Oxidative stress in diabetes – circulating advanced glycation end products, lipid oxidation and vascular disease

Abstract

Individuals with both Type 1 and Type 2 diabetes show vascular complications that may remain undetected for many years until the disease is at an advanced stage. Clinical trials to date have been unsuccessful in identifying a therapeutic approach that addresses both the underlying problem of poor glycaemic control in diabetes and the high incidence of microvascular disease. Oxidative stress, an imbalance of oxidants and antioxidants in the favour of oxidants, has been thought to play a central part in the complications of diabetes arising from protein glycation. Neutralization of oxidants by increased antioxidant availability has been considered as one possible way to mitigate oxidative stress. Indeed, several human intervention studies have been undertaken to determine whether dietary antioxidants can exert beneficial effects for patients with Type 2 diabetes. Chronically elevated concentrations of glucose increase the frequency of non-enzymatic glucose adduction with proteins, lipids and DNA to form advanced glycation end products (AGEs). One of the major plasma proteins that can undergo secondarymodification by glucose or oxidised lipids is the cholesterolcarrying low density lipoprotein (LDL). In Type 2 diabetes, LDL is more glycated and more susceptible to oxidation, increasing its clearance bymacrophages in a nonregulated manner and increasing foam cell formation. Complications such as albuminuria are associated with renal protein oxidation, which is often preceded by LDL fatty acid oxidation. The initiator is H2O2 produced from protein glycation, auto-oxidation of homocysteine and increased metabolism of arachidonic acid towards its pro-inflammatory eicosanoids. The backdrop of increased oxidative stress promotes a state of diffuse vasculopathy. In both Type 1 and Type 2 diabetes, there is an increased risk of cognitive impairment in later life. In the glucose control intervention study, cognitive function was an independent predictor of glycaemic control, but the risk of cognitive decline or dementia was not decreased by improving glycaemic control. AGEs, carbonylation of LDL, which is indicative of oxidative stress, and glycation are shared common risk factors for both diabetes and cognitive impairment.