Diabetes-induced hepatic oxidative stress: a new pathogenic role for glycated albumin

Abstract

Increased oxidative stress and advanced glycation end-product (AGE) formation are major contributors to the development of type 2 diabetes. Here plasma proteins e.g. albumin can undergo glycoxidation and play a key role in diabetes onset and related pathologies. However, despite recent progress linking albumin-AGE to increased oxidative stress and downstream effects, its action in metabolic organs such as the liver remains to be elucidated. The current study therefore investigated links between oxidative perturbations and biochemical/structural modifications of plasma albumin, and subsequent downstream effects in transgenic db/db mouse livers and HepG2 cells, respectively. Our data reveal increased oxidative stress biomarkers and lipid accumulation in plasma and livers of diabetic mice, together with albumin glycoxidation. Purified mouse albumin modifications resembled those typically found in diabetic patients, i.e. degree of glycation, carbonylation, AGE levels and in terms of chemical composition. Receptor for AGE expression and reactive oxygen species production were upregulated in db/db mouse livers, together with impaired proteolytic, antioxidant and mitochondrial respiratory activities. In parallel, acute exposure of HepG2 cells to glycated albumin also elicited intracellular free radical formation. Together this study demonstrates that AGE-modified albumin can trigger damaging effects on the liver, i.e. by increasing oxidative stress, attenuating antioxidant capacity, and by impairment of hepatic proteolytic and respiratory chain enzyme activities.

Glycation of human serum albumin impairs binding to the glucagon-like peptide-1 analogue liraglutide

“…These AGE adducts were further identified as previously described by mass shift determination of AGE-modified peptides resulting from the trypsin digestion of each albumin sample (28). Results from this identification are shown in Tables 1-2.…”

Serum Antioxidant Parameters are Significantly Increased in Patients with Type 2 Diabetes Mellitus after Consumption of Chinese Propolis: A Randomized Controlled Trial Based on Fasting Serum Glucose Level

“…Evidence from both experimental and clinical studies suggests that oxidative stress is involved in the development of insulin resistance and β-cell dysfunction, and plays a major role in the pathogenesis of T2DM [ 33 – 36 ]. Meanwhile, hyperglycemia also contributes to oxidative stress through several pathways: polyol, hexosamine, protein kinase C, glycolysis, and advanced glycation end-product production [ 37 , 38 ]. Therefore, it is very important to improve antioxidant function in T2DM in order to protect against oxidative stress.…”

Redox Signaling and Advanced Glycation Endproducts (AGEs) in Diet-Related Diseases

“…A positive correlation between oxidative stress markers and glycated albumin levels has been described in patients with type 2 diabetes mellitus [96,115]. Moreover, the long-term oxidative stress produced by AGEs may result in protein damage that finally leads to endothelial dysfunction [116]. Thereby, the accumulation of AGEs has been related to diabetes and also to its associated complications [117][118][119][120][121][122][123][124][125][126] (Figure 3).…”