The Unfolded Protein Response: A Pathway That Links Insulin Demand with β-Cell Failure and Diabetes

Abstract

The endoplasmic reticulum (ER) is the entry site into the secretory pathway for newly synthesized proteins destined for the cell surface or released into the extracellular milieu. The study of protein folding and trafficking within the ER is an extremely active area of research that has provided novel insights into many disease processes. Cells have evolved mechanisms to modulate the capacity and quality of the ER protein-folding machinery to prevent the accumulation of unfolded or misfolded proteins. These signaling pathways are collectively termed the unfolded protein response (UPR). The UPR sensors signal a transcriptional response to expand the ER folding capacity, increase degradation of malfolded proteins, and limit the rate of mRNA translation to reduce the client protein load. Recent genetic and biochemical evidence in both humans and mice supports a requirement for the UPR to preserve ER homeostasis and prevent the beta-cell failure that may be fundamental in the etiology of diabetes. Chronic or overwhelming ER stress stimuli associated with metabolic syndrome can disrupt protein folding in the ER, reduce insulin secretion, invoke oxidative stress, and activate cell death pathways. Therapeutic interventions to prevent polypeptide-misfolding, oxidative damage, and/or UPR-induced cell death have the potential to improve beta-cell function and/or survival in the treatment of diabetes.

Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

“…The life-long stimulus for the beta cell to secrete large amounts of insulin for maintaining euglycaemia is associated with an increased protein-folding burden in the ER. This may lead to accumulation of misfolded proteins, most importantly proinsulin, resulting in ER stress [54,55]. This, together with oxidative stress elicited by excessive mitochondrial generation of reactive oxygen species, leads to beta cell dysfunction [56,57].…”

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

“…ER stress is induced under conditions such as overload of protein synthesis/processing, accumulation of structurally abnormal proteins, disturbance of post-translational modification and ER calcium homeostasis abnormalities. When ER stress develops, cells respond by unfolded protein response (UPR), facilitating protein folding via the induction of chaperone proteins, attenuation of translations, as well as degradation of misfolded proteins, a process called ERassociated degradation [23][24][25]. If the stress is severe, apoptosis is induced.…”

HIV Protease Inhibitors Induce Endoplasmic Reticulum Stress and Disrupt Barrier Integrity in Intestinal Epithelial Cells

“…11,23 Numerous studies have suggested that ER stress signaling pathways are implicated in various diseases, including atherosclerosis, metabolic disease, liver disease, and inflammatory bowel disease. 6,[24][25][26][27] However, whether HIV PI-induced apoptosis is also associated with the activation of the ER stress response in IECs has not been explored. Herein, we describe our investigation of whether HIV PI-induced activation of the ER stress response is involved in the induction of apoptosis and disruption of normal intestinal barrier function both in in vitro cell culture models and in in vivo mice models.…”