RU2535069C2 - Composition of antioxidant composition aimed at suppression of oxidative process in case of type 2 diabetes - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compositions of an antioxidant composition aimed at the suppression of oxidative stress in type 2 diabetes. The said compositions contain, counted per 1 dose: 50-120 mg of coenzyme Q10, 30-160 mg of dihydroquercetin, and 30-60 mg of A-lipoic acid or 50-100 mg of coenzyme Q10, 50-100 mg of dihydroquercetin, 30-60 mg of A-lipoic acid and 50-100 mg of nicotineamide.

EFFECT: compositions possess an antioxidant activity and prevent the development of the fatty tissue dysfunction.

2 cl, 1 dwg, 2 tbl, 2 ex

Description

The invention relates to medicine and relates to compositions that can be made including in the form of biologically active additives with the properties of antioxidants and stimulators of the restoration of antioxidant systems of various cells of the human body, including adipose tissue cells and are intended to correct adipose tissue dysfunction, etc. organs with various types of oxidative stress, including obesity and type 2 diabetes (hereinafter - D2T).

The invention consists in the fact that for the prevention and correction of oxidative stress and adipose tissue dysfunction, a complex composition is proposed whose components have a synergistic effect on various metabolic and signaling systems, including genome activation and activation of antioxidant systems or suppression of prooxidant systems and correction of the dysregulation of lipid reaction systems exchange of adipocytes of white adipose tissue, as well as cells of other tissues and organs.

The composition for the prevention and treatment of oxidative stress of various tissues and for the treatment of adipose tissue dysfunction contains: coenzyme Q10, dihydroquercytin and alpha lipoic acid, and may also contain nicotinamide.

Composition of antioxidant composition aimed at suppressing oxidative stress in type 2 diabetes, containing per dose:

coenzyme Q10 - 50-120 mg; dihydroquercytin - 30-160 mg; A-lipoic acid 30-60 mg. As well as a composition of an antioxidant composition aimed at suppressing oxidative stress in D2T, containing per dose:

coenzyme Q10 - 50-100 mg; dihydroquercytin - 50-100 mg; A-lipoic acid - 30-60 mg;

nicotinamide - 50-100 mg.

The invention provides an expansion of the arsenal of agents with antioxidant activity, as well as agents that prevent the development of adipose tissue dysfunction.

D2T is considered a pandemic of the 21st century [1]. According to WHO, the number of overweight patients with obesity metabolic syndrome (MS) and D2T in developed countries exceeds 50%. This figure has doubled over the past 20 years. Among adolescents and children, the number of patients with MS and D2T exceeds 18%, and among the adult population, 24-26% [1-3]. The number of patients with D2T in Russia exceeds 15 million people, including more than 4 million patients in adolescence and childhood.

D2T is a chronic metabolic metabolic disorder in the body, caused mainly by excessive consumption of high-calorie foods in combination with a sedentary lifestyle. D2T is characterized at first by redundancy and in the later stages by insufficiency of the pancreatic secretion function and (or) ineffective action of insulin (Ins), as an activator and main regulator of glucose consumption by insulin-dependent tissues and organs. This condition is called insulin resistance. D2T is characterized by chronic hyperglycemia, dyslepidemia and disturbances in the metabolism of carbohydrates, lipids and proteins in various tissues [2-4]. Long chain fatty acids (LCFAs), which come from high-calorie foods or re-form with excess carbohydrates, are considered a key toxin in D2T.

Many researchers believe [4–8] that oxidative stress plays a central role in the pathogenesis of this multifactorial disease, caused by an excess of toxins circulating in the blood - LCFA and glucose.

It is believed that oxidative stress leads to dysfunction of various organs and tissues. The sequential development of obesity in MS and further may lead to the occurrence of:

- cardiovascular diseases and endothelial dysfunction - 20-30%;

- tumor diseases - 10%;

- dysfunction of the liver (non-alcoholic steatohepatitis) or pancreas (steatosis and acute pancreatitis) and the development of D2T with the subsequent development of liver cirrhosis and (or) chronic pancreatitis - 60-70%.

The life span of patients does not exceed 20–25 years since the onset of MS [2,4].

Recently, in addition to dysfunction of the vascular system, liver and pancreas, adipose tissue dysfunction has also been considered. The term “sick fat” is introduced, since adipose tissue dysfunction carries a great pathogenic potential [2]. Only in recent years has it become clear that white adipose tissue is the most important endocrine and immune organ in the body, producing dozens of useful adipokines. In conditions of obesity, MS and the subsequent development of D2T, the formation and death of hypertrophied adipocytes leads to the activation of macrophages and the transformation of WAT from a useful organ to an organ producing pro-inflammatory cytokines, such as tumor necrosis factor (TNFa), interleukins 1.6, etc. Under such conditions, from an active buffer organ capable of storing toxic LCFAs in the form of neutral triglycerides (in a satiated state) and secreting LCFA into the blood under conditions of hunger and an organ producing beneficial adipokines, the WAT turns into an organ that is unable to ivno store and oxidize the LCFA, producing pro-inflammatory cytokines.

The mass of adipose tissue in a healthy person can be 15-18 kg, and in patients with obesity, MS and D2T up to 30-50 kg or more, which in conditions of WAT dysfunction and death of hypertrophic cells poses a serious danger to the whole body [2].

The development of oxidative stress and endoplasmic reticulum stress in WAT, liver, pancreas is characterized by suppression of the activity of antioxidant systems: metabolic pathways for the synthesis of NADPH and reduced glutathione (GSH), as well as neutralization reactions of reactive oxygen species (ROS), H2O2, etc., including superoxide dismutase ( SOD), catalase (CAT), glutathione peroxidase (GSHPx), etc., and an increase in the activity of prooxidant systems involving NADPH oxidase (NOX) and arachidonic acid metabolism reactions, including cytoplasmic phospholipase (PLA2), lipoxygenase (LO 5.12), etc. [7.9-11].

To a large extent, such metabolic rearrangements may be associated with the activation of nuclear Ca-dependent factors (including NFAT and NFkb) that occur in the presence of elevated Ca ++ levels in the cytoplasm of different cells in patients with MS and D2T [12].

It is currently unknown what may be the primary factor in the chain of events - obesity → MS → D2T: liver dysfunction (non-alcoholic steatohepatitis), pancreatic dysfunction and fatty degeneration (acute steatopancreatitis), or WAT hypertrophy and dysfunction.

In our opinion, in most cases, the primary cause of MS and D2T is WAT dysfunction, which leads to WAT's inability to efficiently remove toxic LCFAs and glucose and its transformation into an organ that produces pro-inflammatory cytokines, which, when combined with LCFA, causes nonspecific oxidative stress in the body .

Antioxidants are widely used as possible remedies for MS and D2T.

Antioxidants are molecules or substances that can slow down or prevent the oxidation of other molecules. In turn, oxidation is the transfer of electrons from an oxidized substance to an oxidizing agent in reactions associated with the production of free radicals, reactive oxygen species (ROS), peroxides (H2O2), etc., which in turn include chains of reactions that damage various cell systems.

Developing non-specific oxidative stress is a by-product of a number of natural physical and physiological processes, such as intense physical exercise, physical and emotional stress, chemotherapy, drug poisoning, the effects of polluting and toxic substances, radiation, etc. Oxidative stress is also considered as one of the aging factors. in which there is also a pronounced extinction of aerobic (mitochondrial) energy metabolism of cells of various types.

Developing non-specific oxidative stress is controlled with the participation of antioxidant systems (listed above) and dysfunction of this protection or depletion of antioxidant systems leads to DNA and RNA damage, undesired oxidation of amino acid residues of proteins and lipids and subsequent apoptosis of cells.

Most well-known and common diseases, including neoplastic diseases, hepatic encephalopathies, neurodegenerative diseases, etc. along with MS and D2T are also characterized by the presence of oxidative stress associated with activation of the known set of prooxidant markers listed above [13, 14].

In MS and D2T, the oxidative stress associated with the toxic effect of LCFA and proinflammatory cytokines (TNFa, IL1.6, etc.) is global in nature and affects almost all endocrine organs (liver, pancreas, WAT) and vascular endothelial cells [3, 14 ]. There is a process also associated with stress of the endoplasmic reticulum and possible nitrosative stress.

The development of nitrosative stress, in turn, is associated with the activation of inducible NO synthesis (iNOS) by pro-inflammatory cytokines and with the suppression of the activity of the NO → cGMP → PKG chain, the activity of which in our opinion plays an important role both in maintaining Ca2 + cell homeostasis and in the induction of antioxidant systems.

The role of Ca2 + in the development of oxidative stress and in the development of dysfunction of WAT and other organs in D2T is also underestimated, although patented methods for the correction of dyslepidemia and insulin resistance using consistent use of hyper and hypo-calcium diets are well known [15, 16].

Attempts to use antioxidants in the treatment of D2T have been made for many years and include the use of: vitamins C and E, coenzyme Q10, A-lipoic acid, riboxitaurin, dihydroquercytin, ω ₃ polyunsaturated fatty acids, as well as extracts from natural products containing antioxidants, including : bananas, bitter gourd, black garlic, and combinations of various herbs [17-24].

A recent meta-analysis of the clinical use of various antioxidants in the treatment of D2T showed that there is no pronounced advantage of using antioxidants in comparison with known pharmacological drugs [25].

At the same time, a number of substances listed above are not direct-acting antioxidants, and their effect can be mediated by induction of the synthesis of enzymes of various metabolic and signaling systems. This primarily refers to: coenzyme Q10 [20] - one of the key elements of the respiratory chain of mitochondria and an inducer of mitochondriogenesis; to A-lipoic acid, one of the key cofactors involved in the transfer of acyl groups by mitochondrial NADH-dependent dihydrogenases. Moreover, it has recently become clear that A-lipoic acid is not only an inducer of mitochondriogenesis, but also has an activating effect on the activation of de novo kinase G (PKG) synthesis [26, 27].

In turn, PKG and the NO - cGMP - PKG signaling pathway play an important role in the regulation of Ca2 + cell homeostasis of various types and adipose tissue lipogenesis. Recently, it has also become clear that activation of PKG via atrionatriuretic atrial peptide (ANP) also plays an important role in the regulation of WAT lipolysis. In a number of scientific studies, the activation of this pathway is considered as one of the possible options for the correction of D2T.

It was previously shown that LCFA and their activated derivatives (AcylCoA), activating the Ca2 + channels of the endoplasmic reticulum (IP3 and ryanodine-dependent depots), lead to the growth of Ca2 + in the cytoplasm with the occurrence of nonspecific Na ⁺ conductivity of the plasmalemma and cell death, not by the type of apoptosis but by type necrosis [28].

As our studies have shown, the same mechanism of activation of reticular depots in the chronic version leads to: adipocyte hypertrophy (due to the activation of Ca2 + dependent nuclear factors NFAT and NFkb); activation of the phospholipase cascade; development of oxidative stress and death of adipocytes. Activation of macrophages eliminating dying adipocytes, in turn, leads to the production of pro-inflammatory WAT cytokines (TNFa, IL1,6 and angiotensin II (ANGII)), to further development of oxidative stress due to activation of cascades of reactions involving phospholipases (primarily PLA2). Along with the cytokines produced by adipocytes under these conditions, ANGII provides Ca2 + entry into cells, which leads to even greater activation of cascades of reactions involving phospholipases and, as a result, leads to dysregulation of the key signaling pathway: eNOS - NO - sGC - cGMP - PKG - CD38 - RyR - Ca2 + plays an important role in maintaining Ca2 + cell homeostasis.

Thus, in obesity, MS and D2T, an excess of LCFA, ensuring the growth of Cai in the cell cytoplasm, leads to the formation of a vicious cycle of activation of Ca ++ dependent processes (primarily with the participation of phospholipases PLC, PLD and KPLA2), causing a series of cascade reactions (activation NADH oxidases and lyroxigenases LO5,12) the development of oxidative stress [3, 14, 28, 29].

In contrast to the antioxidant use regimens previously proposed by various authors, we proposed the combined use of coenzyme Q10, A-lipoic acid, dihydroquercetin and nicotinamide (vitamin PP). This combination, as it turned out, has a synergistic effect aimed at inducing mitochondriogenesis, correcting Ca-signaling pathway dysfunction with PKG and RyR, decreasing peroxidase system activities, activating lipolysis and eliminating WAT dysfunction.

The examples below illustrate these points.

Example 1

Table 1 presents data on the generation of reactive oxygen species (ROS) by WAT adipocyte cultures of 9 DIV mice isolated from preadipocytes of epididymal depots in healthy animals (4-6 weeks). The data on ROS growth for 30 minutes with cell growth on glucose (10 mM), on glucose and palmitoylcarnitine (PC 3 μM), as well as in the presence of S1 protector containing A-lipoic acid (100 μM) in the cell culture medium, are presented, and also Q10 (200 μM) and dihydroquercytin (100 μM) dissolved in DMSO.

It can be seen that cell growth in the presence of activated derivatives of LCFA (3 μM PC) leads to an increase in ROS accumulation. When 30 mM PC cells are introduced into the incubation medium, there is almost a twofold increase in ROS growth, both by cells growing on glucose and by cells growing in the presence of 3 μM PC. In this case, there is a pronounced difference in the production of ROS between the cells growing in the absence and presence of the antioxidant composition S1, which indicates the protective properties of the claimed composition.

This conclusion is supported by data on the antioxidant activity of composition S1 in experiments performed on adipocyte cultures grown from preadipocytes obtained from animals with D2T (table 2). From this table it can be seen that under all conditions, the increase in ROS in these cultures is higher than in the previous case. However, culturing cells with S1 also leads to an almost twofold decrease in ROS growth in the presence of 15 μM PC.

The use of large concentrations of PC 30 mm as in an environment with cultures of adipocytes isolated from cells of healthy animals leads to rapid cell death by the type of necrosis described above. In the experiments, animals (mice) were used, in which D2T was caused by the introduction of pig spinal fat (with known LCFA composition) into the diet at the rate of 300-500 mg / 30-50 g of animal weight for 8-12 months. The experiments used WAT epididymal cells depot from animals with indicators of glucose 10-13 mm and Ins 2-4 mg / l after 12 hours of fasting.

Example 2

In this experiment, animals were injected with composition S2, containing: coenzyme Q10, A-lipoic acid, dihydroquercetin and nicotinamide dissolved in dehydrogenated soybean oil at the rate of 20 mg / kg, 10 mg / kg, 15 mg / kg and 15 mg / kg, respectively. The composition was injected with a pper os pipette for four weeks. Table 3 shows comparative data on the increase in ROS produced by suspensions of mature adipocytes isolated from healthy animals and animals with D2T in the absence and presence of 15 μM PC in the cell incubation medium. In this case, the pronounced antioxidant effect of composition S2 is also visible, leading to the suppression of ROS production from 20.3 ± 3.1 to 13.2 ± 2.4 conventional units (table 2).

In fig. Figure 1 shows immunoblotting data on the expression of key proteins (enzymes) - markers of various metabolic and signaling pathways of adipocytes (eNOS, PKGI, cPLA2 and LO-5,12) which allow us to judge the activity of these signaling pathways in healthy animals and in animals with D2T treated or not receiving tread S2. It is seen that animals with D2T are characterized by an increased content (expression) of eNOS, cPLA2 and LO-5 and a decrease in PKG expression (activity), which may indicate dysfunction of the eNOS-NO-cGMP-PKG signaling pathway and activation of prooxidant pathways involving phospholipases ( cPLA2) and the formation of leukotrienes (LO-5,12) leading to depletion of NADPH and GSH. From these data it can be seen that feeding the tread composition S2 to animals leads to a decrease in eNOS expression, an increase in PKG and a decrease in the expression of prooxidant system proteins with PLA2 and LO-5.12.

The high content of eNOS in mice with D2T does not reflect the high activity of this enzyme, but, apparently, is a compensatory reaction to a decrease in the concentration of NADPH (eNOS substrate) in animals with D2T under conditions of the development of oxidative stress.

Thus, the data presented in table 2 and in fig. 1 indicate that the antioxidant composition S2, as well as the composition S1, suppresses ROS production, suppresses the induction of prooxidant pathways, and eliminates PKG signaling pathway dysregulation.

Fig. 1. Comparative data on signaling enzyme markers of healthy mice and D2T mice that received (white bars) and did not receive (black bars) the antioxidant composition of S ₂ . Data for healthy animals is taken as 1. Data on protein expression (immunoblotting) of eNOS, PKGI, .cPLA2 and LO-5.12 in relative units are given.

SUMMARY OF THE INVENTION

The object of the invention are complex compositions having both a direct antioxidant effect and a synergistic effect on various anti- and prooxidant systems of adipocytes and cells of other tissues and organs and capable of:

- ensure the suppression of activated at D2T prooxidant oxidation systems of arachidonic acid and reactions of ROS production by mitochondria;

- increase the activity of signaling pathways involving PKG.

Table 1 Generation of reactive oxygen species (ROS) by adipocyte cultures (9 DIV). The effect of activated derivatives of fatty acids (palmitoylcarnitine - PC) and the tread. Adipocyte cultures (9DIV) isolated from healthy animals preadipocytes PC supplementation in incubation medium Cultivation medium Glucose Glucose + PC (3M) Glucose + PC (3M) + Protector S1 No 4.1 ± 1.2 8.0 ± 2.5 6.4 ± 1.8 30 M RS 8.2 ± 1.6 16.0 ± 2.4 11.2 ± 2.1 Adipocyte cultures (9 DIV) isolated from preadipocytes of animals with D2T PC supplementation in incubation medium Cultivation medium Glucose Glucose + PC (3M) Glucose + PC (3M) + Protector S1 No 7.1 ± 1.3 12.2 ± 3.1 10.8 ± 2.3 15 M PC 11.3 ± 2.8 23.5 ± 3.4 14.7 ± 2.7

ROS growth in 30 minutes. Registration of ROS growth () by fluorescence of Mito Sox Red. Relative units. Average data for 30 cells in 5 experiments.

table 2 The increase in ROS production in a suspension of mature adipocytes isolated from healthy animals and from animals with D2T. PC additives Incubation medium Healthy animal cells Animal cells with D2T - S2 tread - S2 tread - 5.2 ± 1.6 5.0 ± 1.1 8.8 ± 2.6 7.9 ± 1.9 15 m 9.6 ± 2.4 8.5 ± 1.8 20.3 ± 3.1 13.1 ± 2.4

The animals were given S2 per os tread for 1 month. ROS growth in 30 minutes in relative units.

Literature

1. Zimmet P, Alberti KG, Shaw J., Global and societal implications of the diabetes epidemic. Nature. 2001 Dec 13; 414 (6865): 782-7.

2. Harold E Bays, J Michael González-Campoy, George A Bray, Abbas E Kitabchi, Donald A Bergman, Alan Bruce Schorr, Helena W Rodbard, Robert R Henry. Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Expert Review of Cardiovascular Therapy, March 2008, Vol.6, No.3, Pages 343-368.

3. American diabetes association. Diabetic information. All about diabetes. http://www.diabetes.org/about-diabetes.jsp [November 2012].

4. Bays HE. Adiposopathy, diabetes mellitus, and primary prevention of atherosclerotic coronary artery disease: treating "sick fat" through improving fat function with antidiabetes therapies. Am J Cardiol. 2012 Nov 6; 110 (9 Suppl): 4B-12B. dot: 10.1016 / j.amjcard.2012.08.0.029.

5. Cole BK, Lieb DC, Dobrian AD, Nadler JL. 12- and 15-lipoxygenases in adipose tissue inflammation. Prostaglandins Other Lipid Mediat. 2012 Aug 20.

6. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes. 2005 Mar; 54 (3): 603-8.

7. Blüher M. Adipose tissue dysfunction in obesity. Exp Clin Endocrinol Diabetes. 2009 Jun; 117 (6): 241-50. doi: 10.1055 / S-0029-1192044.

8. Capurso C, Capurso A. From excess adiposity to insulin resistance: the role of free fatty acids. Vascul Pharmacol. 2012 Sep-Oct; 57 (2-4): 91-7. doi: 10.1016 / j.vph.2012.05.05.003.

9. Souhad El Akoum, Vikie Lamontagne, Isabelle Cloutier, Jean-Francois Tanguay. Nature of fatty acids in high fat diets differentially delineates obesity-linked metabolic syndrome components in male and female C57BL / 6J mice. Diabetol Metab Syndr. 2011; 3: 34. Published online 2011 December 14. doi: 10.1186 / 1758-5996-3-34

10. Strissel KJ, Stancheva Z, Miyoshi H, Perfield JW 2nd, DeFuria J, Jick Z, Greenberg AS, Obin MS. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes. 2007 Dec; 56 (12): 2910-8. Epub 2007 Sep 11.

11. Gregor MF, Hotamisligil GS. Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res. 2007 Sep; 48 (9): 1905-14. Epub 2007 May 9. Review.

12. Aggarwal BB, Prasad S, Reuter S, Kannappan R, Yadev VR, Park B, Kim JH, Gupta SC, Phromnoi K, Sundaram C, Prasad S, Chaturvedi MM, Sung B. Identification of Novel Anti-inflammatory Agents from Ayurvedic Medicine for Prevention of Chronic Diseases: "Reverse Pharmacology" and "Bedside to Bench" Approach. Curr Drug Targets 12 (11): 1595-653, 10/2011. e-Pub 5/2011. PMCID: PMC3170500.

13. Sun GY, Horrocks LA, Farooqui AA. The roles of NADPH oxidase and phospholipases A2 in oxidative and inflammatory responses in neurodegenerative diseases. J Neurochem. 2007 Oct; 103 (1): 1-16. Epub 2007 Jun 11.

14. Cole BK, Lieb DC, Dobrian AD, Nadler JL. 12- and 15-lipoxygenases in adipose tissue inflammation. Prostaglandins Other Lipid Mediat. 2012 Aug 20.

15. Xue B, Greenberg AG, Kraemer FB, Zemel MB. Mechanism of intracellular calcium ([Ca2 +] i) inhibition of lipolysis in human adipocytes. FASEB J. 2001 Nov; 15 (13): 2527-9. Epub 2001 Sep 17.

16. Zemel MB, Sun X. Dietary calcium and dairy products modulate oxidative and inflammatory stress in mice and humans. J Nutr. 2008 Jun; 138 (6): 1047-52.

17. Montonen J, Knekt P, Jarvinen R, Reunanen A. Dietary antioxidant intake and risk of type 2 diabetes. Diabetes Care. 2004 Feb; 27 (2): 362-6.

18. Rainsford KD. Anti-inflammatory drugs in the 21st century. Subcell Biochem. 2007; 42: 3-27.

19. Shen W, Liu K, Tian C, Yang L, Li X, Ren J, Packer L, Cotman CW, Liu J. R-alpha-lipoic acid and acetyl-L-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes. Diabetologia. 2008 Jan; 51 (1): 165-74. Epub 2007 Nov 17.

20. Golbidi S, Badran M, Laher I. Diabetes and alpha lipoic Acid. Front Pharmacol. 2011; 2:69. doi: 10.3389 / fphar.2011.00069.

21. Dewanjee S, Maiti A, Sahu R, Dua TK, Mandal V. Effective Control of Type 2 Diabetes through Antioxidant Defense by Edible Fruits of Diospyros peregrina. Evid Based Complement Altemat Med. 2011; 2011: 675397. doi: 10.1093 / ecam / nep080.

22. Golbidi S, Ebadi SA, Laher I. Antioxidants in the treatment of diabetes. Curr Diabetes Rev. 2011 Mar; 7 (2): 106-25.

23. P.P. Singh, Farzana Mahadi, Ajanta Roy, and Praveen Sharma. Reactive oxygen species, reactive nitrogen species and antioxidants in etiopathogenesis of diabetes mellitus type-2. Indian J Clin Biochem. 2009 October; 24 (4): 324-342. Published online 2009 December 30. doi: 10.1007 / s12291-009-0062-6 PMCID: PMC3453064

24. Shao CH, Wehrens XH, Wyatt TA, Parbhu S, Rozanski GJ, Patel KP, Bidasee KR. Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation. J Appl Physiol. 2009 Apr; 106 (4): 1280-92. doi: 10.1152 / japplphysiol. 91280.2008.

25. Thompson D, Karpe F, Lafontan M, Frayn K. Physical activity and exercise in the regulation of human adipose tissue physiology. Physiol Rev. 2012 Jan; 92 (1): 157-91. doi: 10.1152 / physrev.00012.2011.

26. Kawanishi N, Yano H, Yokogawa Y, Suzuki K. Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-induced obese mice. Exerc Immunol Rev. 2010; 16: 105-18.

27. Bird SR, Hawley JA. Exercise and type 2 diabetes: new prescription for an old problem. Maturitas. 2012 Aug; 72 (4): 311-6. doi: 10.1016 / j.maturitas.2012.05.01.015.

28. A.V. Berezhnov, E.I. Fedotova, M.N. Nenov, V.P. Zinchenko, V.V. Dynnik Role of phospholipases in cytosolic calcium overload and cardiomyocytes death in the presence of activated fatty acid derivatives. Biochemistry (Moscow) Supplemental Series A: Membrane and Cell Biology, 2010; 4 (1): 56-63.

29. Turovsky E.A., Turovskaya M.V., Tolmacheva A.V., Dolgacheva L.P., Zinchenko V.P., Dynnik V.V. β-adrenergic receptors as regulators of intracellular calcium in white fat adipocytes. Zhurn. "Basic research." 2012 (12), 74-87.

Claims (2)

1. The composition of the antioxidant composition aimed at suppressing oxidative stress in type 2 diabetes, containing per dose: Coenzyme Q10 - 50-120 mg, dihydroquercytin - 30-160 mg, A-lipoic acid 30-60 mg. 2. The composition of the antioxidant composition aimed at suppressing oxidative stress in type 2 diabetes, containing per dose: Coenzyme Q10 - 50-100 mg, dihydroquercytin - 50-100 mg, A-lipoic acid - 30-60 mg, nicotinamide - 50-100 mg.

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