The Fibroblasts Response to Endoplasmic Reticulum Stress (FRES) Predicts the Onset of Diabetes: Towards a Functional Assay for Diabetes Risk Assessment

Presentation Number: SUN 577
Date of Presentation: April 2nd, 2017

Hippokratis Kiaris*1 and Amanda Havighorst2
1University of South Carolina, Columbia, SC, 2Univeersity of South Carolina, Columbia, SC

Abstract

The accumulation of misfolded proteins induces conditions that are toxic to the cells and have been designated as stress of the endoplasmic reticulum (ER). The cells in order to resolve ER stress initiate a biochemical response that aims to resolve tissue homeostasis, involves chaperone production and attenuation of protein translation and has been termed the unfolded protein response (UPR). During advanced or prolonged ER stress the cells initiate a pro-apoptotic cascade that ultimately results in tissue and organ dysfunction. Unequivocal evidence show that deregulation of the UPR occurs during aging and indeed is causatively linked to the onset of various aging-associated pathologies such as diabetes and neurodegenerative diseases. Despite though that such clear association exists, this fundamental knowledge has not been leveraged in the clinical practice. We hypothesized that the intensity of the UPR in cultured primary cells from younger subjects may bear considerable predictive value for the onset of ER stress-associated pathologies such as diabetes. A potential methodological limitation in testing this hypothesis in experimental animals such as the conventional laboratory mice (Mus) is related to their inbred nature that restricts their informative value in testing the consequences of endogenous heterogeneity of naturally existing populations. In order to overcome this limitation we utilized animals of the genus Peromyscus (P. maniculatus), the common deer mice that are maintained as outbred stocks in the facilities of the Peromyscus Genetic Stock Center of the University of South Carolina. A series of results we have accumulated show that primary fibroblast cultures from these animals show high intra-species variability in their response to ER stress that accurately predicts the individual animals’ sensitivity to diabetes induced by high fat/sucrose diet. Specifically, by assessing primary fibroblasts’ response to ER stress (FRES) we found that animals exhibiting intense UPR are more resistance to subsequent diabetes induction than animals initiating a moderate or low response to ER stress in cultured fibroblasts. Among the various chaperones evaluated calnexin and GRP94 exhibited increased predictive value in FRES. It is likely that this is related to the fact that abundant chaperone expression protects from diabetes by promoting maintenance of cellular homeostasis during the earlier stages of metabolic stress. Besides integrating the endogenous capacity for the UPR to diabetes susceptibility it is conceivable that optimization of this methodology in terms of chaperones assessed, fibroblast culture conditions and origin of cells subjected to this analysis may set the basis for the development of a novel functional bioassay assessing the individuals’ sensitivity to diabetes. Finally these results may be relevant to various ER stress-related pathologies.

 

Nothing to Disclose: HK, AH