氧化应激和糖尿病.docx

ReviewsOxidative stress, insulin signaling, and diabetesJustin L. Rains, Sushil K. JainDiabetes is a complex metabolic disorder characterized by defects in the bodys ability to control glucose and insulin homeostasis. Diabetes has become an epidemic and remains a major public health issue.Oxidative stress is thought to be a major risk factor in the onset and progression of diabetes. Many of the common risk factors, such as obesity, increased age, and unhealthy eating habits, all contribute to an oxidative environment that may alter insulin sensitivity either by increasing insulin resistance or impairing glucose tolerance. The mechanisms by which this occurs are often multifactorial and quite complex, involving many cell signaling pathways.PI3K is the main signal mediator of the metabolic and mitogenic actions of insulin. It is composed of a p85 regulatory subunit, which binds to IRS proteins, and a p110 catalytic subunit. After the association of p85 with IRS-1/2, the p110 subunit has increased catalytic activity. This allows phosphorylation of its substrate, PtdIns(4,5)P2, on the 3’ position of the inositol ring to generate PtdIns(3,4,5)P3[11] . The second messenger, PtdIns(3,4,5)P3 recruits the serine kinases PDK-1, PKB/Akt, and PKC to the plasma membrane via their PH domains. The activation of these kinases results in several of insulins responses, such as GLUT4 translocation to the membrane, glycogen synthesis by phosphorylation of GSK-3, and lipogenesis by up-regulating synthesis of the fatty acid synthase gene.It is now known that oxidative stress conditions can result in the activation of various stress pathways such as NF- κB, JNK/SAPK, and p38 MAPK. The apparent cross talk between oxidative stress -induced path ways and normal insulin signaling creates the possibility for multiple disruptions in the ability of insulin to maintain its normal functions.Activated PKC contributes directly to the oxidative stress environment by activating NF-κB and various membr