Plasma Protein Glycation, Oxidation and Nitration Markers for Improved Risk Prediction of Type 1 Diabetes Mellitus

Abstract

Type 1 diabetes mellitus (T1DM) is characterized by hyperglycaemia caused by a deficiency of insulin resulting from autoimmune destruction of insulin-secreting beta cells of the pancreas. T1DM is caused by interaction of complex-trait genetic factors and environmental triggers such as viruses, endotoxin and possibly dietary effects. Recent studies have suggested that increased serum protein content of an advanced glycation endproduct is associated with increased risk of T1DM and also, with increased risk of cardiovascular disease in T1DM patients. The aim of this study is to quantify levels of Nε-Carboxymethyl-lysine (CML), other glycation endproducts, oxidation and nitration adducts in serum protein, in addition to related serum free adducts and amino acid metabolomics of monozygotic twins discordant for T1DM, and T1DM patients with HDL of high and low HAE, and compare these with plasma from healthy subjects. HDL apoA-1 exchange (HAE) – a measure of its ability to release lipid-poor apolipoproteinA-1, an essential step in reverse cholesterol transport. Monozygotic twins discordant for T1DM were studied from a London cohort and studies of T1DM patients with HDL of high and low HAE were based on an Oslo cohort. Major chemically-defined markers of protein damage by glycation, oxidation, and nitration were quantified in samples of plasma protein and in ultrafiltrate (glycated, oxidized and nitrated amino acids) by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. In monozygotic twins there were increased protein glycation and oxidation markers in plasma and decreased nitration markers of plasma protein for the diabetic twin. However, increased nitration was observed in the second cohort of diabetic twins. In T1DM patients with HDL of high and low HAE, there were increased levels of glycation, oxidation and nitration of plasma protein in both patients groups with HDL of high and low HAE activity. There were changes in the amino acid metabolome in plasma of diabetic patients. This study reveals that dicarbonyl stress is a potential contributory impairment in T1DM and thereby very likely contributes to risk of CVD. Measurement of protein glycation, oxidation and nitration markers provides evidence of protein damage in healthy and patients with T1DM and also provides additional facility in the prediction for developing specific complications of metabolic disease.