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

Abstract

The 37 amino acid hormone Amylin is co‐secreted with insulin from β cells in the pancreas. In pre‐diabetic and obese humans, chronic amylin hyper‐secretion parallels the course of disease and is involved in the pathophysiology of beta cell destruction in the pancreas. 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 non‐targeted GC‐MS 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 t‐test (p<0.05) compared to wildtype control hearts (0.1–34.3 fold different, N=8/group). Similarly, we identified 30 metabolites significantly different in the HIP brain by t‐test (p<0.05) compared to wildtype control brains (0.2–25.2 fold different (N=~10/group). HIP livers had 58 metabolites significantly altered by t‐test (p<0.05) compared to wildtype livers (0.01–99.4 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. Phenylalanine metabolism and aminoacyl‐tRNA biosynthesis were specifically decreased 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 up‐regulator 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 multi‐system level beyond the effects on glucose metabolism.Support or Funding InformationThis 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 F.D.) and the Leducq Foundation (to M.W.).