Age-Dependent Modulation of the Unfolded Protein Response Is Beneficial for the Management of Diabetes in the Elderly

Presentation Number: SUN 594
Date of Presentation: April 2nd, 2017

Ioulia Chatzistamou*1, Chrysovalantou Mihailidou2 and Hippokratis Kiaris3
1University of South Carolina, School of Medicine, Columbia, SC, 2University of Athens, Athens, Greece, 3University of South Carolina, Columbia, SC

Abstract

The accumulation of misfolded and unfolded proteins results in the induction of endoplasmic reticulum (ER) stress that in turn triggers the unfolded protein response (UPR). The UPR at its initial stages is adaptive and aims to restore tissue homeostasis by stimulating chaperone production and by promoting translation attenuation while at subsequent stages becomes proapoptotic clearing the cells that have been subjected to unresolvable ER stress. Unequivocal evidence links the pathogenesis of diabetes with ER stress by a manner according to which the increased demands for insulin production subject beta cells to ER stress triggering pancreatic dysfunction. In addition, ER stress in the periphery has been linked to the acquisition of insulin resistance, also contributing to diabetes onset. Our laboratory showed that the cell cycle regulator p21 confers resistance to ER stress-associated death and is suppressed by the proapoptotic transcription factor CHOP (1). Thus, we hypothesized that chemical activation of p21 may be beneficial for diabetes management promoting beta cell survival especially under conditions at which ER stress is more intense (2). To test this hypothesis we subjected wild type, p21-deficient and CHOP-deficient animals to diabetes-induction protocols and evaluated disease development following administration of ciclopirox (CPX), an activator of p21 expression. Our results showed that CPX administration attenuated the development of diabetes by a manner that depended on both p21 and CHOP activity. These beneficial effects of CPX and the sensitivity to diet-induced diabetes were more pronounced in older animals (about 1 year old as compared to 2 months old) confirming and extending previous observations on the link between deregulated UPR and aging. Indeed, cultured islets from older animals, under glucotoxic conditions were more sensitive to ER stress than their younger counterparts in both terms of survival and UPR induction, while both these effects were alleviated by CPX. Noteworthy, despite its antidiabetic activity in animals, CPX inhibited insulin release in cultured islets suggesting that optimization of insulin production during the increased demands dictated by high glucose may suppress ER stress and therefore attenuate its harmful cytotoxic consequences. Collectively, our results suggest that pharmacological activation of p21 may be particularly useful for the management of diabetes, especially in the elderly.

 

Nothing to Disclose: IC, CM, HK