Oxidative stress in type 2 diabetes: the role of fasting and postprandial glycaemia

Abstract

Oxidative stress, through the production of reactive oxygen species (ROS), has been proposed as the root cause underlying the development of insulin resistance, beta-cell dysfunction, impaired glucose tolerance and type 2 diabetes mellitus (T2DM). It has also been implicated in the progression of long-term diabetes complications, including microvascular and macrovascular dysfunction. Excess nourishment and a sedentary lifestyle leads to glucose and fatty acid overload, resulting in production of ROS. Additionally, reaction of glucose with plasma proteins forms advanced glycation end products, triggering production of ROS. These ROS initiate a chain reaction leading to reduced nitric oxide availability, increased markers of inflammation and chemical modification of lipoproteins, all of which may increase the risk of atherogenesis. With the postulation that hyperglycaemia and fluctuations in blood glucose lead to generation of ROS, it follows that aggressive treatment of fasting and postprandial hyperglycaemia is important for prevention of micro and macrovascular complications in T2DM.

Figure 1

Glucose in the plasma undergoes non-enzymatic reaction with circulating proteins (including lipoproteins) to form AGEs. AGEs bind with RAGE on the surface of endothelial cells lining blood vessels, triggering the production of ROS, in particular super oxide anion, by NADPH oxidase. ROS are also produced as a result of glucose overload within the mitochondria. Once formed, ROS activate NFκB, which results in the transcriptional activation of genes relevant for inflammation, immunity and atherosclerosis. AGE, advanced glycation/glycoxidation endproduct; RAGE, receptor for AGE; ROS, reactive oxygen species; O₂^–, super oxide anion; NADPH, nicotinamide adenine dinucleotide phosphate (reduced form); NFκB, nuclear factor κB; TNF-α, tumour necrosis factor α; IL, interlukin; PAI-1, plasminogen activator inhibitor 1; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule; NO, nitric oxide.