Targeting Select Cellular Stress Pathways to Prevent Hyperglycemia-Related Complications: Shifting the Paradigm.

Despite the advances made in preventing complications of diabetes, there is still substantial residual risk. Hence the need for developing new therapeutic agents that target the various facets of the pathogenesis of complications in people with diabetes. Traditionally four general biochemical pathways had been recognized as major contributors to glucotoxicity. These include the polyol pathway, the protein kinase C (PKC) pathway, glycosylation pathway, and oxidative stress. The latter has been proposed as a common impetus of the other pathways of glucotoxicity. More recently, the cross talk between oxidative stress and other recognized cellular stresses such as endoplasmic reticulum (ER), inflammatory, and mitochondrial stresses has emerged as an important additional mechanism of glucotoxicity. The observation that targeting oxidative stress with antioxidants has been associated with unfavorable clinical outcomes and the recognition that in cell cultures antioxidants may aggravate ER stress, suggests that selective targeting of individual cellular stresses may not be sufficient for preventing glucotoxicity. Future efforts should focus on developing therapeutic agents that can ameliorate cellular stress globally by simultaneously targeting the oxidative, ER, mitochondrial, and inflammatory stresses.