Is diabetes an acquired disorder of reactive glucose metabolites and their intermediates?

Abstract

Aims/hypothesis We hypothesised that diabetic patients would differ from those without diabetes in regard to the handling of glucose-derived reactive metabolites, evidenced by triosephosphate intermediates (TP INT ) and methylglyoxal (MG), irrespective of the type of diabetes, plasma glucose level or HbA 1c value. Methods To test this hypothesis, erythrocytes were isolated from patients with type 1 (n012) and type 2 (n012) diabetes with varying blood glucose and HbA 1c levels. These were then compared with erythrocytes isolated from individuals without diabetes (n010), with respect to MG, as determined by HPLC, and TP INT , as determined by endpoint enzymatic assays. Results The concentrations of intracellular TP INT and MG were significantly elevated in erythrocytes from diabetic patients. Normalisation of either TP INT or MG to intracellular glucose concentration (nmol glucose/mgHb) confirmed that erythrocytes from diabetic patients accumulated more reactive metabolites than did those from healthy controls. Conclusions/interpretation Diabetic patients can be characterised by an increased formation of TP INT and MG. The 25-fold increase of MG in type 1 and the 15-fold increase in type 2 diabetes, together with a several-fold increase in TP INT and decreased glyceraldehyde-3-phosphate dehydrogenase activity even under normal glucose conditions, imply that normalising glucose level cannot completely prevent late diabetic complications until this acquired error of metabolism has been restored.

Dicarbonyl Stress in the Absence of Hyperglycemia Increases Endothelial Inflammation and Atherogenesis Similar to That Observed in Diabetes

“…It has recently been argued that all therapeutic strategies for the prevention of complications associated with diabetes rely on the premise that the deleterious effects of high glucose levels and an enhanced metabolic flux are mediated by the generation of toxic metabolites (3,4). Of these, reactive a-dicarbonyls like MG are among the most important (6).…”

“…A number of metabolic and hemodynamic factors contribute to accelerated atherosclerosis in the setting of diabetes. One key pathway is the increased production of reactive dicarbonyls generated from triose phosphate intermediates of glycolysis, glycerol and ketone peroxidation, overactivation of the polyol pathway, and the degradation of glycated proteins (3)(4)(5)(6). In experimental diabetes, circulating and tissue levels of methylglyoxal (MG) are three to five times higher than in the nondiabetic state (7,8).…”

The analysis of advanced glycation endproducts

“…With this improved technique, increased plasma concentrations of GO, MGO and 3-DG were found in patients with T2DM as compared to healthy individuals. These results were in reasonable agreement with data described in literature 69,[78][79][80] . Nevertheless, absolute concentrations differ between studies and are most likely due to differences in sample preparation and sample handling during storage.…”

“…Although immunoassays can be applied as a high throughput, simple and cheap method to quantify AGEs, it remained difficult to produce reliable and reproducible results. In the following years ELISA-based techniques were improved and several antibodies against mainly CML-modified proteins were developed and used for AGE analysis [76][77][78][79][80] . However, quantification of AGEs with ELISA-based techniques did not give satisfying results.…”

High Tissue Glucose Alters Intersomitic Blood Vessels in Zebrafish via Methylglyoxal Targeting the VEGF Receptor Signaling Cascade

“…In plasma of healthy people, MG concentrations of ;100 nmol/L have been detected, whereas in diabetic patients, MG levels increase up to 700 nmol/L (12). A direct link between elevated MG concentrations and diabetes complications has now been identified for the development of metabolic hyperalgesia (13).…”