Evaluation of the impact of protein glycation on islet amyloid polypeptide (IAPP) cytotoxicity
Diabetes mellitus; Protein glycation; Islet amyloid polypeptide; Saccharomyces cerevisiae.
Diabetes mellitus has become a global epidemic, responsible for more than 1.6 million deaths recorded in 2021. Type 2 diabetes mellitus is associated with loss of pancreatic β-cell function and ineffective insulin action. Environmental and genetic factors have been linked to the occurrence of this disease. High glucose levels promote increased demand for insulin and islet amyloid polypeptide (IAPP) production. This high demand can overload protein production and promote an increase in the production of unfolded or misfolded molecules in the endoplasmic reticulum. Excessive misfolded proteins can trigger endoplasmic reticulum damage and widespread oxidative stress. High glucose availability also overloads the glycolytic pathway, leading to the formation of high levels of dihydroxyacetone, which results in higher levels of the reactive compound methylglyoxal. The accumulation of substrates for protein glycation reactions drives the formation of AGEs, and consequently, protein damage, accumulation, and aggregation events become more frequent. Given this context, this study aims to map the role of IAPP glycation in the cytotoxicity and aggregation of this polypeptide using a eukaryotic cell model using wild-type and GLO1 mutant Saccharomyces cerevisiae transformed to express the human form of IAPP.