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Review
. 2009 Dec;9(6):763-70.
doi: 10.1016/j.coph.2009.07.003. Epub 2009 Aug 6.

Endoplasmic reticulum stress in beta-cells and development of diabetes

Sonya G Fonseca  1 , Mark Burcin, Jesper Gromada, Fumihiko Urano
Affiliations
Review

Endoplasmic reticulum stress in beta-cells and development of diabetes

Sonya G Fonseca et al. Curr Opin Pharmacol. 2009 Dec.

Abstract

The endoplasmic reticulum (ER) is a cellular compartment responsible for multiple important cellular functions including the biosynthesis and folding of newly synthesized proteins destined for secretion, such as insulin. A myriad of pathological and physiological factors perturb ER function and cause dysregulation of ER homeostasis, leading to ER stress. ER stress elicits a signaling cascade to mitigate stress, the unfolded protein response (UPR). As long as the UPR can relieve stress, cells can produce the proper amount of proteins and maintain ER homeostasis. If the UPR, however, fails to maintain ER homeostasis, cells will undergo apoptosis. Activation of the UPR is critical to the survival of insulin-producing pancreatic beta-cells with high secretory protein production. Any disruption of ER homeostasis in beta-cells can lead to cell death and contribute to the pathogenesis of diabetes. There are several models of ER-stress-mediated diabetes. In this review, we outline the underlying molecular mechanisms of ER-stress-mediated beta-cell dysfunction and death during the progression of diabetes.

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Figures

Figure 1
Figure 1. ER stress
There are several causes of ER stress, including protein overload. ER stress activates the Unfolded Protein Response (UPR), which has two outputs: 1) homeostatic (blue) and 2) apoptotic (red). The homeostatic output leads to resolution of ER stress, while the apoptotic output, resulting from an insufficient UPR, favors the activation of pro-apoptotic over anti-apoptotic UPR
Figure 2
Figure 2. ER stress signaling networks
There are three main regulators of the UPR: IRE1, PERK, and ATF6. Each of these transducers activate downstream targets which in turn mitigate stress.
Figure 3
Figure 3. The role of ER stress in type 1 diabetes
Exposure of β-cell to inflammatory cytokines leads to nitric oxide production, causing ER stress and activation of the UPR pro-apoptotic factor, CHOP.
Figure 4
Figure 4. Type 2 diabetes and ER stress
There is a feedback loop between insulin resistance, ER stress, and beta cell dysfunction/death. Insulin resistance leads to β-cell exhaustion due to high demand for insulin biosynthesis. This protein overload causes ER stress and activation of pro-apoptotic UPR components. One of these, JNK phosphorylation, indirectly leads to further insulin resistance.
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