Endoplasmic reticulum stress and pancreatic β-cell death

Abstract

In pancreatic β-cells, the endoplasmic reticulum (ER) is an important cellular compartment for insulin biosynthesis, which accounts for half of the total protein production in these cells. Protein flux through the ER must be carefully monitored to prevent dysregulation of ER homeostasis and stress. ER stress elicits a signaling cascade known as the unfolded protein response (UPR), which influences both life and death decisions in cells. β-cell loss is a pathological component of both type 1 and type 2 diabetes, and recent findings suggest that ER stress is involved. In this review, we address the transition from the physiological ER stress response to the pathological response, and explore the mechanisms of ER stress-mediated β-cell loss during the progression of diabetes.

Figure 1. The ER stress signaling network

There are three main regulators of the unfolded protein response (UPR): IRE1, PERK, and ATF6. Each of these stress transducers activates downstream targets which mitigate ER stress.

Figure 2. Causes of ER stress in the β cell

There are several causes of ER stress in the β cell ranging from physiological stress, such as high glucose levels which follow meal intake, to pathological causes such as the expression of mutant insulin protein.

Figure 3. The balance between death and survival

The UPR acts as a binary switch between cell survival and death decisions when ER stress is present in the cell. Mild stress induces a regulated UPR, in which survival effectors outweigh death effectors, leading to adaption and survival of the cell. When severe stress is present, on the other hand, the UPR becomes hyperactivated, a situation in which the death effectors outweigh survival effectors, ultimately leading to apoptosis.

Figure 4. ER stress: The tipping point between β cell death and dysfunction

ER stress mediated β cell dysfunction plays an important role in the transition from a pre-diabetic state to an overt diabetic state. In the pre-diabetic state some β cell loss has already occurred and residual β cells have to work harder to keep up with insulin output. This leads to additional ER stress, causing β cell dysfunction. This dysfunction is the tipping point leading to additional cell loss and the progression to a diabetic state.