associated with cardiac and brain defects might be identified. Methods: 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). Results: 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. Conclusion: 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.",
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T1 - 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

AU - Ilaiwy, Amro

AU - Liu, Miao

AU - Parry, Traci L.

AU - Bain, James R.

AU - Newgard, Christopher B.

AU - Schisler, Jonathan C.

AU - Muehlbauer, Michael J.

AU - Despa, Florin

AU - Willis, Monte S.

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N2 - Introduction: 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. Objectives: Identify systemic mechanisms/markers by which human amylin associated with cardiac and brain defects might be identified. Methods: 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). Results: 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. Conclusion: 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.

AB - Introduction: 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. Objectives: Identify systemic mechanisms/markers by which human amylin associated with cardiac and brain defects might be identified. Methods: 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). Results: 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. Conclusion: 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.

KW - Amylin

KW - Cardiomyopathy

KW - Diabetes

KW - Metabolomics

KW - Neurodegenerative disease

KW - Proteotoxicity

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