Diabetes as a disease of endoplasmic reticulum stress

Abstract

Endoplasmic reticulum (ER) stress is an integral part of life for all professional secretory cells, but it has been studied to greatest depth in the pancreatic β-cell. This reflects both the crucial role played by ER stress in the pathogenesis of diabetes and also the exquisite vulnerability of these cells to ER dysfunction. The adaptive cellular response to ER stress, the unfolded protein response, comprises mechanisms to both regulate new protein translation and a transcriptional program to allow adaptation to the stress. The core of this response is a triad of stress-sensing proteins: protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6. All three regulate portions of the transcriptional unfolded protein response, while PERK also attenuates protein synthesis during ER stress and IRE1 interacts directly with the c-Jun amino-terminal kinase stress kinase pathway. In this review we shall discuss these processes in detail, with emphasis given to their impact on diabetes and how recent findings indicate that ER stress may be responsible for the loss of β-cell mass in the disease.

Crude extract of Ceriporia lacerata has a protective effect on dexamethasone-induced cytotoxicity in INS-1 cells via the modulation of PI3K/PKB activity

“…Pancreatic β-cells have a well-developed ER and express high amounts of chaperones and protein disulfide isomerases to meet the high demand for translation of many proteins. There is strong evidence that excessive or severe ER stress in β-cells is linked to the development of diabetes (41) and also diabetes is a disease of ER stress (42). In general, cells undergoing ER stress display many cellular alterations, including upregulation of molecular chaperones (GRP78) (43), reduction of p90ATF-6 (44), and phosphorylation of eIF-2α (45).…”

Type 2 Diabetes Mellitus (T2DM): Biological Overview from Pathways to Organelles and its Translation toward a Torpid Wound Healing Process

“…The relationship between ER stress and diabetes derived from 1980's investigations showing that ER function inducing compounds can normalize glucose-insulin homeostasis and eliminate insulin resistance and T2DM. Today it is acknowledged that ER stress plays a central role in peripheral insulin resistance and T2DM at the molecular, cellular, and organism levels [68]. The well-known diabetic glucolipotoxicity is a metabolic stress that induces ER stress and the unfolded protein response (UPR), which, up to a limit, can afford erroneous protein synthesis reduction and an increase in chaperones manufacture, required for proper protein folding.…”

Unravelling the story of protein misfolding in diabetes mellitus

“…The precise details of UPR signaling and its links to cell death have been reviewed elsewhere [11,12,27] . However, it is worth examining some aspects of ER stress and cell death again, as these may provide a novel target for therapeutic intervention in the future.…”

“…In parallel, ER stress signaling pathways cause an increase in many ER resident proteins including molecular chaperones, which enable higher levels of client proteins to be folded. This mechanism has been called the Unfolded Protein Response (UPR) [11,12] The major client protein of the β-cell ER is proinsulin [12] . Recently, defects in insulin folding have been shown to underlie rare cases of familial permanent neonatal diabetes mellitus (OMIM #606176) [13] .…”