A Reevaluation of the Role of the Unfolded Protein Response in Islet Dysfunction: Maladaptation or a Failure to Adapt?

Endoplasmic reticulum (ER) stress caused by perturbations in ER homeostasis activates an adaptive response termed the unfolded protein response (UPR) whose function is to resolve ER stress. If unsuccessful, the UPR initiates a proapoptotic program to eliminate the malfunctioning cells from the organism. It is the activation of this proapoptotic UPR in pancreatic beta-cells that has been implicated in the onset of type 2 diabetes and thus, in this context, is considered a maladaptive response. However, there is growing evidence that beta-cell death in type 2 diabetes may not be caused by a maladaptive UPR but by the inhibition of the adaptive UPR. In this review, we discuss the evidence for a role of the UPR in beta-cell dysfunction and death in the development of type 2 diabetes and ask the following question: Is beta-cell dysfunction the result of a maladaptive UPR or a failure of the UPR to adequately adapt? The answer to this question is critically important in defining potential therapeutic strategies for the treatment and prevention of type 2 diabetes. In addition, we discuss the potential role of the adaptive UPR in staving off type 2 diabetes by enhancing beta-cell mass and function in response to insulin resistance.