Molecular Mechanisms of Carbohydrate Metabolism-Related Disorders: Investigation in Experimental Models and Clinical Samples. Summary of the Doctoral Thesis

Abstract

Modern therapy of diabetes mellitus (DM) aims both to control blood glucose levels and also to prevent late complications, thus improving the patients' quality of life. Consequently, the molecular mechanisms of late complications, including glyoxalase enzyme system, are intensively studied. Given the fact that the carbohydrate metabolism disorders are associated with impaired energy metabolism, the optimization of glucose and fatty acid metabolism could improve the treatment of the disease as well as associated complications. The aim of the thesis was to discover novel molecular markers and possibilities for the regulation of the molecular mechanisms underlying energy metabolism pathways. This study is the first to associate a lower blood glyoxalase 1 (Glo1) activity with development of the painful peripheral diabetic neuropathy in type 1 and 2 diabetes mellitus patients thus providing the experimental evidence for the role of altered Glo1 activity in the development of painful diabetic neuropathy. Lower Glo1 activity in the neuronal tissues was associated with higher blood glucose and triglyceride concentrations, as well as impaired endothelium-dependent relaxation to acetylcholine in aortic rings in the experimental model of type 2 diabetes. Obtained results show that blood Glo1 activity could not be used as an early marker of the development of vascular complications, but nevertheless the measurements of blood Glo1 activity might be a useful approach to study the development of late complications of DM. Novel insights into molecular mechanisms of action of mildronate have been provided in the thesis. Thus, the mildronate-induced reduction in bioavailability of Lcarnitine improves adaption to hyperglycemia- and hyperlipidemia-induced metabolic disturbances. These processes include activation of peroxisome proliferator-activated receptor α (PPARα)/ PPARγ coactivator 1α (PGC1α) signaling pathways and redirection of fatty acid metabolism, which protects the mitochondria against long-chain fatty acid overload. The results of the study provide evidence that the reduction of Lcarnitine bioavailability could be useful approach to delay the development of late complications of DM.