Correction of Lipid Peroxidation Processes in Patients with Type 2 Diabetes Mellitus under Various Treatment Regimens Involving Antioxidant Therapy

The dissertation is devoted to the study of the role of lipid peroxidation processes and the antioxidant defense system in the pathogenesis of vascular complications of type 2 diabetes mellitus. The work examines the mechanisms of oxidative stress arising from disruption of carbohydrate metabolism, evaluates the state of lipid metabolism, the activity of antioxidant defense enzymes of erythrocytes and plasma, and the level of indirect markers of nitric oxide (nitrites and nitrates of blood plasma). The effectiveness of two antioxidant drugs of bi flavonoid origin — dicvertin (Russian production) and tanakan (French production) — in terms of correcting the identified disorders and preventing the progression of diabetic retinopathy is investigated. Special attention is devoted to the comparative assessment of the influence of these drugs on clinical and biochemical indicators and the ophthalmoscopic picture of the fundus of the eye in patients with type 2 diabetes mellitus with proliferative diabetic retinopathy.

Relevance of the Topic

Diabetes mellitus [DM] is one of the most pressing problems of modern medicine. According to WHO data, there are currently more than 100 million patients with diabetes mellitus worldwide, and this number doubles every 10–15 years [8]. The expected prevalence by 2010 is approximately 250 million people [186]. This occurs mainly due to the increase in the number of patients with type 2 diabetes mellitus. This type of diabetes is characterized by delayed diagnosis and underdetection in the general population, which leads to a significantly underestimated assessment of its prevalence. The severity and prognosis of diabetes mellitus are determined by the time of onset and the rate of progression of late vascular complications of diabetes mellitus (micro- and macroangiopathies). Macroadenopathies include lesions of the vessels of the heart, brain, and large arteries of the lower extremities. Diabetic microangiopathies are a systemic manifestation of the disease and are found throughout the vascular bed, affecting the kidneys, retina, peripheral nerves, myocardium, and skin. The risk of blindness in patients with diabetes mellitus is increased 25-fold, the likelihood of limb amputations increases 40-fold, and the development of renal insufficiency is observed 20 times more frequently compared with the general population [3, 5, 6]. The number of patients with diabetes mellitus in Russia increases by 5.8% annually, and this trend persists.

In turn, the increase in the number of patients with diabetes mellitus contributes to the increase in the frequency of one of the most serious complications of this disease — diabetic retinopathy [DR], which is one of the leading causes of visual impairment and blindness. Disability among persons of working age creates serious problems of not only medical but also socioeconomic character [6, 7, 8]. Even at the St. Vincent Conference, held under the auspices of WHO and the International Diabetes Federation, it was recognized that diabetes mellitus is the foremost medical and social problem in the world. The conference adopted the declaration — «Diabetes-2000», in which one of the stated tasks was to reduce the frequency of blindness from DR by 30% [93].

However, achieving compensation of diabetes mellitus as the sole means of preventing vascular lesions remains a matter of dispute. This determines the necessity of further study of the pathogenesis of vascular complications in patients with diabetes mellitus in order to more fully and accurately decipher their complex mechanisms and to substantiate new aspects of complex therapy and prevention of diabetic angiopathy.

According to modern concepts, the main role in the development of vascular complications of diabetes belongs to oxidative stress caused by disruption of carbohydrate metabolism. Under normal conditions, a balance is maintained in the organism between the rate of lipid peroxidation (LOP) and the activity of the antioxidant system [8, 9, 10]. To date, the question of the use of antioxidant drugs for the prevention and treatment of diabetic angiopathy remains a matter of discussion. From this standpoint, it appears expedient to study the activity of antioxidant defense enzymes, the level of LOP, nitrites and nitrates in plasma (indirect markers of nitric oxide), to investigate the fundus picture and the changes in these parameters under the influence of antioxidants of the flavonoid group.

Despite the variety of forms of diabetes mellitus, the majority of patients are persons with type 2 diabetes mellitus. In various populations and ethnic groups, this figure reaches 80.0–95.0% [8, 21]. Unlike other forms of diabetes mellitus, the actual prevalence exceeds the registered one by 3–5 times. Type 2 diabetes mellitus is characterized by the fact that, on average, 7–10 years pass before its detection. Therefore, at the time of diagnosis, a number of micro- and macrovascular complications are already identified, which lead the patient to disability [6, 7, 36]. The actual prevalence of DR among patients exceeds the registered one 4.8 times [93]. An analysis of the frequency of complications among patients with type 2 diabetes mellitus taking into account their age showed a lawful increase in the probability of development of vascular complications with increasing patient age [7, 36].

The medical and social significance of this problem, the economic costs borne by society, determine the relevance of the problem of prevention of late complications of diabetes mellitus. Treatment of DR proves to be effective provided careful dynamic observation and, mainly, at early stages of the disease. Prolonged asymptomatic course, diversity of clinical variants, absence of a unified approach to understanding the pathogenesis and classification create difficulties in early diagnosis and assessment of the effectiveness of treatment of this pathology.

Objective of the Work

Determination of the role of the antioxidant defense system, nitric oxide, and lipid peroxidation activity in the pathogenesis of vascular complications in type 2 diabetes mellitus, and study of the possibilities of using antioxidant drugs to correct the identified disorders.

Accordingly, the following tasks were set:

1. To conduct quantitative determination of antioxidant defense enzymes of erythrocytes: superoxide dismutase, catalase, glutathione peroxidase, plasma glutathione peroxidase.

2. To determine the level of indirect markers of nitric oxide, nitrites and nitrates in the blood plasma of patients with type 2 diabetes mellitus and the control group.

3. To investigate the influence of dicvertin and tanakan therapy on indicators of carbohydrate and lipid metabolism in patients with type 2 diabetes mellitus.

4. To assess the state of the fundus of the eye in patients with type 2 diabetes mellitus, and the presence and dynamics of changes in the fundus of the eye under the influence of drugs of the flavonoid group: tanakan and dicvertin.

5. To compare the relative therapeutic effectiveness of dicvertin and tanakan.

Scientific Novelty of the Research

For the first time, pathogenetically justified therapy with dicvertin (a drug with pronounced antioxidant activity) was applied to patients with type 2 diabetes mellitus with proliferative DR, and its effectiveness and dynamics of clinical indicators were evaluated. The influence of a new antioxidant agent, dicvertin, on the state of lipid peroxidation, the antioxidant defense system, the level of nitrites and nitrates (indirect markers of nitric oxide), the state of the fundus of the eye, and DR in patients with type 2 diabetes mellitus was studied. For the first time, a comparative study of the influence of the bi flavonoids dicvertin and tanakan on indicators of carbohydrate and lipid metabolism was conducted.

Practical Significance

The results of clinical and biochemical studies make it possible to expand the concepts of general and local pathophysiological processes occurring in DR, as well as to outline new approaches to the treatment of the disease. The proposed use of the complex drug dicvertin for the treatment and prevention of the occurrence and progression of DR is pathogenetically targeted and justified. Dynamic observation of patients who underwent a course of treatment with tanakan and dicvertin revealed stabilization of visual functions and the ophthalmoscopic picture of the fundus of the eye.

As a result of the conducted research, the methodology of antioxidant therapy with dicvertin was optimized. Improvement of visual functions is accompanied by a decrease in secondary products of lipid peroxidation and restoration of the activity of antioxidant defense enzymes.

Thesis to be Defended:

1. Achievement of compensation of carbohydrate metabolism is a necessary, but not a sufficient condition for normalization of the functional state of erythrocytes in patients with type 2 diabetes mellitus.

2. The use of bi flavonoids dicvertin and tanakan leads to relative normalization of antioxidant defense enzymes and MDA, indirect markers of nitric oxide (nitrites and nitrates of blood plasma) against the background of restoration of lipid and carbohydrate metabolism.

3. Prescribing therapy with dicvertin and tanakan with the same effect stabilizes the course of proliferative diabetic retinopathy in patients with type 2 diabetes mellitus.