Molecular Intricacies and the Role of ER Stress in Diabetes

Copyright © 2012 Muthuswamy Balasubramanyam et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Diabetes mellitus is a metabolic disease caused by both genetic and environmental factors. The pathogenic mech-anism(s) of diabetes are complex, and the complicated networks related to this disease involve distinct signaling pathways. Evidence has recently been provided that ER stress might be involved in the pathogenesis of diabetes and its complications. Early steps in the maturation of secretory proteins take place in the ER, for example, the folding of the nascent polypeptide chains and posttranslational modifications important for proper folding and function of the protein. At a stage (due to several metabolic disturbances), when unfolded polypeptide exceeds the folding and/or processing capacity of the ER, cells are susceptible to a phenomenon referred to as " ER stress. " Under these conditions, specific signaling pathways, termed the unfolded protein response (UPR), are activated to return the ER to its normal physiological state. Prolonged activation of the ER stress and the UPR can lead to cell pathology and subsequent tissue dysfunction. There is now ample evidence that the UPR is chronically activated in many disease states including diabetes and its complications. Therefore, a better understanding of the pathways regulating ER stress and UPR is warranted in order to be instrumental for the design of novel therapies for diabetes and its complications. In this focused issue of the journal, we have assembled several invited reviews, from well-recognized experts in their fields, as well as original research articles. These reviews provide state-of-the-art knowledge dealing with several mechanisms not only related to the genesis of diabetes but also to its progression to diabetic complications, all of which potentially originate or converge from chronic ER stress. In addition, several excellent original research articles demonstrate novel pathophysiologic aspects of diabetes with mechanistic studies central to ER stress and give hope and directionality for identifying new drug targets and developing newer therapeutic measures. Of all the professional secretory cells we possess, β-cells are the most sensitive to ER stress because of the large fluctuations in protein synthesis (including insulin) they face daily. M.-K. Kim et al. have reviewed how this " protein quality-control machinery " of the cell is responsible for appropriate insulin biosynthesis and how ER stress plays an important …