Diabetes mellitus (DM) is one of the global medical and social problems of the 21st century. According to the International Diabetes Federation, in 2021, 400 million people will be diagnosed with diabetes in the world. It is predicted that by 2035, the total number of people suffering from diabetes will increase and reach 592 million people, while more than 90% of them will have type II diabetes. Over the past 10 years, the number of patients with diabetes mellitus in Ukraine has increased more than 1.5 times and amounts to more than 1.3 million patients. The social significance of DM is also determined by serious complications, such as angiopathy, retinopathy, cardiomyopathy, nephropathy, myocardial infarction, stroke, gangrene of the lower extremities, etc., which lead to early disability and high mortality. Therefore, the optimization of DM therapy is one of the urgent medical and social problems of our time.
The multigene concept of the development of DM made it possible to move away from the "glucocentric" theory, which justified the therapy of diabetes for a number of years, and to define new approaches to its treatment. A rather large amount of knowledge in the field of the pathogenesis of DM and the availability of many therapeutic options did not contribute to the improvement of the metabolic control of the disease from the stage of glucose tolerance to the expanded clinic of DM. Therefore, today, priority should be given to antidiabetic drugs, the pharmacodynamics of which are not limited to hypoglycemic action, but allow to reveal a positive effect on several main pathogenetic links of the disease.
Among the main pathogenetic factors that contribute to the development of DM of both types and its complications, a special place is given to oxidative stress. It is known that -cells are particularly sensitive to the toxic effect of oxygen free radicals, since the content of antioxidant enzymes in -cells is on average 10-20 times lower than in other organs.
It is also known that an imbalance of pro- and anti-inflammatory cytokines plays an important role in the pathogenesis of both types of diabetes. According to modern ideas about the pathogenesis of DM, one of the leading roles in the development of the disease is played by pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, tumor necrosis factor, etc. For example, IL-1 is involved in the development of inflammation and the formation of insulin resistance, inhibits insulin secretion, which causes inhibition of glucose utilization by tissues and depression of glycogen formation. Cytokine disturbances also play a leading role in the development of complications of DM.
Type I and II diabetes mellitus have different pathogenesis. The basis of the development of type I DM is selective autoimmune damage to β-cells. In the pathogenesis of type II diabetes, the development of insulin resistance and disruption of insulin secretion by β-cells play an important role. However, research in recent years proves that the main links of the mechanism of the development of diabetes of various types are common, namely, an imbalance between the levels of glucose and insulin, the number and sensitivity of tissue insulin receptors; activation of free radical oxidation processes, which is accompanied by suppression or depletion of antioxidant protection of cells; the presence of metabolic disorders, such as, for example, negative changes in lipid and protein metabolism. Another common link in the pathogenesis of DM is the activation of apoptosis and destruction of β-cells, which is realized through a cascade of internal changes involving cysteine proteases with subsequent activation of endonucleases, leading to DNA fragmentation. In general, the damage and death of -cells in the early phase of the immune response is accompanied by an increase in the local concentration of cytokines with a paracrine effect on the immediate environment. Later, an inflammatory reaction develops with the participation of active immunocompetent cells, the secretion of cytokines, the activation of proteases, the formation of oxygen radicals and other immune mediators increases. That is, the death of -cells in diabetes occurs, presumably, both by the mechanism of necrosis and by the mechanism of apoptosis.
Therefore, according to the modern concept, autoimmune mechanisms, glucose and lipotoxicity, cytokine imbalance, metabolic disorders, and systemic oxidative stress can be considered important key links in the pathogenesis of -cell damage in diabetes.
It has been proven that taking sugar-lowering drugs affects the daily rhythms of carbohydrate metabolism. The causal mechanisms of such dependence lie in the chronopharmacological regulation of glucose in patients with diabetes. Therefore, it is necessary to study rhythmic changes in the tissue level of endocrine regulation - "secondary mediators" of the hormonal signal, as well as to determine the influence of environmental factors on the chronostructure of carbohydrate metabolism. In the future, research on the dependence of the hypoglycemic effect of drugs on the time of day and diet in patients with diabetes is necessary. Unfortunately, there are currently no chronopharmacological data on many hypoglycemic drugs. The lack of comprehensive research in this area does not allow for the creation of evidence-based chronopharmacological regulation of circadian rhythms of carbohydrate metabolism. Studying the chronopharmacological features of antidiabetic drugs is one of the directions for improving the pathogenetic pharmacotherapy of diabetes.
Analyzing the above, it can be assumed that the traditional principles of treatment of diabetes should be revised. It is obvious that correction of only carbohydrate metabolism is far from sufficient component of diabetes therapy. Treatment should be supplemented with the use of drugs that can simultaneously affect the main pathogenetic links of the disease. Promising directions for the development of pathogenetic therapy of both types of diabetes are inhibition of the synthesis and activity of pro-inflammatory cytokines, increase in survival and normalization of the functional activity of β-cells, inhibition of the development of oxidative stress, correction of metabolic disorders, as well as research into the chronopharmacological features of the use of modern and perspective antidiabetic drugs.
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