Endoplasmic reticulum stress, pancreatic β-cell degeneration, and diabetes

Abstract

Overwhelming of protein folding in the endoplasmic reticulum (ER)--referred to as "ER stress"--activates a set of intracellular signaling pathways termed the unfolded protein response (UPR). Beneficial outputs of the UPR promote adaptation in cells experiencing manageably low levels of ER stress. However, if ER stress reaches critically high levels, the UPR uses destructive outputs to trigger programmed cell death. Genetic mutations in various UPR components cause inherited syndromes of diabetes mellitus in both rodents and humans, implicating the UPR in the proper functioning and survival of pancreatic islet β cells. Markers of chronically elevated ER stress, terminal UPR signaling, and apoptosis are evident in β cells in these rare disorders; these markers are similarly present in islets of human patients with common forms of diabetes. These findings promise to enhance our molecular understanding of human diabetes significantly and may lead to new and effective therapies.

Figure 1.

Proximal sensors of endoplasmic reticulum (ER) stress—IRE1α, ATF6, PERK. Combinatorial outputs from these three ER transmembrane sensors are integrated over time to determine cell fate outcomes under ER stress.

Figure 2.

Divergent cell fates result from both the magnitude and duration of ER stress signaling. Adaptive UPR outputs can contain low levels of ER stress by reducing the concentration of unfolded proteins in the ER. However, continued activation of the UPR sensors indicates the inability to reestablish homeostasis. Depending on the time and severity of stress experienced by the cell, thresholds separating distinct cell states are crossed. If ER stress is unrelieved, UPR signaling morphs to terminal states, promoting cell dedifferentiation and inflammation and eventually triggering apoptosis.

Figure 3.

UPR players and effects of gene mutations on β-cell degeneration and diabetes. Early adaptive events are shown in green, and subsequent pro-apoptotic events are shown in red. A point of no return is crossed when mitochondria are permeabilized by the terminal gatekeepers Bax and Bak to liberate cytochrome “c”—mitochondrial outer membrane permeabilization (MOMP). Gene mutations promoting diabetes (red asterisks) remove adaptive players in the UPR; downstream removal of pro-apoptotic CHOP is protective (green asterisk).

Figure 4.

Conjectural scheme for a central role of ER stress and divergent UPR signaling in human diabetes (both types 1 and 2). See text for details.

Figure 5.

Molecular details of the UPR homeostatic–apoptotic switch. (A) adaptive UPR events reduce protein load acutely through reversible translational attenuation and mRNA decay (mediated by PERK and IRE1α, respectively). Synthesis of gene products through de novo transcription/translation enhances ER protein-folding functions and ER-associated degradation (ERAD). (B) The terminal UPR occurs when ER unfolded proteins cannot be sufficiently reduced, and therefore UPR sensor signaling is not quelled. In that instance, destructive UPR outputs occur through continued IRE1α mRNA endonucleolytic decay and continued translational blocks through PERK. Downstream amplification of the terminal UPR occurs through JNK and CHOP impinging on Bax and Bak to promote MOMP.