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Delayed apoptosis allows islet β-cells to implement an autophagic mechanism to promote cell survival
Journal article   Open access   Peer reviewed

Delayed apoptosis allows islet β-cells to implement an autophagic mechanism to promote cell survival

Heather L Hayes, Brett S Peterson, Jonathan M Haldeman, Christopher B Newgard, Hans E Hohmeier and Samuel B Stephens
PloS one, Vol.12(2), pp.e0172567-e0172567
2017
DOI: 10.1371/journal.pone.0172567
PMCID: PMC5315295
PMID: 28212395
url
https://doi.org/10.1371/journal.pone.0172567View
Published (Version of record) Open Access

Abstract

Increased β-cell death coupled with the inability to replicate existing β-cells drives the decline in β-cell mass observed in the progression of both major forms of diabetes. Understanding endogenous mechanisms of islet cell survival could have considerable value for the development of novel strategies to limit β-cell loss and thereby promote β-cell recovery. Insulinoma cells have provided useful insight into β-cell death pathways but observations made in cell lines sometimes fail to translate to primary islets. Here, we report dramatic differences in the temporal regulation and engagement of the apoptotic program in primary rodent islets relative to the INS-1 derived 832/13 cell line. As expected, 832/13 cells rapidly induced cell stress markers in response to ER stress or DNA damage and were fully committed to apoptosis, resulting in >80% cell death within 24 h. In contrast, primary rat islets were largely refractory to cell death in response to ER stress and DNA damage, despite rapid induction of stress markers, such as XBP-1(s), CHOP, and PUMA. Gene expression profiling revealed a general suppression of pro-apoptotic machinery, such as Apaf-1 and caspase 3, and sustained levels of pro-survival factors, such as cIAP-1, cIAP-2, and XIAP, in rat islets. Furthermore, we observed sustained induction of autophagy following chronic ER stress and found that inhibition of autophagy rendered islet β-cells highly vulnerable to ER stress-induced cell death. We propose that islet β-cells dampen the apoptotic response to delay the onset of cell death, providing a temporal window in which autophagy can be activated to limit cellular damage and promote survival.
 Animals Apoptosis - physiology Apoptotic Protease-Activating Factor 1 Autophagy - physiology Caspase 3 - metabolism Cell Line Cell Survival - physiology Cells, Cultured Endoplasmic Reticulum Stress Glucose - metabolism Inhibitor of Apoptosis Proteins - metabolism Insulin - metabolism Insulin Secretion Insulinoma - pathology Islets of Langerhans - cytology Islets of Langerhans - physiology Pancreatic Neoplasms - pathology Rats

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