Role of Endoplasmic Reticulum Stress in Diabetic Neuropathy

Neuropathy affects up to 50 % of people with di-abetes and is a major risk factor for foot ul-ceration and amputation (1). The etiology ismultifactorial, and currently there is no satis-factory treatment except maintenance of good glycemic control (2), thereby highlighting the importance of identi-fying novel therapeutic targets. The endoplasmic reticulum (ER) forms a membranous network throughout the cytosol and is contiguous with the outer nuclear membrane. The ER has three major func-tions: 1) synthesis, folding, and maturation of proteins; 2) Ca2+ storage; and 3) lipid biosynthesis. The ER provides a Ca2+-rich oxidizing environment for the formation of disulphide bonds and accurate protein folding. This process is controlled by Ca2+-dependent molecular chaperones and protein-folding enzymes such as glucose-regulated protein 78/immunoglobulin binding protein (GRP78/BiP), glucose-regulated protein 94, and protein