Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized ("hyperglycemic memory"). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.

Oxidative stress and diabetic complications

It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.

Mechanisms of Diabetic Complications

Diabetes, oxidative stress and therapeutic strategies

The formation and accumulation of methylglyoxal (MGO), a highly reactive dicarbonyl compound, has been implicated in the pathogenesis of type 2 diabetes, vascular complications of diabetes, and sev...

https://journals.physiology.org/doi/pdf/10.1152/physrev.00001.2019

Methylglyoxal, a highly reactive dicarbonyl compound, in diabetes, its vascular complications and other age-related diseases

http://wrap.warwick.ac.uk/67564/1/WRAP_1-s2.0-S0006291X15001874-main.pdf

Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease.

Aims/hypothesis
High-dose supplements of thiamine prevent the development of microalbuminuria in experimental diabetes. The aim of this pilot study was to assess whether oral supplements of thiamine could reverse microalbuminuria in patients with type 2 diabetes.

/pdf/high-dose-thiamine-therapy-for-patients-with-type-2-diabetes-28yvnodi3h.pdf

High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study

Obesity is one of the leading cause of diabetes mellitus in the world population due to the growing trend of sedentary lifestyle and increased food consumption of high caloric diet. A concomitant increase due to this has been observed in coronary heart diseases, hypertension and even diabetes. High lipid profile of the serum is one of the factors that may result in the development of obesity in diabetes mellitus and thus the progression of diabetes. This study was carried out to determine the effect of various physical and biochemical parameters of obesity to ascertain the link to presence and severity of diabetes. For this purpose physical parameters such as BMI, waist circumference, and biochemical parameters such as FBS, glycated HbA1c, albumin excretion rate, urine creatinine level, and lipid profile parameters such as cholesterol, triglyceride, HDL, LDL and VLDL were measured by standard referred protocols. Elevated serum leptin level was associated with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglyceride levels, fasting blood sugar, glyacated HbA1c, total serum proteins and decreased high-density lipoprotein cholesterol levels in obese diabetes as compared to lean, non-obese and normal subjects. The results were found to be significant with p biochemical parameters are greater in obese diabetes as compared to non-obese diabetes group and also in lean. Proteins levels such as leptin are also greater in obese diabetes as compared to non-obese and lean objects.

/pdf/obesity-as-risk-factor-and-study-of-obesity-related-proteins-x9dzlf9fgs.pdf

Obesity as risk factor and study of obesity related proteins in diabetes mellitus

To the Editor: We thank Alkhalaf and co-authors for their comment on our recent paper in Diabetologia [1]. We are grateful for their interest in our work and the recognition of its potential importance in stimulating further research, which may lead to a significant improvement in the treatment of diabetic nephropathy. They have made several comments on issues that could not be dealt with in our short communication [2]. We now address these comments. The urinary albumin excretion (UAE) data in Table 1 of our paper are the median (minimum–maximum) values of the 24 h UAE values for the treatment groups at the study times indicated. The data illustrated in Fig. 1a are the median values of data distributions of 24 h UAE change from baseline deduced for each patient. These data sets are not the same: one is absolute UAE values (distributions summarised in Table 1) and the other is of changes in UAE from baseline for each patient (medians of changes shown in Fig. 1a). This, and the non-parametric distribution of the data sets, accounts for the different values for the difference between median UAE after 3 months of treatment and at baseline (−13.6 mg/24 h) that can be deduced from Table 1 and the median of 24 h UAE changes from baseline (−17.7 mg/24 h) shown in Fig. 1a for the thiamine treatment group. Computing a data distribution of analyte change from baseline is a strategy often employed where there is large dispersion of baseline data, and the response to therapy (rather than change in absolute value) is of greatest interest. Change in UAE was the primary endpoint of our study. There was a trend for UAE data during the posttreatment washout period to show a continuing decrease beyond that achieved in the treatment period. We stated that the decrease in UAE in the post-treatment period was ‘maintained’, as the trend for further decrease was not statistically significant. This is not a concern, but rather it might be expected that patients have continued benefit during the washout period from the thiamine supplementaDiabetologia (2009) 52:1214–1216 DOI 10.1007/s00125-009-1334-7

/pdf/thiamine-in-diabetic-nephropathy-a-novel-treatment-modality-3radi4n5qa.pdf

M. W. Akhtar

Papers

High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study

Obesity as risk factor and study of obesity related proteins in diabetes mellitus

Thiamine in diabetic nephropathy: a novel treatment modality? Reply to Alkhalaf A, Kleefstra N, Groenier KH et al. [letter]