Chaperones Ameliorate Beta Cell Dysfunction Associated with Human Islet Amyloid Polypeptide OverexpressionReport as inadecuate




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In type 2 diabetes, beta-cell dysfunction is thought to be due to several causes, one being the formation of toxic protein aggregates called islet amyloid, formed by accumulations of misfolded human islet amyloid polypeptide hIAPP. The process of hIAPP misfolding and aggregation is one of the factors that may activate the unfolded protein response UPR, perturbing endoplasmic reticulum ER homeostasis. Molecular chaperones have been described to be important in regulating ER response to ER stress. In the present work, we evaluate the role of chaperones in a stressed cellular model of hIAPP overexpression. A rat pancreatic beta-cell line expressing hIAPP exposed to thapsigargin or treated with high glucose and palmitic acid, both of which are known ER stress inducers, showed an increase in ER stress genes when compared to INS1E cells expressing rat IAPP or INS1E control cells. Treatment with molecular chaperone glucose-regulated protein 78 kDa GRP78, also known as BiP or protein disulfite isomerase PDI, and chemical chaperones taurine-conjugated ursodeoxycholic acid TUDCA or 4-phenylbutyrate PBA, alleviated ER stress and increased insulin secretion in hIAPP-expressing cells. Our results suggest that the overexpression of hIAPP induces a stronger response of ER stress markers. Moreover, endogenous and chemical chaperones are able to ameliorate induced ER stress and increase insulin secretion, suggesting that improving chaperone capacity can play an important role in improving beta-cell function in type 2 diabetes.



Author: Lisa Cadavez , Joel Montane , Gema Alcarraz-Vizán, Montse Visa, Laia Vidal-Fàbrega, Joan-Marc Servitja, Anna Novials

Source: http://plos.srce.hr/



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