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

Introduction

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. ¹ 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.^2–4 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. ⁵

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 secondary modification by glucose or oxidised lipids is the cholesterol-carrying low density lipoprotein (LDL). In Type 2 diabetes, LDL is more glycated and more susceptible to oxidation, ⁶ increasing its clearance by macrophages in a non-regulated 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. ⁷

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. ⁸ AGEs, carbonylation of LDL, which is indicative of oxidative stress, and glycation are shared common risk factors for both diabetes and cognitive impairment.^9,10

Free radicals, AGEs and biomarkers

The generation of free radicals physiologically is a common phenomenon. ¹¹ Where there is an imbalance between radical production and scavenging, detrimental effects on macromolecules are observed.^10,12 Due to their high reactivity with biological macromolecules free radicals cannot be easily directly monitored unless trapped, for example, through reaction with a lipid molecule, to form stable end products of radical attack.

Accumulating evidence suggest that AGEs are involved in a vicious cycle of free radical generation.^13,14 AGEs increase the expression and activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in human endothelial cells, an important source of vascular oxidative stress in Type 2 diabetes. ¹⁵ Increased NADPH oxidase activity results in formation of free radicals and depletion of cellular antioxidants such as glutathione, glutathione peroxidase, superoxide dismutase and catalase. Free radical mediated lipid peroxidation of polyunsaturated fatty acids gives rise to formation of several reactive α-, β-unsaturated aldehydes such as 4-hydroxy-trans-2-nonenal (HNE), 4-oxotrans-2-nonenal (4-ONE), acrolein and 4-oxo-trans-2-hexanal, all of which are aldehydes such as glucose, and have the potential to be considered as biomarkers of glycaemic status but can also form advanced lipid peroxidation end products (ALE). The detection of 4-HNE and malondialdehyde (MDA) adducts and oxidised LDLs within the atherosclerotic plaque is a hallmark in atherosclerosis. ¹⁶ Similarly, the radical oxidised lipid, MDA has been shown to generate ALE and, together with AGEs, these cause secondary damage to proteins. ¹⁴ 8-iso-PGF_{2 α} is widely used as a biomarker of lipid oxidation. It is measured in plasma or urine by mass spectrometry techniques or enzyme-linked immunosorbent assay. However, discrepancies between the specificity of these methods means care must be taken when interpreting findings between different studies. ¹⁷ Nevertheless, it is widely adopted as a marker for measuring in vivo lipid oxidation. A recent meta-analysis considered the evidence for the association of F₂-isoprostanes with coronary artery disease, stroke and peripheral artery disease: differences in sample handling/storage and analytical variation were seen as key contributors to variation between studies. Nevertheless, high concentrations of F₂-isoprostanes in urine or blood did appear to be a non-specific indicator of cardiovascular disease and should be explored in prospective studies. ¹⁸

Given the rapidly increasing incidence of Type 1 diabetes and obesity-associated Type 2 diabetes in mid-life which contributes to increased risk for dementia, recently termed Type 3 diabetes, ¹⁹ there is an urgent need to understand how systemic changes in metabolism may predispose to dementia in order to develop early risk biomarkers which can be applied for monitoring health outcomes. With sufficient care taken in sample collection coupled with analytical precision, F₂-isoprostanes may prove to be useful and offer improved biomonitoring opportunities to support the implementation of strategies to minimize vascular complications. ¹⁸