Pathological ER stress in β cells

Diabetes mellitus is a global chronic disease, major cause of morbidity and mortality, and significantly decreases both quality of life and life expectancy. The reduction in functional β cell mass due to increased β cell apoptosis and decreased β cell proliferation is a crucial factor in the pathogenesis of diabetes mellitus. Mounting clinical and experimental research findings suggest that endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) play fundamental roles in the diminution of functional β cell mass during the prediabetic phase. In this chapter, the physiological purpose of ER stress in the pancreatic β cell is reviewed and the pathological features of chronic ER stress and unwarranted UPR activation in the progression to β cell dysfunction and diabetes progression are described. The molecular pathways activated during the transition from physiological to pathological UPR and proapoptotic signaling in a variety of environmental and genetic diabetic conditions are addressed. In addition, therapeutic approaches to modulate the level of β cell ER stress and mitigate UPR activation are discussed. Finally, we propose that the identification of clinical biomarkers for detection of overt ER stress and UPR activation would herald ER stress and the UPR as viable targets in the prevention of diabetes progression or treatment of established diabetes.