The dissertation is devoted to the research of the main mechanisms of influence of different types of hypoxia on energy metabolism, and to create new approaches to pathogenetic correction of metabolic disorders. The study was performed in Wistar rats under the influence of acute, periodic, chronic hypoxia, simulation of primary, respiratory hypoxia and immobilization stress; gender and ontogenetic differences are characterized. Clinical trials have been performed in healthy middle-aged and elderly volunteers, as well as patients with metabolic syndrome, prediabetes, type 1 and 2 diabetes, plain and mid-mountain residents, under the influence of acute, chronic, intermittent interval hypoxia.
The results showed that the main reaction to the influence of various types of hypoxia is the development of a hypometabolic state associated with impaired ATP synthesis in cells. Transcription factors HIF-1α and HIF-3α were identified as key molecules in this response, which stimulate the activation of protective and adaptive genes, including iNOS, MnSOD, caveolin-3, Akt, GLUT-1 and -4. Hypoxia-resistant proteins of the aerobic part of energy metabolism and glycolysis, and KATP channels are activated. Also, mitochondrial dysfunction, especially of complex I, decreased oxidation of NAD-dependent and the prevalence oxidation of FAD-dependent substrates, the development of oxidative stress and hyperglycemic reaction were found due to hypoxia. Complex changes in metabolic parameters indicate common features of stress-reactive mechanisms, and responses to hypoxia of different genesis.
The phase nature of metabolic changes in response to hypoxia of various genesis and stress has been established. The hypometabolic phase lasts 5-9 days depending on the depth and duration of the hypoxic stimulus. After a short transition phase, a hypermetabolic phase develops, which is characterized by a significant increase in energy metabolism and HIF-3-dependent limitation of HIF-1 function. In mitochondria, the coupling of oxidation and phosphorylation increases, the functioning of complex 1 of the electron transport chain resumes, the oxidation of NAD-dependent substrates dominates over FAD-dependent ones, the ATP production rises, and heat production decreases. According to the increase in oxygen consumption, the respiration rises. The expression of insulin receptors and glucose transporters increases, hypoglycemia develops; in patients with metabolic disorders there is an improvement in carbohydrate and lipid metabolism. After 16-18 days, the adaptive phase develops, the functional parameters of the body are normalized, and a new state of energy metabolism of the body is established, in which the reaction to a hypoxic or stressful stimulus is reduced or absent. An important result is the establishment of the fact that the change of phases is not affected by the level of readiness of the oxygen transport system to increase the metabolic needs of tissues, which is a risk factor. The developed methods of correction and theoretical conclusions allow to recommend the appointment of glucocorticoid hormones as components of pathogenetic therapy, which allows to delay the onset of the hypermetabolic phase, as well as treatment with cerium nanoparticles to correct disorders in the hypometabolic phase.
