1. Glycated Insulin Exacerbates the Cytotoxicity of Human Islet Amyloid Polypeptides: a Vicious Cycle in Type 2 Diabetes
- Author
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Biao Cheng, Yuchen Chen, Kun Huang, Ling Zheng, Yang Li, Liang Ma, Chen Yang, Cheng Cheng, and Lianqi Huang
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Amyloid ,Cell Survival ,Protein Conformation ,medicine.medical_treatment ,Type 2 diabetes ,01 natural sciences ,Biochemistry ,Cell Line ,Protein Aggregates ,03 medical and health sciences ,chemistry.chemical_compound ,Glycation ,Internal medicine ,medicine ,Humans ,Insulin ,Amino Acid Sequence ,geography ,geography.geographical_feature_category ,010405 organic chemistry ,Cell Membrane ,Monosaccharides ,Methylglyoxal ,Type 2 Diabetes Mellitus ,Fructose ,General Medicine ,medicine.disease ,Islet ,Islet Amyloid Polypeptide ,0104 chemical sciences ,Molecular Weight ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,chemistry ,Molecular Medicine - Abstract
The aggregation of human islet amyloid polypeptide (hIAPP) is one of the triggering factors of type 2 diabetes mellitus (T2DM). hIAPP is cosynthesized, costored, and cosecreted with insulin in pancreatic β-cells, and insulin inhibits hIAPP aggregation. In T2DM patients, long-term hyperglycemia causes glycation of near 10% of total insulin. The glycation not only modifies insulin but also cross-links insulin into oligomers. However, the effect of glycated human insulin on hIAPP aggregation is unknown. In this study, four physiologically relevant monosaccharides, methylglyoxal, glucose, fructose, and ribose were used to glycate human insulin and two C-terminus truncated insulin analogues. Glycated insulin monomers or low molecular weight oligomers such as dimers significantly exacerbated the cytotoxicity of hIAPP. Notably, glycation-induced cross-linking of insulin inhibited the aggregation, membrane disruption, and cytotoxicity of hIAPP, which was corroborated by a control study using EGS-induced cross-linking of insulin or lysozyme. Removal of B29
- Published
- 2019
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