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The aim of this study was to study the effect of metformin (Met) on the formation of the conditional passive avoidance skills, markers of neurogenesis and oxidative stress in the brain of rats with acute intracerebral hemorrhage (ICH) in the setting of streptozotocin-nicotinamide-induced diabetes. Type 2 diabetes mellitus (T2DM) was induced in rats via the intraperitoneal injection of streptozotocin (STZ) and nicotinamide (NA), ICH – by microinjection of bacterial collagenase into the striatum. Rats were randomly divided into four groups: 1 – intact animals (n=8), 2 – T2DM (n=9); 3 – T2DM+ICH (n=7); 4 – T2DM+ICH+Met (n=7). The passive avoidance test was used to evaluate behavioural activity. Advanced oxidation protein products (AOPP) and lactate were measured by spectrophotometry, advanced glycation end products (AGEs) by quantitative fluorescence, level of 8-hydroxy-2-deoxyguanosine (8-OHdG) was assessed by enzyme-linked immunosorbent assay (ELISA). Histopathological examination was performed using general histological staining techniques and immunohistochemical methods for assessment of expression of endothelial NO-synthase (eNOS), Growth Associated Protein 43 (GAP43), Hypoxia-inducible factor 1-alpha (HIF-1α), neural cadherine (N-cadherine) and vascular endothelial cadherine (VE-cadherine). In this study, metformin had nootropic (anti-amnestic) activity and decreased oxidative stress markers (AGEs, AOPPs and 8-OHdG) levels by 29.1% (p

The review analyzed literature data on the epidemio­logy, risk factors, and mechanisms of acute cerebrovascular accident (ACVA) in patients with diabetes mellitus. The role of insulin resistance and the effectiveness of therapeutic approaches to its correction in cerebral stroke are considered. Diabetes mellitus is recognized as an independent modifiable risk factor for ACVA. In people with diabetes of different age, the risk of stroke is increased by 2–6 times, and the indicators are especially high in patients of young working age. The presence of diabetes mellitus is associated with more severe symptoms, increased risk of complications, longer hospitalization, and higher mortality. Research results show that insulin resistance is one of the main triggers for the development of ischemic stroke due to embolism caused by oxidative stress, endothelial dysfunction and platelet hyperactivation, as well as due to atherosclerotic changes caused by inflammation, proliferation of smooth muscle cells of the vascular wall, dyslipidemia and hypertension on the background of hyperglycemia and hyperinsulinemia. It has been proven that insulin resistance not only provokes ACVA, but also negatively affects their prognosis. Metformin is a key drug for improving insulin sensitivity and is recognized as one of the most important first-line therapeutic agents to achieve and maintain treatment goals in patients with type 2 diabetes. The results of expe­rimental and clinical studies proved that this agent has a whole range of neuroprotective properties, which generally prevent the development of cerebral ischemia and reduce the negative consequences in case of its occurrence. Animals with experimental acute cerebral ischemia who have been treated with metformin had a better overall neurological score, significantly smaller infarct size, better coordination scores, and higher numbers of neurons and microglia. The neuroprotective effect of metformin in stroke is realized through the AMPK (5’AMP-activated protein kinase) signaling pathway with reduction of oxidative stress, neuroinflammation, stimulation of angiogenesis and neurogenesis, autophagy, and inhibition of apoptosis. According to data from cohort and randomized clinical trials, the use of metformin is associated with a significantly lower risk of developing ACVA. Long-term use of this drug in type 2 diabetes contributes to a milder course of stroke, is associated with better functional recovery, and a decrease in disability and mortality rates.

Cardiovascular disorders are one of the leading causes of mortality and morbidity worldwide, and their likelihood increases with the addition of risk factors such as sedentary lifestyle, diabetes, obesity, hyperlipidemia, and hypertension. Elevated blood sugar levels can lead to oxidative stress, dyslipidemia, and endothelial dysfunction, culminating in increased cardiovascular risk. Hyperglycemia adversely affects the cardiovascular system, it is a cause of micro- and macrovascular diseases. Harmful biochemical mechanisms of hyperglycemia are associated with the phenomenon of insulin resistance. Metformin (MF) reduces insulin resistance and, therefore, exerts an antihyperglycemic and insulin-lowering effect in patients with type 2 diabetes. MF, like hypolipidemic statins, also has an additional beneficial pleiotropic, anti-inflammatory and antioxidant effect on the vascular system, in addition to its hypolipidemic and antihyperglycemic effects. Primary is the effect of MF on endothelial dysfunction, as endothelial integrity is a critical long-term determinant of vascular health and, therefore, the occurrence of cardiovascular disease. MF has a very simple chemical structure. The simple structure means that the development of new agents with similar or better properties and mechanisms of action is unlikely, so future use of pharmacokinetic, pharmacodynamic and therapeutic targeting data should be expected to unlock the full therapeutic potential of MF. This approach has recently been demonstrated using a sustained-release MF drug that acts in the distal intestine and exhibits intestinal hormone-dependent antihyperglycemic effect. There are virtually no hidden adverse effects for MF, so it has the potential to provide an effective and safe treatment for hyperglycemia in the future, particularly through its beneficial effects on cardiovascular diseases, including endothelial dysfunction and atherosclerosis. [ABSTRACT FROM AUTHOR]

The modification of the used and development of new treatment regimens significantly improved the overall, recurrence-free survival and quality of life of patients with malignant oncological diseases. Recently, drugs used in non-oncological pathology have been introduced into cancer treatment regimens. This phenomenon is associated with a better understanding of the biology of tumor cells and the mutations that can change this biology. Metformin is actively researched in terms of the treatment of various oncological diseases. For the most part, the modification of the neoadjuvant treatment regimen for early or locally advanced stages of breast cancer results in a less traumatic variant of surgical procedure, thereby increasing recurrence-free survival. The aim is to systematize the data on the possibilities of the antitumor metformin usage for neoadjuvant treatment of breast cancer and to study the results of clinical and morphological effectiveness of the treatment by reviewing the literature. A search of PubMed from February 2023 showed 258 results on the antitumor effects of metformin, of which only 159 were published in the last 5 years. On this subject only four clinical studies were carried out, and only one of them pertained to the implementation of metformin in the systemic treatment of breast cancer. For this review, 55 sources of general and specialized information on anticancer effects of metformin were analyzed. It should be noted that approximately 60% of the study results were published more than 5 years ago and primarily focused on the biological, not clinical aspects of metformin usage. Only one study regarding the implementation of metformin for systemic treatment of breast cancer was carried out by Ukrainian scientists. Currently, there are 2 main hypotheses regarding the antitumor effect of metformin. First one is driven by its impact on the metabolic function of cells and energy deficit. Second – the method of regulating the proliferation of tumor cells involves the PIK3 branch of the regulatory cascade of biological reactions in cancer cells. In addition, metformin reduces the development of resistance in breast cancer cells, thus allowing active chemotherapy agents to act in synergism. However, further studies on the effect of metformin used alone or in combination with standard chemotherapy regimens require a more adequate definition of proto-oncogenic mutations and somatic mutation load. However, it should be considered that more aggressive therapy of oncological diseases can be a nosocomial selector of more aggressive clones of the pool of tumor cells. The main questions are whether metformin can be a targeted drug for the treatment of tumor, whether it is appropriate to use it at the time when the manifestation of evolution disturbances of tumor cell is minimal and homogeneity is maximal.

Background. The cellular and molecular mechanisms underlying gastrointestinal complications caused by type 2 diabetes mellitus (T2DM) may involve accumulation of misfolded proteins in the endoplasmic reticulum that disrupts protein homeostasis and activates a signaling pathway termed the unfolded protein response (UPR). The goal of the present study was to assess the state of the UPR system in gastric glandulocytes of untreated and metformin- and propionate-treated T2DM rats. Materials and methods. Rats with induced T2DM received metformin, propionate, and their combination. Analysis of the levels of 78-kDa glucose-regulated protein (GRP78), activating transcription factor 6 (ATF6), protein kinase R-like endoplasmic reticulum kinase (PERK), and inositol-requiring enzyme 1 (IRE1) was performed by Western blotting and immunohistochemical assessment of slices. Results. In T2DM rats, an increase in GRP78 vs. control (normal) group was found. Metformin and propionate treatment led to an increase in GRP78; under combination therapy, its content was registered at the level in untreated T2DM group. An increase in the ATF6 in T2DM rats was found, and all treatment regimens contributed to its growth. The PERK level in T2DM rats exceeded that in controls, and propionate treatment caused its decrease to the level observed in control group. An immunohistochemical assessment revealed a tendency to increase the intensity of immunoreaction for GRP78 in T2DM rats. With metformin treatment, an intensive immunoreaction for GRP78 was revealed. The general trend in T2DM rats was a significant increase in ATF6 expression. Conclusions. Combination treatment with metformin and propionate led to a significant decrease in GRP78, which may indicate a positive effect of such therapy. New data on propionic acid effect on UPR in the stomach have been obtained that may be beneficial for developing possible treatment strategies in complications of gastropathy caused by diabetes.

Background. Monotherapy for type 2 diabetes (T2DM) has been found to be effective only for a limited time. At the same time, the rationality of drug combinations remains an important component of successful management of T2DM. In this context, given the complex multifactorial pathogenesis of T2DM, it is optimal to influence various mechanisms of hyperglycemia. The purpose of the study is to determine the effectiveness and safety of additional administration of a combination of metformin and glimepiride in patients with type 2 diabetes with a glycated hemoglobin (HbA1c) level of 8.5–9.5 % who took dapagliflozin alone for at least three months. Materials and methods. Fourteen men (mean age 57.9 ± 8.4 years) and 18 women (mean age 58.2 ± 9.3 years) with T2DM were included in the study. The average duration of T2DM was 9.7 ± 4.2 years. The patients were in a state of decompensation of T2DM (HbA1c over 8.5 %) against the background of dapagliflozin monotherapy in the maximum dose for at least three previous months. In addition to dapagliflozin (10 mg/day), patients were prescribed a combination of metformin and glimepi­ride (Duglimax tablets, 500 mg/2 mg once a day) for three months. Results. The average level of HbA1c in 32 patients with T2DM was 9.72 ± 0.81 %, fasting plasma glucose was 10.71 ± 1.42 mmol/l. Three months after the start of a combined treatment, the HbA1c level decreased significantly to 7.54 ± 0.46 % (p

Background. Metabolic syndrome (MS) is a complex of disorders characterized by abdominal obesity, insulin resistance and glucose tolerance, arterial hypertension, and all types of metabolic disorders. Taking into account the wide range of symptoms accompanying MS, the use of preparations with pleiotropic effects on metabolic processes in the body could be promising for its treatment. Objective. The aim of this study is comparative estimation of metformin or its combination with vitamins' complex or liposomal preparation treatment effects on DNA, RNA, histones, ATP, ADP, AMP contents, and DNA fragmentation processes in testes of rats with MS induced in juvenile age. Methods. MS model was induced by full replacement of drinking water with 10% fructose solution in Wistar male rats of 21–23 days age (50–70 g). DNA, RNA, histones, ATP, ADP, AMP contents, and DNA fragmentation processes investigations were carried out after 60 days of MS modeling and metformin or its combination with vitamins' complex or liposomal preparation treatment. Results. In experiments with pubertal rats with MS and metformin or its combination vitamins' complex or liposomal preparation treatment, we established partially corrective effects of these medications for DNA, RNA, histones, ATP, ADP, AMP contents, and DNA fragmentation processes changes caused by MS development. Conclusions. A comparative analysis of the studied preparations' effects under MS simulation in the juvenile age showed that none of these drugs was able to completely normalize the disorders in studied indicators caused by MS. However, both combinations of metformin with vitamins' complex or liposomal preparation were still more effective in these negative changes' correction then metformin itself. Metformin with vitamins' complex caused a more pronounced influence on the processes of DNA fragmentation, the levels of adenyl nucleotides, and the energy charge of rat testicular cells, while the corrective effect of metformin with liposomal preparation was more noticeable with respect to the content of chromatin components.

The relevance of improvement and clinical approval of modern treatment regimens is determined by the insufficient efficiency of protocols for the treatment of malignant tumors in dogs and the lack of research on the possibility of repurposing certain pharmacological agents for use in veterinary oncology. The manuscript demonstrates the results of a pilot study of using metformin as part of a chemotherapy protocol in female dogs with poorly differentiated tubular mammary carcinoma after mastectomy. Considering the hypoglycemic effect of metformin, it was used as part of an adjuvant protocol in a metronomic mode in female dogs with a normal and high body mass index. Combined oral administration of cyclophosphamide (endoxan) and metformin at a dose of 12.5 mg/m2 and 10 mg/kg, respectively, for 6 months prolonged the median survival in female dogs with a normal body index (from 135.8 days, 95% CI 40–234 to 178.6 days, 95% CI 22–394, p < 0.01) as well as in overweight patients (from 93.4 days, 95% CI 15–174 to 237.8 days, 95% CI 38–373, p < 0.001). Herewith, a high body mass index compared to a normal one recognized as the risk of animal death due to the disease progression. The feasibility of using metformin in overweight patients is consistent with a reliably high glucose level before starting treatment. Herewith, blood content of triglycerides and total cholesterol did not depend on the body weight of the dogs and was within the physiological norm in all dogs. Adjuvant therapy with cyclophosphamide (endoxan) and metformin in a metronomic mode for six months was accompanied by a slight decrease (within the lower limit of reference values) of the blood glucose level against the background of the absence of pronounced changes in the concentration of triglycerides and total cholesterol. Improved long-term prognosis and the insignificant risk of side effects allow recommending metronomic therapy with cyclophosphamide (endoxan) and metformin after mastectomy in female dogs with mammary gland carcinoma.

Introduction and purpose: PCOS is identified by the presence of underdeveloped follicles in the ovaries caused by a lack of ovulation, and it is linked to heightened production of androgens in the ovaries. The observable symptoms of PCOS encompass irregular or absent menstrual cycles, obesity, and indications of excess androgens such as acne or oily skin. Metformin could be advantageous for a specific group of women with PCOS. The aim of this study is to summarize the current knowledge regarding the effectiveness of metformin in the treatment of PCOS based on available scientific literature. A brief description of the state of knowledge: Metformin indirectly aids in enhancing ovulation and alleviating long-term metabolic issues, although its impact is considered moderate. Metformin also diminishes the levels of particular markers linked to arterial issues and chronic inflammation beneath the surface. This indicates a potential decrease in the continual risks of type 2 diabetes (DM) and cardiovascular disease (CVD) for women dealing with PCOS. Summary (conclusions): Managing PCOS involves personalized targets due to its diverse nature. In clinical practice, metformin is a recommended first step for managing PCOS in overweight or obese patients, particularly when oral contraceptives are not suitable or insulin resistance is evident.

Type 2 diabetes mellitus (T2DM) is associated with a number of complications, in particular, gastrointestinal tract dysfunction. Impaired mucin secretion by the gastric mucosa in rats with T2DM may affect the absorption of drugs in the stomach and may explain the poor efficacy of treatment and correction of the condition. The aim of our work was to study changes in mucin secretion by the mucous membrane of the gastric fundus in rats with T2DM and the administration of metformin in combination with propionate. T2DM was modelled in rats by a high-fat diet for 3 months with a single administration of streptozotocin (25 mg/kg). Pharmacological correction was performed by intragastric administration of metformin (60 mg/kg), propionate (60 mg/kg), and combined administration of the mentioned drugs for 14 days. Structural changes in the gastric mucosa and mucopolysaccharide secretion activity were assessed by histochemistry. Western blot analysis of MUC5AC expression was performed. A significant decrease in mucin production was observed in the lower stomach of rats, which was associated with a decrease in the density of cells actively producing acidic mucopolysaccharides. Metformin administration to animals with T2DM did not restore mucin production in the gastric fundus, whereas propionate administration increased acid mucopolysaccharide secretion. An increase in the neutral component of mucus and MUC5AC was found in T2DM. The combined administration of metformin and propionate helped to reduce the content of this mucin. The identified morphofunctional changes in the gastric fundus require further research and should be taken into account when using oral hypoglycaemic drugs because the loss of the mucin barrier layer may affect the state of the gastric mucosa and the absorption of drugs. [ABSTRACT FROM AUTHOR]

Literature data on epidemiology, mechanisms of development, features of the course of cognitive disorders in type 2 diabetes mellitus (T2DM), as well as prospects for their treatment and prevention were analyzed. Diabetes mellitus is recognized as an independent factor for cognitive impairment and is associated with an increased risk of dementia, the main causes of which are Alzheimer’s disease and vascular dementia. Results of recent research have shown that T2DM due to insulin resistance and a number of other mechanisms accelerates the aging of the brain and the decline of cognitive functions from mild cognitive impairment to dementia, the risk of which is almost doubled. Epidemiological, neuroimaging, and autopsy studies confirm the presence of both cerebrovascular and neurodegenerative mechanisms of brain damage in T2DM. Poor glycemic control is associated with cognitive decline while longer course of diabetes — with deterioration of cognitive functions. According to current guidelines, annual screening is indicated for adults aged 65 and older for early detection of mild cognitive impairment or dementia. The strategy for the treatment and prevention of cognitive impairment in diabetes should be individualized in such a way as to minimize the occurrence of both hyperglycemia and hypoglycemia, and should also be effective in preventing the deve­lopment of vascular complications. Elderly patients with cognitive impairment should have less stringent glycemic goals (such as glycated hemoglobin < 8.0 %). The results of experimental and clinical studies proved that metformin has a whole range of neurospecific properties, which generally prevent the progression of diabetic cerebral disorders and provide a nootropic effect. It has been found that the drug can improve cognitive functions and mood in patients with T2DM, and also prevents the development of dementia, including Alzheimer’s type. The use of metformin allows you to preserve cognitive functions due to a powerful hypoglycemic effect, a low risk of hypoglycemia, as well as a positive effect on other pathogenetic links in the development of diabetic cerebral changes — insulin resistance, hyperinsulinemia, dyslipidemia, inflammation, micro- and macrovascular disorders, which makes it a priority in the treatment of patients with diabetes of any age.

Background. Monotherapy for type 2 diabetes (T2DM) has been found to be effective only for a limited time. At the same time, the rationality of drug combinations remains an important component of successful management of T2DM. In this context, given the complex multifactorial pathogenesis of T2DM, it is optimal to influence various mechanisms of hyperglycemia. The purpose of the study is to determine the effectiveness and safety of additional administration of a combination of metformin and glimepiride in patients with type 2 diabetes with a glycated hemoglobin (HbA1c) level of 8.5–9.5 % who took dapagliflozin alone for at least three months. Materials and methods. Fourteen men (mean age 57.9 ± 8.4 years) and 18 women (mean age 58.2 ± 9.3 years) with T2DM were included in the study. The average duration of T2DM was 9.7 ± 4.2 years. The patients were in a state of decompensation of T2DM (HbA1c over 8.5 %) against the background of dapagliflozin monotherapy in the maximum dose for at least three previous months. In addition to dapagliflozin (10 mg/day), patients were prescribed a combination of metformin and glimepiride (Duglimax tablets, 500 mg/2 mg once a day) for three months. Results. The average level of HbA1c in 32 patients with T2DM was 9.72 ± 0.81 %, fasting plasma glucose was 10.71 ± 1.42 mmol/l. Three months after the start of a combined treatment, the HbA1c level decreased significantly to 7.54 ± 0.46 % (p < 0.05). The average reduction in HbA1c after switching to additional metformin therapy with glimepiride was 1.48 ± 0.38 %. The proportion of patients who achieved HbA1c < 7.5 % was 34.5 % after 3 months (p < 0.05). The effectiveness of the additional administration of metformin and glimepiride is also confirmed by the high percentage of patients (12.5 %) who achieved HbA1c < 7.0 % (p < 0.05). The level of fasting plasma glucose decreased to an average of 7.19 ± 1.06 mmol/l after 3 months. The average decrease reached 3.06 ± 1.08 mmol/l, which in relative terms was 31.4 ± 8.7 % of baseline. No cases of hypoglycemia or other adverse events were registered during the entire study period. Conclusion. The analysis of indicators in 32 patients with type 2 diabetes who had a high level of HbA1c (over 9 %) against the background of dapagliflozin monotherapy allowed us to conclude that it is necessary to intensify the therapy by additionally prescribing a combination of metformin and glimepiride for achieving the target levels of HbA1c. Glucocentric and cardiocentric views on T2DM can be reconciled and integrated by using a combination therapy to address the different etiopathological features of the disease from the very beginning of treatment. [ABSTRACT FROM AUTHOR]

Background. Obesity, prediabetes and type 2 diabetes mellitus (T2DM) are global diseases affecting the population of Ukraine, with an annual increase in morbidity. Insulin resistance occurs in up to 90 % of obese patients, contributing to the accumulation of white adipose tissue, and has a risk for the further development of prediabetes and T2DM. However, other factors also play a negative role in the development of obesity, particularly cholecalciferol (vitamin D) deficiency. Vitamin D is a steroid hormone the main function of which is to regulate calcium and phosphorus metabolism, but this molecule also exhibits va­rious properties, including the effects on carbohydrate metabolism. The purpose of this study was to identify and evaluate the role of vitamin D elevation in patients receiving glucagon-like peptide-1 agonists (GLP-1a) in combination with lifestyle interventions for the treatment of obesity and to compare its effectiveness with that in patients treating with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2i). Materials and methods. A prospective study included 155 obese patients, and follow-up data were available for 49 of them. The study group consisted of 30 patients receiving combination therapy with GLP-1a liraglutide at a dose of 1.2 to 3.0 mg per day. The control group included 19 patients recei­ving combination therapy with metformin in daily doses of 500 to 2,000 mg, and SGLT2i in daily doses of 10 to 12.5 mg. Treatment of vitamin D deficiency was performed with cholecalciferol at a dose of 4,000 IU/day. Results. In study group GLP-1a, 25 (83.3 %) patients had vitamin D insufficiency, which is statistically similar to control group (p > 0.05) — 17 (89.5 %) cases. All patients with vitamin D insufficiency received 4,000 IU of cholecalciferol daily during the follow-up period. In study group GLP-1a, the mean body mass before the treatment was 104.6 kg, after treatment — 96.36 kg (p = 0.000007), the mean weight lost was 7.8 % (range is 1–23.71 %) of the initial level. Mean body mass index (BMI) before treatment was 37.1 kg/m2, after treatment — 34.11 kg/m2 (p = 0.000006). In the control group, the mean weight before the treatment was 99.4 kg, after treatment — 91.74 kg (p = 0.000196), the mean weight lost was 7.73 % (range is 0–16.9 %) of the initial level. BMI before treatment averaged 35.6 kg/m2, after treatment — 34.11 kg/m2 (p = 0.000196). The analysis of carbohydrate metabolism parameters showed a significantly lower blood glucose level — 5.75 mmol/l in the study group GLP-1a compared to 8.42 mmol/l in the control group (p = 0.00024). It should be noted that a similar clinical picture was also observed after treatment, despite the compensation of T2DM in all patients: a significantly lower blood glucose level — 5.03 mmol/l in the study group GLP-1a compared to 5.99 mmol/l in controls (p = 0.002453). However, significantly higher levels of insulin were detected in the study group GLP-1a before treatment — 27.02 mU/L compared to 18.59 mU/L in control patients (p = 0.003286). After treatment, a similar situation was observed in terms of significantly higher levels of insulin: 19.41 mU/l in patients of the study group GLP-1a compared to 14.42 mU/l in controls (p = 0.0024). Corresponding changes were also observed for the HOMA index. Conclusions. Our results suggest high effectiveness of increasing the level of vitamin D in case of its insufficiency as a part of measures for the treatment of obese patients with liraglutide, metformin or SGLT2i.

Literature data on epidemiology, mechanisms of development, features of the course of cognitive disorders in type 2 diabetes mellitus (T2DM), as well as prospects for their treatment and prevention were analyzed. Diabetes mellitus is recognized as an independent factor for cognitive impairment and is associated with an increased risk of dementia, the main causes of which are Alzheimer’s disease and vascular dementia. Results of recent research have shown that T2DM due to insulin resistance and a number of other mechanisms accelerates the aging of the brain and the decline of cognitive functions from mild cognitive impairment to dementia, the risk of which is almost doubled. Epidemiological, neuroimaging, and autopsy studies confirm the presence of both cerebrovascular and neurodegenerative mechanisms of brain damage in T2DM. Poor glycemic control is associated with cognitive decline while longer course of diabetes — with deterioration of cognitive functions. According to current guidelines, annual screening is indicated for adults aged 65 and older for early detection of mild cognitive impairment or dementia. The strategy for the treatment and prevention of cognitive impairment in diabetes should be individualized in such a way as to minimize the occurrence of both hyperglycemia and hypoglycemia, and should also be effective in preventing the development of vascular complications. Elderly patients with cognitive impairment should have less stringent glycemic goals (such as glycated hemoglobin < 8.0 %). The results of experimental and clinical studies proved that metformin has a whole range of neurospecific properties, which generally prevent the progression of diabetic cerebral disorders and provide a nootropic effect. It has been found that the drug can improve cognitive functions and mood in patients with T2DM, and also prevents the development of dementia, including Alzheimer’s type. The use of metformin allows you to preserve cognitive functions due to a powerful hypoglycemic effect, a low risk of hypoglycemia, as well as a positive effect on other pathogenetic links in the development of diabetic cerebral changes — insulin resistance, hyperinsulinemia, dyslipidemia, inflammation, micro- and macrovascular disorders, which makes it a priority in the treatment of patients with diabetes of any age. [ABSTRACT FROM AUTHOR]

Background. Dry eye disease is a multifactorial condition, which is characterized by impairment of tear film formation. Lacrimal glands metabolism plays a critical role in dry eye disease. Emotional stress may impair lacrimal glands function. Purpose. We aimed to study production of nitric oxide from constitutive and inducible NO-synthases, activity of arginases and oxidative stress markers in lacrimal glands of rats during modeling of water avoidance stress (WAS) and its correction by metformin and corvitin. Material and methods. We concluded our experiment on 36 adult male rats of Wistar line weighing 190-240 g. Animals were divided into 6 groups consisting from 6 animals each, namely: control group, WAS group, group of correction by metformin (200 mg/kg) and group of correction by corvitin (10 mg/kg) during WAS modeling. And two drug-control groups. Results. WAS leads to increased activity of inducible NO-synthase, superoxide dismutase, catalase and concentration of MDA by 1.59, 1.93, 1.97 and 1.28 times respectively. Metformin and corvitin decreased activity of inducible NO-synthase by 8.25 and 8.5 times respectively, concentration of MDA decreased by 1.35 and 1.26 times respectively. Activities of superoxide dismutase did not change after introduction of metformin and corvitin. Metformin decreased catalase activity by 1.47 and corvitin increased it by 1.55 times. Production of superoxide dropped during WAS by 1.59 times and was increased to level below or equal that of control animals with introduction of metformin and corvitin. Conclusion. Increased activity of inducible NO-synthase during WAS is a possible reason of tissue damage in lacrimal glands of rats. Introduction of metformin or corvitin during WAS are an effective means for correction of tissue damage in lacrimal glands of rats due to their ability to lower increased inducible NO-synthase activity.

Background. The obesity is found in 24.8 % (approximately 10 million people) and overweight in 34.3 % of the population of Ukraine, mainly in females. Obesity is associated with hereditary factors, overeating as well as a sedentary lifestyle. An integrated approach is applied to treat obesity such as combination of adequate eating behavior, high physical activity and administration of pharmacological correction, including glucagon-like peptide 1 agonist (GLP-1). Currently, the little is known about utility and effectiveness of GLP-1 in combination with adequate physical activity for obesity management among Ukrainian patients. The purpose of this study was to determine and evaluate the role of GLP-1 in combination with high physical activity for weight loss in obese patients and to compare with obese patients receiving treatment with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2i). Materials and methods. A prospective study included 155 obese patients, and follow-up data were available of 49 patients. The study group GLP-1 consisted of 30 patients receiving combination therapy GLP-1 liraglutide in daily doses of 1.2 to 3 mg per day. The control group consisted of 19 patients receiving complex therapy with metformin in daily do­ses from 500 to 2000 mg, and SGLT2i in daily doses from 10 to 12.5 mg. Body mass index (BMI), waist circumference (WC), hip circumference (HC), and WC/HC ratio were evaluated. Number of daily steps was determined using pedometers built into smartphones or smartwatches. Evaluation of the obtained data was performed using non-parametric statistical methods. Results. In study group GLP-1 the mean weight before the treatment was 104.6 kg, after treatment 96.36 kg (p = 0.000007), the mean weight lost was 7.8 % (range 1–23.71 %) of initial body weight. Mean BMI before treatment was 37.1 kg/m2, after treatment 34.11 kg/m2 (p = 0.000006). In the control group, the mean weight before the treatment was 99.4 kg, after treatment 91.74 kg (p = 0.000196), the mean weight lost was 7.73 % (range 0–16.9 %) of initial body weight. Mean BMI before treatment was 35.6 kg/m2, after treatment 34.11 kg/m2 (p = 0.000196). Analyses of the entrie chorot showed that before treatment, the daily number of steps > 5000/day was determined in 25 (51 %) patients, after treatment in 48 (98 %); the daily number of steps > 10,000/day before treatment was determined in 6 (11 %) patients, after treatment it was 5 times more frequent in 31 (63 %) patients. These results indicate a significant intensification of physical activity, and high motivation for weight loss in both study groups. Conclusions. Our findings suggest that weight loss in obese people is effective in case of administration of GLP-1, metformin, SGLT2i in combination with high physical activities of daily steps > 5000, which is part of life style intervention.

This comparative research is aimed to study the effect of perindopril and metformin on the levels of biochemical markers of endothelial dysfunction in rats with type 2 diabetes mellitus (T2DM) complicated by a brain hemorrhage. The study was carried out on 30 white male Wistar rats. T2DM was simulated by a single intraperitoneal injection of nicotinamide and streptozotocin (NA/STZ). Intracerebral hemorrhage (ICH) was induced by microinjection of 1 μL of bacterial collagenase 0.2 IU/μL into the striatum on the 60th day of the experiment. Animals were randomized into 5 groups: A – negative control (intact, n=6); B – positive control 1 (NA/STZ, n=6); C – positive control 2 (NA/STZ+ICH, n=6); D – perindopril (“Prestarium”, 2 mg/kg+NA/STZ+ICH, n=6); E – metformin (“Siofor”, 250 mg/kg+NA/STZ+ICH, n=6). The studied drugs were administered intragastrically for 20 days, starting from the 50th day after the induction of T2DM. Endothelial function was assessed by the content of homocysteine (Hcy), advanced glycation end products (AGEs), endothelin-1 (ET-1), and von Willebrand factor (vWF) in blood serum. It was found that long-term separate T2DM is accompanied by hyperhomocysteinemia, as well as an increase in AGEs, ET-1, and vWF levels, indicating dysregulation of the hemostasis system and vascular tone. It should be noted that brain hemorrhage in T2DM can enhance these manifestations, although the obtained differences were characterized only by a persistent trend. At the same time, the effect of perindopril was limited only by a significant decrease in AGEs levels by 31.2% (p

The polycystic ovarian syndrome is an endocrine disorder with a high prevalence affecting reproductive-aged women and adolescent girls. The most common symptoms are infertility, numerous ovarian cysts, hyperandrogenism, menstrual cycle abnormalities. The disease has a great impact on patients, impairing their quality of life. Bearing that in mind, innovative therapeutic approaches are needed. We aim to describe current management and treatment concepts adopted in PCOS therapy. The analysis of previously published studies was conducted by using the PubMed, Google Scholar, and Scopus databases.Mentioned studies show that lifestyle changes may benefit PCOS therapy in multiple ways. Dietary and exercise interventions have a notable influence on women’s body composition as well as biochemical parameters. The reduction of body weight or BMI is a therapeutic achievement likewise patients’ contribution to managing PCOS. Pharmacotherapy provides plentiful treatment choices to adopt. Studies show that hormonal contraceptive has a significant impact on both hyperandrogenism and menstrual abnormalities. Metformin is proven to reduce BMI, improve LDL levels, and lower the risk of OHSS in women undergoing IVF/ICSI-ET. A meta-analysis proved metformin’s monotherapy superiority over clomifene citrate or their combination in treating infertility. However, both substances are not recommended as the first-line choice. Regrettably, many studies mention short of evidence, lack of larger sample sizes, or insufficient duration preventing further research.The conclusion we draw is that approaches of managing and treating PCOS are constantly advancing and updating. However, there is a necessity for future studies to expand their research by gathering more data and considering diverse cases.

Introduction: Life expectancy of human population is being constantly prolonged, hence there is a lot of research into drug that will prevent the effects of aging. There are many reports that metformin, which is a drug used in type 2 diabetes, has anti-aging effects. It belongs to the group of biguanides and has been used since the 1950s. It is a relatively safe, cheap and effective drug, which makes it a promising subject for many studies. The purpose of this review is to present the latest developments in this field. Material and methods: PubMed scientific base was searched using following keywords: metformin, aging, anti-aging, in years 2017-2021. Results: Numerous studies show that metformin has an impact on aging through the nutrient pathway, AMPK signaling pathway, and its effects on reactive oxygen species. In addition, it has an anti-cancer effect, inhibiting, among others, rectal cancer cells and p53 mutant colon cancer. Research in rodents has shown that this drug has anti-aging effects on many organs, including the CNS, ovaries, prostate, heart muscle and skin. Conclusions: Metformin, which is the most commonly used oral drug in type 2 diabetes, has many other mechanisms of action. Its anti-aging effect works on many organs in our bodies, which gives hope to find an anti-aging substance. However, multicentre, randomized trials are needed to determine the exact anti-aging dose, its possible side effects, and effects on various organisms.

INTRODUCTION AND PURPOSE: Metformin is one of the most frequently prescribed medications in the whole world. This lipophilic biguanide is widely used as a first-line medicine for patients suffering from type 2 diabetes mellitus because of its high effectiveness in monotherapy, and in connection with other antidiabetic drugs. Glucose-lowering properties of metformin were initially used only in the therapy of type 2 diabetes mellitus, but some data indicate that these properties might state an alternative in the prevention or treatment of some cancers both among diabetic and non-diabetic patients. STATE OF KNOWLEDGE: Metformin molecular mechanisms of action were thoroughly investigated, differentiated, and described, but in the context of the glucose-lowering effect. As a multiway drug, used mainly in diseases characterized by an increased level of glucose in the blood, numerous medical trials were conducted to find other treating properties of metformin. Recently, a few reports presented the potential connection between using metformin in the prevention and treatment of neoplasms in the same mechanisms. The scientists analyzed the influence of metformin’s action on various cancers and drew conclusions. The research on potential anti-cancer features of metformin was conducted for a relatively short period and still presents a challenge to scientists. CONCLUSIONS: The aim of this review is to gather current knowledge and present the latest discoveries about potential anti-cancer features of metformin. We discuss the potential underlying molecular mechanisms of metformin’s action in the human body and indicate the connection between the prevention and treatment of neoplasms. Additionally, we point out the exact cancers in which metformin might play a significant role.

Introduction: Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disease. It is characterized by persistent pruritus, usually occurring after 30 weeks of pregnancy, and by elevated levels of bile acids and transaminases, which decrease over the course of 2-3 weeks postpartum. [1,2]The occurrence of ICP in the mother may be associated with significant complications in the fetus, such as: preterm labor, intrauterine asphyxia, or sudden fetal death. Currently, the treatment of choice is ursodeoxycholic acid (UDCA).[2,6] Recently, it was observed that the administration of metformin in cases not responding to standard therapy improved lipid disorders in pregnant women. The aim of the study: The aim of the study is to present the possibility of using metformin in the treatment of ICP in pregnant women not responding to standard treatment and to present a clinical case.. Material and methods: The work is a review of the literature on the management of ICP and the use of metformin in the treatment of lipid metabolism disorders, as well as a brief case report of a patient with intrahepatic cholestasis of pregnancy. Description of the state of knowledge: Metformin is an oral antidiabetic drug belonging to the group of biguanides. However, the latest observations show that metformin also has a beneficial effect on the liver function and on the lipid metabolism in pregnant women. In these patients, the levels of bile acids and liver enzymes decreased after the use of metformin. Summary: The mechanism of action of metformin explaining its beneficial effect on the lipid metabolism in pregnant women with intrahepatic cholestasis is not fully understood.

Background. Obesity, prediabetes and type 2 diabetes mellitus (T2DM) are global diseases affecting the population of Ukraine, with an annual increase in morbidity. Insulin resistance occurs in up to 90 % of obese patients, contributing to the accumulation of white adipose tissue, and has a risk for the further development of prediabetes and T2DM. However, other factors also play a negative role in the development of obesity, particularly cholecalciferol (vitamin D) deficiency. Vitamin D is a steroid hormone the main function of which is to regulate calcium and phosphorus metabolism, but this molecule also exhibits various properties, including the effects on carbohydrate metabolism. The purpose of this study was to identify and evaluate the role of vitamin D elevation in patients receiving glucagon-like peptide-1 agonists (GLP-1a) in combination with lifestyle interventions for the treatment of obesity and to compare its effectiveness with that in patients treating with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2i). Materials and methods. A prospective study included 155 obese patients, and follow-up data were available for 49 of them. The study group consisted of 30 patients receiving combination therapy with GLP-1a liraglutide at a dose of 1.2 to 3.0 mg per day. The control group included 19 patients receiving combination therapy with metformin in daily doses of 500 to 2,000 mg, and SGLT2i in daily doses of 10 to 12.5 mg. Treatment of vitamin D deficiency was performed with cholecalciferol at a dose of 4,000 IU/day. Results. In study group GLP-1a, 25 (83.3 %) patients had vitamin D insufficiency, which is statistically similar to control group (p > 0.05) — 17 (89.5 %) cases. All patients with vitamin D insufficiency received 4,000 IU of cholecalciferol daily during the follow-up period. In study group GLP-1a, the mean body mass before the treatment was 104.6 kg, after treatment — 96.36 kg (p = 0.000007), the mean weight lost was 7.8 % (range is 1–23.71 %) of the initial level. Mean body mass index (BMI) before treatment was 37.1 kg/m², after treatment — 34.11 kg/m² (p = 0.000006). In the control group, the mean weight before the treatment was 99.4 kg, after treatment — 91.74 kg (p = 0.000196), the mean weight lost was 7.73 % (range is 0–16.9 %) of the initial level. BMI before treatment averaged 35.6 kg/m², after treatment — 34.11 kg/m² (p = 0.000196). The analysis of carbohydrate metabolism parameters showed a significantly lower blood glucose level — 5.75 mmol/l in the study group GLP-1a compared to 8.42 mmol/l in the control group (p = 0.00024). It should be noted that a similar clinical picture was also observed after treatment, despite the compensation of T2DM in all patients: a significantly lower blood glucose level — 5.03 mmol/l in the study group GLP-1a compared to 5.99 mmol/l in controls (p = 0.002453). However, significantly higher levels of insulin were detected in the study group GLP-1a before treatment — 27.02 mU/L compared to 18.59 mU/L in control patients (p = 0.003286). After treatment, a similar situation was observed in terms of significantly higher levels of insulin: 19.41 mU/l in patients of the study group GLP-1a compared to 14.42 mU/l in controls (p = 0.0024). Corresponding changes were also observed for the HOMA index. Conclusions. Our results suggest high effectiveness of increasing the level of vitamin D in case of its insufficiency as a part of measures for the treatment of obese patients with liraglutide, metformin or SGLT2i. [ABSTRACT FROM AUTHOR]

Introduction and purpose Insulin resistance is a state of decreased tissue sensitivity to insulin, despite normal or elevated levels of this hormone in the blood serum. People with insulin resistance for a long time do not show symptoms, which makes it particularly difficult to detect and treat in early stages. It mainly leads to impaired glucose homeostasis and the development of type 2 diabetes, which contributes to the exacerbation of the global problem that diabetes has become. This results in the search for innovative therapies that will help combat insulin resistance better and better. The purpose of this study is to highlight the complexity of the IR and review the current literature for non-pharmacological and pharmacological possibilities of treatment for insulin resistance. Description of the state of knowledge Due to the increase in obesity and the metabolic syndrome, the number of people suffering from insulin resistance is constantly increasing. In modern times, there are various diagnostic and therapeutic methods that affect the course of insulin resistance. Early detection and introduction of appropriate therapy become the main goal in preventing complications that may occur in the course of this disease. Summary Treatment methods for insulin resistance can be divided into two groups - non-pharmacological and pharmacological. Both of them are often used together in the form of combination therapy aimed at obtaining the best results in the treatment of insulin resistance. For people for whom known therapies do not work, researches for new treatments is becoming a hope.

Polycystic ovary syndrome (PCOS) is a known disease among endocrinologists and gynecologists. The aforementioned disease entity affects up to six to twelve percent of women of reproductive age. [1] In 2017, the incidence among women of childbearing age was 82.44 per 100,000 population. A decade ago, it was 1.45% lower.[2] PCOS is a disease in which we have abnormal hormone levels. The result may be a problem with regular menstruation, problems with becoming pregnant, acne or excessive body weight. [3] Most often, patients arediagnosed only when complications occur. It is closely related to asignificant reduction in living standards. There are problems such as hair loss, acne and infertility.

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Purpose: To examine changes in the activity of endothelial nitric oxide (NO) synthase in the development of endothelial dysfunction in experimental diabetic retinopathy corrected by various methods. Material and Methods: Albino (Wistar) rats (weight, 180-200 g) were used in this study and divided into 7 groups 60 animals each. Results: We found impaired endothelial function at day 30 of the experiment, and, subsequently, animals exhibited progression of pathological changes. Hypoglycemic agent only caused a mild, but not significant improvement in endothelial dysfunction, and did not allow restoration of normal synthesis of the proper amount of NO. Application of L-arginine and aflibercept in combination with hypoglycemic therapy for diabetic retinopathy led to repair of endothelial dysfunction and contributed to restoration of the physiological pathway for production of NO. Application of aflibercept and bromfenac in combination with hypoglycemic therapy for diabetic retinopathy led to a less pronounced effect than multi-component therapy including L-arginine, and this effect was not durable and significantly decreased by day 180. Application of aflibercept, L-carnitine and bromfenac in combination with hypoglycemic therapy showed more promising results than the above methods: endothelial NO synthase (eNOS) activity increased at time point 1, and continued to increase subsequently, although normal values were not achieved. Conclusion: Aflibercept, L-arginine and citicoline in combination with hypoglycemic therapy was the most effective method among those tested in this study, with eNOS activity not only increasing as early as day 30, but also continuing to increase subsequently (days 60 and 180) and achieving normal values at day 180.

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Chronic hyperglycemia, insulin resistance, endothelial dysfunction, and disturbance of the integrity of the blood-brain barrier are considered as strategically important links in the development of cognitive deficits in diabetic encephalopathy. Taking this into account, one of the modern trends in the optimization of the treatment of cognitive impairments induced by prolonged hyperglycemia is the co-administration of agents with antihyperglycemic and nootropic activity, in particular, metformin with piracetam. It has been shown that under conditions of experimental alloxan-induced hyperglycemia, piracetam has insufficient nootropic potential for eliminating cognitive deficits. Metformin has a weak nootropic effect in short-term use in low doses, without exhibiting these properties in prolonged administration. When combined with piracetam, metformin potentiates its antiamnesic properties, which helps to restore cognitive functions impaired by hyperglycemia. It is assumed that the mechanisms of such synergism are mediated by a decrease in the content of early and late markers of the destruction of protein molecules, the level of stable nitric oxide metabolites in the cerebral cortex, as well as a significant limitation of the manifestations of ultrastructural destructive changes in hippocampal neurons with a simultaneous improvement in the state of its microvasculature. The obtained results indicate the expediency of the combined use of metformin with nootropic agents for the prevention or treatment of cognitive impairments that occur as a result of diabetes mellitus.

According to experts from the International Diabetes Federation, the total number of people with diabetes mellitus (DM) will increase from 463 million in 2019 to 578 million in 2030 and to 700 million in 2045. In the context of the COVID-19 pandemic, patients with type 2 DM are more vulnerable to infection and severe pathology. Approaches to the choice of antihyperglycemic therapy to achieve ideal glycemic status are changing, given the emergence of new data on the pathogenesis of DM complications. Nowadays, the concept is adopted about individualization of antihyperglycemic therapy, i.e. the selection of treatment regimens based on information about a particular patient, the course and risk of developing diabetic complications. Given the increase in the proportion of elderly people, the treatment of type 2 DM in this age group is one of the important medical and social problems. Antihyperglycemic therapy in this population is difficult due to the increased risk of hypoglycemia, the presence of multiorgan and comorbid pathology, which significantly affects the course of type 2 DM. The literature review considers the issues of adequate prescription of drugs, in particular dipeptidyl peptidase-4 inhibitors. The presence of the expected hypoglycemic effect without the risks of hypoglycemia, good tolerability, favorable cardiovascular potential allows their widespread use in the elderly and senile patients with type 2 DM. The focus of the review is made on the VERIFY study that found that early combination therapy with vildagliptin and metformin reduces the risk of glycemic control loss by 49 %, exceeds the strategy of gradual intensification, provides stable control of glycated hemoglobin for 5 years, ensures its consistently low level, which is especially important in the first year of therapy to slow the progression of type 2 DM complications. Therefore, early combination therapy with vildagliptin and metformin in patients with type 2 DM has advantages over the strategy of gradual intensification.

Diabetes mellitus (DM) is a recent problem due to the high prevalence of the disease and the high mortality of patients. The most common complications of type I and II diabetes include heart and kidney damage. Metformin, as a first-line drug in the treatment of type 2 diabetes, are known to reduce the risk of cardiovascular and renal complications. Recently, metformin has been shown to increase H2 S in the organs of rats, which is a known cardio- and nephroprotector. However, the effect of metformin on H2 S metabolism in the heart and kidneys in experimental diabetes remains uncertain. The ability of H2 S donors to modify the antidiabetic effect of metformin is also unknown. Objective: to evaluate the effect of metformin and its combination with sodium hydrogen sulfide on H2 S system, the content of profibrogenic mediator galectin-3, the activity of free radical oxidation of lipids and proteins in the heart and kidneys of rats with streptozotocin-induced diabetes. Object and methods of research. The experiments were carried out on 40 white laboratory rats of both sexes, weight 220-280 g. DM model was initiated by a single intraperitoneal injection of streptozotocin (40 mg/kg) in three groups of animals. From the 3rd to the 28th day after streptozotocin injection, one group of animals was administered metformin (500 mg/kg) intragastrically once per day, and the other group along with metformin was administered a H2 S donor – NaHS • H2 O (3 mg/kg) once per day intraperitoneally. Peripheral blood glucose was measured using a glucometer, galectin-3 levels were determined by enzyme-linked immunosorbent assay (ELISA) kit in myocardial and renal homogenates, H2 S content, cystathionine-γ-lyase (CGL) activity, levels of malonic dialdehyde (MDA group) and carbonic acid. Statistical processing of the results was performed using SPSS Statistica 17.0. Research results. According to our results, a single injection of streptozotocin caused a number of metabolic disturbances : an increase in blood glucose by 4.6 times (p

Almost half of deaths in Poland (approximately 49%) are caused by cardiovascular system diseases. It means that in 2018 it contributed to the death of over two hundred thousand people in our country. Myocardial infarction, stroke and heart failure are the most common of cardiovascular diseases (CVD). The main risk factor for progression of cardiovascular diseases is type 2 diabetes mellitus (T2D). It is estimated that almost 3 million people suffer from T2D in Poland. Metformin is a promising medicine that reduces cardiovascular risk in patients with T2D. It is currently used as the first line drug in patients suffering from T2D. The aim of the presented article is to review current research on the effectiveness of the metformin as a medicine that reduces cardiovascular risk in patients with T2D. Metformin is the oldest and most commonly used medicine that reduces the concentration of glucose in the peripheral blood in patients with T2D. Due to its very good safety profile, low cost and high effectiveness, metformin is used in the first-line treatment for T2D. Recent studies indicate its protective effect by vasodilation, reducing the size of myocardial infarction, inhibiting apoptosis of cardiomyocytes or reducing oxidative stress. Currently, metformin can be seen to have a great potential in the treatment of cardiovascular complications occurring in the course of T2D. Despite the fact that this medicine has been on the market for many years, the studies on its cardioprotective effects have been carried out for a relatively short period of time. It is possible that the detailed understanding of all mechanisms of action of metformin will lead to future advances in the treatment of not only T2D, but also cardiovascular and cancer diseases.

Type 2 diabetes mellitus (DM) is one of the most common diseases in the world. According to data of the International Diabetes Federation, there are more than 425 million people suffering from this disease in the world. The course of type II DM is accompanied by a progressive lesion of the macrovasculature, which is associated with an increase in the risk of developing atherosclerosis in this category of patients by 4-5 times in comparison with patients without diabetes. This in turn leads to some complications such as blindness, strokes, vascular damage of the limbs and chronic renal failure (CRF), which is often the leading cause of death. The occurrence of any inflammatory process against the background of diabetes is a significantly aggravating factor for the patient, as the body’s reserves are reduced, especially in the presence of CRF. The need for urgent surgical intervention in a patient with an inflammatory process against the background of diabetes is another stress factor. In addition, patients with DM are constantly taking hypoglycemic drugs, the effect of which in a stressful situation is not always predictable for the patient and therefore these drugs should be canceled. However, if the patient has CRF and long-term administration of drugs, their effect does not immediately stop. The combination of all the above points puts the patient with DM at a high risk group for the development of serious complications requiring intensive care (IT). Such complications in the early postoperative period may be lactic acidosis, persistent hypoglycemia, electrolyte disorders, cerebral edema. In the clinical case the pathogenesis of the development of these conditions and IT methods are described. Conclusions have been drawn regarding the need for close attention of anesthetists and intensive care physicians during perioperative therapy in patients with DM, complicated CRF, and which are receiving metformin.

The aim of the study was to analyze changes in erythrocyte diphosphoglycerate levels and Willebrand factor in the development of hypoxia and endothelial dysfunction in experimental diabetic retinopathy. The study was performed on white Wistar rats weighing 180-200 g. Our results indicate the development of hypoxia on the 30th day of development of experimental diabetic retinopathy with subsequent progression of pathological changes on the 60th and 180th day of the study, as evidenced by the decrease level of 2,3 diphosphoglycerate of erythrocytes in the 2nd group (p rd stage of the experiment (p rd stage of the experiment (p

The aim of our research is investigating the changes in the level of interleukin 1β in experimental animals, which were simulated diabetic retinopathy and against the background of its correction. The obtained indicate that already on the 30th day of the development of experimental diabetic retinopathy, a significant increase in the pro-inflammatory cytokine level draws attention. Analyzing the data of group No. 3, it was established that the correction of the pathological condition with hypoglycemic agents has a positive effect but requires the involvement of additional means of correction in addition to the normalization of the level of glycemia. The results of the 4th experimental group indicate that the involvement of a nitric oxide donor and aflibercept in the correction of diabetic retinopathy has a positive effect on the reduction of the level of Interleukin 1β, but it does not reach an approximation to the norm. It is observed that the correction of the simulated pathological condition by reducing hyperglycemia, administration of aflibercept and bromfenac (group No. 5) gives positive results, but less pronounced than involvement in the complex correction of L-arginine solution in the study of nitric oxide synthases, in the analysis of the pro-inflammatory cytokine level the results are better. It is also worth noting that this method of correction is not characterized by longevity and on the 180th day there is already a pronounced decrease in its effectiveness. It was found that in rats in which diabetic retinopathy was modeled with subsequent correction of hyperglycemia, administration of aflibercept, L-carnitine and bromfenac (group No. 6), there is a pronounced effectiveness of the proposed method of correction in comparison with the previously considered methods. As for the correction applied in the 7th group, in the first and second stages, the inflammation indicator is more elevated compared to the two previous groups (No. 5 and No. 6), but in the third stage, a marked decrease in the level of the marker was established, which indicates the effectiveness of the correction of the 7th group at more distant stages of the experiment.

To date, the key role of endothelial dysfunction in the occurrence and progression of diabetes mellitus and diabetic retinopathy has been proven. The study was performed on white Wistar rats weighing 180-200 g. According to the tasks, the animals were divided into 7 groups. Our results indicate a violation of vasodilation on the 30th day of experimental diabetic retinopathy with subsequent progression of pathological changes on the 60th and 180th day of the study, as evidenced by a decrease in the content of S-nitrosothiols in group 2 (p rd stage. When analyzing the data of group № 3, it was found that the correction of the pathological condition with the help of hypoglycemic agents has some positive effect, but does not allow to significantly adjust the pathological development of reduced vasodilatory potential. The results of the 4th group indicate that the involvement of nitric oxide donor and aflibercept in the correction of diabetic retinopathy corrects the pathological changes and helps to restore the physiological pathway of nitric oxide synthesis and vascular tone, the maximum effect is observed on the 180th day of the experiment, but normative cannot be achieved. It is observed that the correction of the simulated pathological condition by reducing hyperglycemia, administration of aflibercept and bromfenac (group № 5) gives positive results in the first stage, but less pronounced than involvement in the complex correction of L-arginine solution in subsequent stages. It was found that rats in which diabetic retinopathy was simulated with subsequent correction of hyperglycemia, administration of aflibercept, L-carnitine and bromfenac (group № 6) have a pronounced tendency to normalize the studied marker of hypoxia in comparison with the previous methods in the second stage. nitrosothiols at the time of reaching the 3rd stage is reduced. The obtained data suggest that the method of correction chosen in group 7 (correction of hyperglycemia, aflibercept, L-arginine and citicoline solution) more pronouncedly normalizes the content of the vasodilation marker compared to other groups of our experiment, which is pronounced in long-term correction - on 180th day.

The aim of our study was to analyze the changes in the blood glucose level in experimental animals that simulated diabetic retinopathy and against the background of its correction. The obtained results show the development of experimental diabetes when streptozotocin is administered at a dose of 55 mg/kg of animal weight against the background of a high-fat diet. Correction with hypoglycemic agents in the 3rd group had a positive effect, but it was not able to completely normalize the level of glycemia, so the need arose for the use of additional agents. The use of aflibercept and a nitric oxide donor in the 4th group had a more pronounced positive effect compared to the 3rd group, but the result did not reach the control indicators. Combined administration of bromfenac and aflibercept in the 5th group showed itself to be less effective in the study of the blood glucose level at all stages in comparison with the data of the 4th group, in which the NO donor was involved in the correction. Administation of aflibercept, L-carnitine and bromfenac to the animals of the 6th group had a more pronounced positive effect in comparison with the group No. 5, but did not reach the values of the 4th group of the experiment. The most effective correction was the combination of metformin, aflibercept, L-arginine and citicoline in rats of the 7th group, which is evidenced by the normalization of the level of the studied indicators on the 30th and 60th days of the experiment, and on the 180th, the most pronounced decrease was recorded hyperglycemia.

Hyperglycemia stimulates the development of oxidative stress, which in turn is a powerful pathophysiological mechanism for the development of microvascular complications in diabetes. Increased production of reactive oxygen species is observed both during development and during the progression of diabetic retinopathy.The study was performed on white Wistar rats weighing 180-200 g. According to the tasks, the animals were divided into 7 groups: 1st group - 60 intact animals; Group 2 - 60 animals in which diabetic retinopathy was simulated without further correction. Group 3 - 60 animals, which simulated diabetic retinopathy with subsequent correction of hyperglycemia; Group 4 - 60 animals in which diabetic retinopathy was simulated with subsequent correction of hyperglycemia, administration of aflibercept and L-arginine solution; Group 5 - 60 animals in which diabetic retinopathy was simulated with subsequent correction of hyperglycemia, administration of aflibercept and bromfenac; Group 6 - 60 animals in which diabetic retinopathy was simulated with subsequent correction of hyperglycemia, administration of aflibercept, L-carnitine and bromfenac; Group 7 - 60 animals, which simulated diabetic retinopathy with subsequent correction of hyperglycemia, the introduction of aflibercept, a solution of L-arginine and citicoline.The results indicate the development of oxidative stress from the 30th and with subsequent progression on the 60th and 180th days of experimental diabetic retinopathy, which is confirmed by a decrease in peroxidase activity in the 2nd group, the maximum of which is observed in the 3rd stage. Correction with hypoglycemic agents in group 3 had a positive effect, but was not able to restore the activity of the antioxidant enzyme, so there was a need for additional drugs. The use of aflibercept and nitric oxide donor in group 4 to correct the development of diabetic retinopathy had a positive effect on increasing the activity of peroxidase, which peaked on the 180th day of the experiment, but did not reach the control values. The combined administration of bromfenac and aflibercept in group 5 was shown to significantly increase antioxidant activity, but not as significantly as in group 4. Administration of aflibercept, L-carnitine, and bromfenac to group 6 animals was shown to restore antioxidant protection as early as day 30 and was continued on days 60 and 180 of the study, but the results did not reach control values. The combination of metformin, aflibercept, L-arginine and citicoline in rats of the 7th group proved to be the most effective correction, as evidenced by the normalization of peroxidase activity on the 30th and 60th day of the experiment, and on the 180th recovery of marker activity to control values was recorded.

Background. Polycystic ovary syndrome (PCOS) is a polymorphic disease with an extremely variable clinical picture and different phenotypes, which is observed in 5–10 % of women of reproductive age. During the life of women with PCOS, the risk of developing type 2 diabetes mellitus is increased by 10 times, arterial hypertension and coronary heart disease — by 7 times, including myocardial infarction, and there was more than double risk of ovarian, endometrial and breast cancer. The purpose of the study was to analyze the dynamics of parameters of insulin resistance (IR), dyslipidemia, impaired glucose tolerance after metformin treatment in PCOS patients using Caro index and HOMA­IR. Materials and methods. Twenty­six case histories of patients with PCOS who were treated with metformin for the period from 2012 to 2018 for six months from the date of diagnosis were analyzed. In 2018, all patients underwent blood lipids study, a standard glucose tolerance test, and immunoreactive insulin content study in venous blood plasma. Carbohydrate metabolism was evaluated using the Caro index and HOMA­IR. Results. Metformin use in 26 women with PCOS and insulin resistance resul­ted in a significant fasting immunoreactive insulin decrease (from 21.4 ± 2.3 µIU/ml to 6.9 ± 0.8 µIU/ml; p = 0.005) in 6 months, while significant changes in the level of fasting glycemia were not observed. Accordingly, HOMA­IR decreased from 4.38 ± 1.26 to 1.17 ± 0.18 (p = 0.01), and the Caro index increased from 0.24 ± 0.05 to 0.58 ± 0.14 (p = 0.02). Assessment of lipid metabolism 6 months after initiation of metformin treatment confirmed a significant decrease in cholesterol level — from 5.4 ± 0.3 mmol/l to 3.6 ± 0.5 mmol/l (p = 0.01), and triglyceride content — from 1.7 ± 0.2 mmol/l to 0.8 ± 0.2 mmol/l (p = 0.03). A survey conducted in 2018 in the same patients showed an increase in body weight not only compared with indicators 6 months after metformin treatment, but also with baseline. There was a significant increase in cholesterol to 6.7 ± 0.4 mmol/l (p = 0.01 compared with indicator after the metformin treatment) during the 2018 survey. Conclusions. Women with PCOS and insulin resistance, central obesity, dyslipidemia are at highest risk of developing diabetes and cardiovascular pathology. Metformin is considered a potentially effective method to overcome insulin resistance, improve hormonal, biochemical parameters and possibly reduce cardiovascular risk in PCOS.

Background. Diabetic nephropathy has become the primary cause of end-stage renal disease worldwide. Pigment epithelium-derived factor (PEDF) is an endogenous anti-inflammatory factor in vivo, which can inhibit the expression of pathogenic factors — transforming growth factor β1 and connective tissue growth factor, and suppresses extracellular matrix protein production in diabetic kidney, suggesting an antifibrogenic activity. The aim of this study was to investigate the effect of metformin on renal tissue PEDF expression in type 2 diabetic rats and explore its possible underlying protective mechanisms in renal injury. Materials and methods. Ten clean male Sprague-Dawley rats were randomly selected as the normal control group. Type 2 diabetes model were induced by a high-fat diet and intraperitoneal injection of 30 mg/kg streptozotocin. A total of 30 type 2 diabetic rats were divided into 3 groups, which were treated with metformin 300 mg/kg/day (MET group, n = 10), glibenclamide 5 mg/kg/day (GLY group, n = 10), or saline (DM group, n = 10) by gavage for 8 weeks. Various biochemical parameters, kidney histopathology and renal tissue PEDF expression levels were examined. Results. At the 8th week, fasting blood glucose, glycated hemoglobin, triglyceride levels, urinary albumin and PEDF excretion, serum creatinine and blood urea nitrogen in MET group and GLY group decreased significantly compared to DM group, there were no significant differences in fasting blood glucose and glycated hemoglobin between MET group and GLY group. The histological examinations revealed amelioration of diabetes-induced glomerular pathological changes following treatment with MET and GLY when compared to DM group. In addition, urinary albumin and PEDF excretion were decreased, glomerular pathological changes was lightened and protein and mRNA expression of renal tissue PEDF were increased more in MET group compared with GLY group. Conclusions. Metformin reduced urinary albumin excretion in diabetic rats, and improved podocyte morphology and structural damage. The mechanism may be partly related to its role in restoring PEDF expression and inhibiting urinary excretion of PEDF.

BACKGROUND: Diabetes is very widespread disease. More and more patients suffer from hyperglycaemia and low levels of insulin because of obesity, aging and wrong diet. The most important in treatment based on health condition is to normalize glucose level. It is recommended to treat patients to avoid many complications of hyperglycaemia, e.g. cardiovascular diseases, stroke episodes, neuropathy or nephropathy. The most common cause of death are cardiovascular problems and renal failure. MATERIAL AND METHODS: A proper review of published literature provide to define laboratory indexes, risk factors, complications to precise methods of treatment among patients with diabetes. RESULTS: The problem of growing number of people suffering from diabetes is an important issue to find solutions to conduct their treatment. Basic method is a change of diet and body loss. The most important medicament in treatment is metformin. To achieve the best results of conducting therapy should be extended by pioglitazone or liraglutide. Also addition of aspirin lower dyslipidemia problems. Such a combination provides to minimise side effects of sickness. CONCLUSIONS: Number of people suffering from DM is still and will be growing over the next years. It is significant to diagnose these people because untreated diabetes provides to many complications e.g. stroke or acute coronary syndrome. It is important to examine patients correctly what allows to turn on correct treatment. Basic standards in treatment should contain lower glucose levels, avoid complications to enhance life quality. . Expanded therapy is also concentrated on hypertension, acidosis and ketoacidosis coma to obtain beneficial effects.

Background. Adverse side effect of metformin is disturbance in vitamin B12 metabolism associated with low serum vitamin B12 level. B12 hypovitaminosis is accompanied by peripheral neuropathy. The aim of the study was to determine the effectiveness of methylcobalamin (Diacobal preparation manufactured by Kusum Pharm LLC, Ukraine) in correcting vitamin B12 deficiency in diabetic patients with metformin­associated vitamin B12 deficiency, and to establish its effect on manifestations of diabetic neuropathy. Materials and methods. Thirty patients with type 2 diabetes mellitus and metformin­associated vitamin B12 deficiency (< 190 pg/ml) were examined. Duration of metformin administration was 6.1 years on average, the average dose was 2100 mg/day. Methylcobalamin was administered at a dose of 500 mg three times a day for three months. Determination of vitamin B12 content and assessment of neuropathy manifestations was carried out before and after the course of treatment. Results. After the course of treatment, it was found that the average content of vitamin B12 in the blood serum reached the reference values (312.4 ± 39.8 pg/ml). The positive effect of therapy on the severity of clinical manifestations of peripheral sensory motor neuropathy in the examined patients was revealed: in 17 (56.7 %) patients, the severity of numbness in feet significantly decreased, in 6 (20 %) persons, there was a complete disappearance of numbness. The intensity of the pain syndrome decreased in 19 (63.3 %) patients, the pain syndrome was completely removed in 3 (10 %) persons. Conclusions. The relationship between metformin and B12 hypovitaminosis has been confirmed. Diacobal is an effective and safe drug for the prevention and treatment of metformin­induced vitamin B12 deficiency and diabetic neuropathy.

Background. Recent studies have shown that patients with diabetes mellitus (DM) often have skeletal disorders, in particular, reduced bone mineral density, osteoporosis. Apart from the disease itself, the nature of hypoglycemic therapy can make a significant contribution to increasing the risk of diabetes mellitus. The aim of the study was to evaluate the effect of metformin on the serum vitamin D level in patients with type 2 DM. Materials and methods. There were 47 patients under observation. The main group (n = 25) included patients who suffered from type 2 DM and received treatment with metformin, a hypoglycemic drug. The control group consisted of apparently healthy persons (n = 22). The study excludes patients with pathology of parathyroid glands, thyroid function disorders, kidney disease, and those taking vitamin D or calcium. Le­vels of 25­hydroxyvitamin D (25(OH)D), parathormone, ioni­zed calcium, glycated hemoglobin (HbA1c) were evaluated. Results. Forty­seven patients aged 42 to 69 years (average age 58.0 ± 17.5 years) were examined. A study of serum 25(OH)D level showed that in most patients it was low. The average level of 25(OH)D in the main group was 18.37 ± 7.62 ng/ml (5.89–32.8 ng/ml). The study showed a higher prevalence of vitamin D deficiency among patients with type 2 DM (66.7 %) receiving metformin than in the control group (7.69 %). It was found that vitamin D levels were lower in patients with poorer glycemic control of type 2 DM (HbA1c > 7 %) — 15.03 ± 7.60 ng/ml and 22.75 ± 7.62 ng/ml, respectively. Conclusions. The study showed a higher prevalence of vitamin D deficiency among patients with type 2 DM (66.7 %) receiving metformin than in the control group (7.69 %). A reliable inverse correlation was found between the elevated HbA1c level and reduced 25(OH)D content. The level of 25(OH)D was significantly lower in the main group of patients receiving metformin therapy compared to the control group.

Metformin is one of the most widely used oral antihyperglycemic agents. Adverse effect of metformin is disturbance in vitamin B12 metabolism associated with low serum vitamin B12 level. Vitamin B12 hypovitaminosis is accompanied by peripheral neuropathy. The long-term use can cause anemia and increase the risk of depression, cerebrovascular and neurodegenerative diseases. Clinical studies and meta-analyses have constantly confirmed the association between metformin use and vitamin B12 hypovitaminosis. It was shown that every 25 pmol/l increase in B12 level was associated with a 6% reduction in the risk of neuropathy. The application of B12 would help compensate the disturbances in vitamin B12 metabolism caused by metformin.

The aim of work to investigate the changes in the vascular endothelium growth factor in experimental animals, which were simulated diabetic retinopathy and against the background of its correction. The results of the analysis of the vascular growth factor in the 2nd group confirm the development of diabetic retinopathy, a particularly pronounced increase in the marker was detected on the 180th day of the development of the pathological process. It was established analyzing the data of group No. 3 that the correction of the pathological condition with hypoglycemic agents has partial positive effect but requires the involvement of additional means of correction in addition to the normalization of the level of glycemia. The results of the 4th group indicate that the involvement of a nitric oxide donor and aflibercept in the correction of diabetic retinopathy has positive effect on the reduction of the level of vascular growth factor, more pronounced compared to the 3rd group, but it does not reach normative values. It is observed that the correction of the simulated pathological condition by reducing hyperglycemia, administration of aflibercept and bromfenac (group No. 5) gives positive results, but less pronounced, compared to the data of the 4th group. It was found that in rats in which diabetic retinopathy was modeled with subsequent correction of hyperglycemia, administration of aflibercept, L-carnitine and bromfenac (group No. 6) at the first stage, there is a pronounced effectiveness of the proposed method of correction in comparison with the previously considered methods, the established positive trend is being followed also at the 2nd and 3rd stages of the experiment, which indicates the effectiveness of this correction method. The most pronounced positive effect of normalizing the level of vascular growth factor is observed when using a hypoglycemic drug in combination with the administration of aflibercept, a solution of L-arginine and citicoline (in group No. 7).

The purpose of the study was to analyze the histological changes in the structures of the eyeball in experimental diabetic retinopathy and its correction with metformin, aflibercept, L-arginine solution and citicoline. The obtained results indicate about the development of pathological changes in the retina against the background of the progression of experimental diabetes when streptozotocin is administered at dose 55 mg/kg of animal weight against the background of a high-fat diet. The development of simulated streptozotocin diabetes is accompanied by disturbance in the retina in the form of edematous shifts of fibers and swelling of the cells forming it, uneven distribution of cells of the ganglion layer and vacuolization of the cytoplasm some of them. The using of corrective drugs complex for metabolic disorders and angiopathy, which are characteristic of diabetes mellitus, affects on the retina condition. Under the influence of aflibercept, solution of L-arginine, citicoline, and metformin administration was established that edematous changes in its structural elements are significantly reduced, the number of vessels on the border with the retina visually increases, and the staining of the cells of the ganglion layer becomes more freshly.

Background. Diabetic cardiomyopathy is the leading cause of mortality in patients with type 2 diabetes mellitus. Hypertrophy of cardiomyocytes is one of the main pathomorphological signs of diabetic cardiomyopathy development. Metformin, the first-line drug for the treatment of type 2 diabetes mellitus, along with hypoglycaemic effects, exerts cardioprotective effects. However, the mechanism of metformin action in cardiomyocytes remains unclear. The purpose of the study was to investigate the role of Foxo1 gene expression in the mechanism of antihypertrophic action of metformin in cardiomyocytes. Materials and methods. H9C2 cells were transfected with siRNA Fохо1 and siRNA negative control. Cells were deprived in 0% medium for 24 hours, treated with metformin (5mM) 30 min before cell stress, then put into hypoxic chamber for 16 hours and reoxygenated for 4 hours. Cell area was quantified using ImageJ. Knockdown efficiency was confirmed by real time polymerase chain reaction. Results. At the normal functioning of Fохо1 gene, metformin has the expressed antihypertrophic action under hypoxia. However, blocking Fохо1 gene expression deprives preparation of this effect and causes the hypertrophy of Н9С2 cells in all conditions of the experiment. Conclusions. The strong hypertrophic response in the group of H9C2 cells transfected with siRNA Foxo1 cultured under hypoxia with metformin treatment may be a result of following mechanisms: a) metformin prevents hypertrophy through Foxo1 pathway, thus, Foxo1 silencing totally blocked metformin protective effects on H9C2 hypertrophy; b) metformin protects against hypoxia independently of Foxo1 pathway, therefore, strong hypertrophy of metformin-treated cells incubated in hypoxia is the result of Foxo1 knockdown, a potent hypertrophic stimulus. Consequently, further investigations are still required to clarify the mechanisms by which metformin exerts its cardioprotective effects.

The review deals with the analysis of modern li­terature, including the results of own researches on the mecha­nism of the therapeutic effect of metformin in patients with type 2 diabetes mellitus (DM2) and its complications. Despite the fact that a vast number of patients are treated with metformin, there are a large number of publications around the world in which its clinical effect is discussed, the mechanism of the curative action of metformin remains unclear. The paper pre­sents new data indicating that not only the hypoglycemic effect of metformin plays an important role in the mechanism of the curative effect in DM2 and its complications, but also its favorable effect on inflammation and immunoregulatory processes disturbed in DM2, as evidenced by a decrease in the inflammatory index (N/L index), normalization of the quantity and function of lymphocytes of various immunophenotypes and reduced levels of proinflammatory cytokines and chemokines in the blood.

Copyright of International Journal of Endocrinology / Mìžnarodnij Endokrinologìčnij Žurnal is the property of Zaslavsky O.Yu and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Chronic hyperglycemia, insulin resistance, endothelial dysfunction, and disturbance of the integrity of the blood-brain barrier are considered as strategically important links in the development of cognitive deficits in diabetic encephalopathy. Taking this into account, one of the modern trends in the optimization of the treatment of cognitive impairments induced by prolonged hyperglycemia is the co-administration of agents with antihyperglycemic and nootropic activity, in particular, metformin with piracetam. It has been shown that under conditions of experimental alloxan-induced hyperglycemia, piracetam has insufficient nootropic potential for eliminating cognitive deficits. Metformin has a weak nootropic effect in short-term use in low doses, without exhibiting these properties in prolonged administration. When combined with piracetam, metformin potentiates its antiamnesic properties, which helps to restore cognitive functions impaired by hyperglycemia. It is assumed that the mechanisms of such synergism are mediated by a decrease in the content of early and late markers of the destruction of protein molecules, the level of stable nitric oxide metabolites in the cerebral cortex, as well as a significant limitation of the manifestations of ultrastructural destructive changes in hippocampal neurons with a simultaneous improvement in the state of its microvasculature. The obtained results indicate the expediency of the combined use of metformin with nootropic agents for the prevention or treatment of cognitive impairments that occur as a result of diabetes mellitus. [ABSTRACT FROM AUTHOR]

Copyright of International Journal of Endocrinology / Mìžnarodnij Endokrinologìčnij Žurnal is the property of Zaslavsky O.Yu and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)