Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis

Abstract

Type 2 diabetes is the most prevalent and serious metabolic disease all over the world, and its hallmarks are pancreatic beta-cell dysfunction and insulin resistance. Under diabetic conditions, chronic hyperglycemia and subsequent augmentation of reactive oxygen species (ROS) deteriorate beta-cell function and increase insulin resistance which leads to the aggravation of type 2 diabetes. In addition, chronic hyperglycemia and ROS are also involved in the development of atherosclerosis which is often observed under diabetic conditions. Taken together, it is likely that ROS play an important role in the development of type 2 diabetes and atherosclerosis.

Figure 1

Augmentation of ROS by various pathways under diabetic conditions. (a) ROS are produced by various pathways under diabetic conditions. Hyperglycemia induces ROS through activation of the glycation reaction and electron transport chain in mitochondria. (b) AGEs, insulin, and angiotensin II induces ROS through activation of membrane-bound NADPH oxidase.

Figure 2

Role of ROS in the progression of pancreatic β -cell dysfunction in type 2 diabetes. ROS are provoked by hyperglycemia and/or hyperlipidemia under diabetic conditions, which leads to activation of the JNK pathway in pancreatic β-cells. ROS and subsequent activation of the JNK pathway induce nucleo-cytoplasmic translocation of PDX-1, which leads to reduction of PDX-1 activity and suppression of insulin. Therefore, it is likely that ROS and activation of the JNK pathway are involved in β-cell dysfunction found in type 2 diabetes.

Figure 3

Role of ROS in the development of insulin resistance in type 2 diabetes. The JNK pathway is activated by various factors such as ROS, ER stress, free fatty acids (FFAs), and inflammatory cytokines such as TNFα and is involved in the development of insulin resistance found in type 2 diabetes. It has been also shown that the IkappaB kinase β (IKK) pathway is also activated by such factors and is involved in the development of insulin resistance. Therefore, it is likely that activation of stress signaling is involved in the development of insulin resistance.

Figure 4

Role of ROS in the development of atherosclerosis. ROS are produced by various pathways under diabetic conditions and involved in the development of atherosclerosis in various aspects. Hyperglycemia induces ROS through activation of the glycation reaction and electron transport chain in mitochondria. Also, AGEs, insulin, and angiotensin II induce ROS through activation of NADPH oxidase. Increased ROS are involved in the development of atherosclerosis in various aspects. First, ROS decrease nitric oxide levels, which leads to endothelial cell dysfunction. Second, ROS increase expression of various adhesion molecules such as ICAM-1 and VCAM-1, which leads to inflammatory cell recruitment. Finally, ROS increase expression of various growth factors and activate various stress signaling such as JNK and Pim-1, which leads to proliferation of smooth muscle cell.