KR20020089444A - Synergistic compositions containing choline base and succinic acid for insulin resistance and diabetes - Google Patents

Abstract

The present invention relates to compositions and methods for achieving a synergistic effect of treating insulin resistance and diabetes mellitus in a mammal. More particularly, the present invention relates to an elevated composition comprising a choline base or a pharmacologically acceptable salt thereof, and a succinic acid or a pharmacologically acceptable salt thereof, wherein said composition comprises said choline base or a pharmacologically acceptable salt thereof Possible salts thereof, and succinic acid or a pharmacologically acceptable salt thereof in an amount sufficient to cause a synergistic effect on insulin resistance and diabetic treatment of the mammal. The present invention also relates to a method for achieving a synergistic effect of treating insulin resistance and diabetes in a mammal comprising administering to the mammal an effective amount of a choline base or a pharmacologically acceptable salt thereof and succinic acid or a pharmacologically acceptable salt thereof To a mammal sequentially or simultaneously. The present invention also relates to novel choline derivatives. More particularly, the present invention relates to a novel choline salt bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate {bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate, a method for preparing the salt, and a pharmacological use of the salt, preferably a drug for treating insulin resistance, hyperslipidemia, dyslipidemia or diabetes .

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an elevated composition for treating insulin resistance and diabetes comprising choline base and succinic acid. BACKGROUND OF THE INVENTION < RTI ID = 0.0 >

Insulin is an important anabolic hormone in the body and has multiple effects in various tissues. Insulin promotes the uptake of glucose in muscles and fats and inhibits the release of glucose from the liver. In addition, insulin regulates plasma and tissue lipid metabolism, protein synthesis, cell growth, and electrolyte balance.

Insulin resistance is defined as an impaired biological response to exogenous insulin or endogenous insulin. Measured biological responses could reflect metabolic processes such as changes in carbohydrate, lipid, or protein metabolism as well as cell division processes such as growth, differentiation, DNA synthesis, and gene transcription regulatory changes.

Insulin resistance has been shown to be a major cause of a group of abnormalities including glucose intolerance leading to Type 2 diabetes and decreased hyperlipidemia and dyslipidemia, hypertension, hyperuricemia and plasma fibrinolytic activity (Reaven, GM Physiol- Rev. 75 (3): 473-86 (1995); " Consensus development conference on insulin resistance ", Diabetes Care , 21 (2), 1998). Insulin resistance may be associated with a variety of conditions including gestational diabetes, obesity, aging, atherosclerosis, cardiovascular X syndrome, AIDS, cancer, wasting / chachexia, sepsis, Associated with various disease states such as malnutrition, lupus and other autoimmune diseases, endocrine disorders, hyperuricemia, hyperlipidemia, dyslipidemia, polycystic ovary syndrome or complications arising from locomotor activity .

Clinically, insulin resistance is evident at pathologically elevated fasting plasma insulin levels, and insulin resistance can be assessed by measuring plasma insulin levels.

The term diabetes mellitus refers to metabolic disorders of multiple etiologies that characterize chronic hyperglycemia resulting from insulin secretion, insulin action, or both.

Clinically, diabetes is evident at pathologically elevated levels of plasma glucose and diabetes can be assessed by measuring glucose levels in the blood.

Treatment of insulin resistance with succinic acid or its salts is disclosed in international application PCT / RU 99/00055.

Succinic acid or its salt is described in Japanese Patent No. 61171417 as a diabetes therapeutic agent useful for promoting insulin secretion. In contrast to Japanese Patent No. 61171417, McDonald et al. Found that succinic acid and its salts do not promote insulin secretion from the pancreas, only succinic acid esters are potent insulin secretagogues (MacDonald, MJ and Fahien, LA Diabetes 37 ): 997-999 (1988)). Japanese Patent No. 6,062,798 discloses that succinic acid is used in combination with acetic acid, lactic acid, and gluconic acid as a food ingredient to be provided to people who are poor in glucose tolerance. Disodium succinate used in combination with citric acid and acetic acid has been described as a component of a composition for reducing blood glucose in rabbits with alloxan diabetes (Dzvonkevich, ND et al., Ukr. Biokhim. Zh ., 46 (5): 547-552 (1974)).

Prior to the present invention, it has not been reported to use a choline base or a pharmacologically acceptable salt thereof with succinic acid or a pharmacologically acceptable salt thereof in order to obtain a synergistic effect on the treatment of insulin resistance or diabetes.

Monocholine succinate, an acid salt prepared by reacting choline base and succinic acid in a molar ratio of 1: 1, is described in US Patent 5,124,061 as a component of a plant cryoprotectant composition. However, in the above patent, the salt has never been obtained as a product with regeneration, and is only defined as a reference to a process wherein only choline base and succinic acid are introduced at a molar ratio of 1: 1. Due to the lack of acidity and regeneration of the monocholine succinate, the use of the monocholine succinate described in the patent is limited.

Prior to the present invention, bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate, which is a salt formed by reacting choline base and succinic acid in a 2: 1 molar ratio, There has never been reported use of the salt for the pharmacological use, preferably for the preparation of a therapeutic agent for insulin resistance, hyperlipidemia, dyslipidemia or diabetes. Since " dicholine succinate " is commonly used in literature for the description of succinic acid and choline esters which are well known, the term "bis (2-hydroxy-N, N, Bis (2-hydroxy-N, N, N-trimethylethanaminium succinate) " is used in place of the common name of "dicholine succinate"

The present invention relates to compositions and methods for achieving a synergistic effect of treating insulin resistance and diabetes mellitus in a mammal. More particularly, the present invention relates to an elevated composition comprising a choline base or a pharmacologically acceptable salt thereof, and a succinic acid or a pharmacologically acceptable salt thereof, wherein said composition comprises said choline base or a pharmacologically acceptable salt thereof Possible salts thereof, and succinic acid or a pharmacologically acceptable salt thereof in an amount sufficient to cause a synergistic effect on insulin resistance and diabetic treatment of the mammal. The present invention also relates to a method for achieving a synergistic effect of treating insulin resistance and diabetes in a mammal comprising administering to the mammal an effective amount of a choline base or a pharmacologically acceptable salt thereof and succinic acid or a pharmacologically acceptable salt thereof To a mammal sequentially or simultaneously. The present invention also relates to novel choline derivatives. More particularly, the present invention relates to a novel choline salt bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate {bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate, a method for preparing the salt, and a pharmacological use of the salt, preferably a drug for treating insulin resistance, hyperslipidemia, dyslipidemia or diabetes .

The present invention relates to compositions and methods for obtaining a synergistic effect in the treatment of insulin resistance and diabetes mellitus in mammals. More particularly, the present invention relates to an elevated composition comprising a choline base or a pharmacologically acceptable salt thereof and a succinic acid or a pharmacologically acceptable salt thereof, wherein said composition comprises said choline base or a pharmacologically acceptable Salt, and succinic acid or a pharmacologically acceptable salt thereof in an amount sufficient to cause a synergistic effect in treating mammalian insulin resistance and diabetes. The present invention also relates to a method for obtaining a synergistic effect in the treatment of insulin resistance and diabetes in mammals comprising administering to the mammal an effective amount of a choline base or a pharmacologically acceptable salt thereof and succinic acid or a pharmacologically acceptable salt thereof To a mammal sequentially or simultaneously. In addition, the present invention relates to novel choline derivatives. More particularly, the present invention relates to bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate which is a novel choline salt formed by reacting a choline base and succinic acid at a molar ratio of 2: A method for preparing a salt thereof, and a pharmacological use of said salt, preferably for the treatment of insulin resistance, hyperlipidemia, dyslipidemia or diabetes.

The term " synergistic ", as used herein, refers to the effect achieved by the methods and compositions of the present invention when the choline base or a pharmacologically acceptable salt thereof and a succinic acid or a pharmacologically acceptable salt thereof Means the sum of each effect achieved from the methods and compositions individually included in the amounts shown in the methods and compositions of the present invention.

In accordance with the present invention, the use of an effective amount of a choline base or a pharmacologically acceptable salt thereof and a succinic acid or a pharmacologically acceptable salt thereof makes it possible to obtain a synergistic effect in treating insulin resistance and diabetes mellitus, The effects according to the present invention can not be obtained by separately using the above-mentioned effective amount of the choline base or the pharmacologically acceptable salt thereof and the succinic acid or the pharmacologically acceptable salt thereof, and the effect according to the present invention can be achieved by using a choline base or pharmacologically Is greater than the sum of each effect obtained upon administration of the pharmaceutically acceptable salt thereof and the succinic acid or the pharmacologically acceptable salt thereof separately.

The term " treating " as used herein refers to the management and treatment of mammals to improve disease, condition or disorder and includes the prevention of symptoms or complications, Administering a choline base or a pharmacologically acceptable salt thereof and a succinic acid or a pharmacologically acceptable salt thereof in order to alleviate complications or to eliminate a disease, condition or disorder. Insulin resistance therapy involves increasing insulin sensitivity and other effects in mammals, and insulin resistance treatment increases insulin sensitivity in mammals. Such effects include, but are not limited to, improving carbohydrate, lipid or protein metabolism, improving growth, differentiation, DNA synthesis, and gene transcription regulatory changes.

The present invention provides a method of achieving a synergistic effect in the treatment of insulin resistance in a mammal in need of an insulin resistance treatment wherein the method comprises administering to the mammal a cholinic base or a pharmacologically acceptable salt thereof and a succinic acid or a pharmacologically acceptable & Administering to said mammal an effective amount of a salt. In accordance with the present invention, a favorable effect in the treatment of insulin resistance is to lower pathologically elevated plasma insulin levels. Insulin resistance in mammals has been implicated in the pathogenesis of diabetes and its chronic complications, gestational diabetes, glucose tolerance disorders, obesity, aging, atherosclerosis, X syndrome, cardiovascular disease, AIDS, cancer, ), Septicemia, burn-related trauma, malnutrition, lupus and other autoimmune diseases, endocrine diseases, hyperuricemia, hyperlipidemia, dyslipidemia, polycystic ovary syndrome, or athletic activity Such as a complication that may occur with the patient. Preferably, insulin resistance is associated with diabetes in mammals.

The present invention also provides a method for achieving a synergistic effect in the treatment of diabetes in mammals in need of such treatment, wherein the method according to the present invention comprises administering to said mammal a therapeutically effective amount of a cholinesterase or a pharmacologically acceptable salt thereof and a pharmacologically acceptable Comprising administering to said mammal an effective amount of a salt thereof. According to the present invention, a favorable effect on the value of diabetes is to lower pathologically elevated blood glucose levels.

Preferably, choline chloride is used as the choline base or pharmacologically acceptable salt thereof according to the present invention. In addition, the succinic acid or a pharmacologically acceptable salt thereof according to the present invention is preferably disodium succinate.

The choline base or its pharmacologically acceptable salt and succinic acid or a pharmacologically acceptable salt thereof may be administered sequentially in time, or may be administered simultaneously according to the preferred method of simultaneous administration.

The choline base or a pharmacologically acceptable salt thereof may be administered orally, parenterally, topically or rectally. Preferably, the choline base or a pharmacologically acceptable salt thereof is parenterally administered. The succinic acid or a pharmacologically acceptable salt thereof may be administered orally, parenterally, topically, or rectally. The succinic acid or a pharmacologically acceptable salt thereof is preferably parenterally administered.

The choline base or a pharmacologically acceptable salt thereof is preferably administered for a period of one day or more, more preferably for a period of 3 days to 7 days. The succinic acid or the pharmacologically acceptable salt thereof is preferably administered for a period of one day or more, more preferably for a period of 3 days to 7 days.

The present invention provides a composition for achieving a synergistic effect in the treatment of insulin resistance in a mammal in need of an insulin resistance treatment, said composition comprising an effective amount of a choline base or a pharmacologically acceptable salt thereof and a succinic acid or a pharmacologically acceptable & Salts, and pharmacologically acceptable diluents or carriers. A preferred effect in the treatment of insulin resistance according to the present invention is to lower pathologically elevated plasma insulin levels.

The present invention also provides a composition for achieving a synergistic effect in the treatment of diabetes mellitus in a mammal in need of such treatment, wherein said composition comprises an effective amount of a choline base or a pharmacologically acceptable salt thereof and a succinic acid or a pharmacologically acceptable Salts, and pharmacologically acceptable diluents or carriers. A preferred effect in the treatment of diabetes according to the present invention is to lower pathologically elevated levels of glucose in the blood.

Pharmacologically acceptable salts of choline bases are prepared from non-toxic organic and inorganic acids by known methods. Such acids include, but are not limited to, hydrochloric acid, hydrobromic acid, citric acid, tartaric acid, and succinic acid. As the choline base or pharmacologically acceptable salt in the present invention, choline chloride is preferable.

Pharmacologically acceptable salts of succinic acid are prepared from non-toxic organic bases or inorganic bases by known methods. Examples of the base include non-toxic alkali metal and alkaline earth metal bases such as calcium, lithium, sodium and potassium hydroxide; But are not limited to, ammonium hydroxide and non-toxic organic bases such as triethylamine, butylamine, diethanolamine, triethanolamine, and choline base. Disodium succinate is preferred as the succinic acid or pharmacologically acceptable salt thereof in the present invention.

Examples of the carrier and diluent suitable for the present invention include lactose, dextrose, sorbitol, mannitol, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, methylcellulose, polyvinylpyrrolidone , Water, methyl- and propylhydroxybenzoate, talc, magnesium stearate, stearic acid and mineral oil. The compositions of the present invention may additionally comprise lubricants, wetting agents, emulsifying and suspending agents, preservatives, sweetening or flavoring agents.

The compositions of the present invention can be administered in a wide variety of different formulations, that is, they can be combined with various pharmaceutically acceptable inert carriers such as tablets, capsules, lozenges, troches, solid candies, powders, , Aqueous solutions, elixirs, syrups and the like.

In the methods and compositions of the present invention, the effective amount of said choline base or pharmacologically acceptable salt thereof is preferably from 3 to 300 mg per kg of body weight of the mammal per day.

In the methods and compositions of the present invention, the effective amount of succinic acid or a pharmacologically acceptable salt thereof is preferably 1 to 250 mg per kg body weight of the mammal.

The present invention provides bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate, which has the formula:

[(CH ₃ ) ₃ N ⁺ CH ₂ CH ₂ OH] ₂ ^- OOCCH ₂ CH ₂ COO ^- .

The present invention provides a process for the preparation of the bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate wherein the choline base is reacted with succinic acid in the presence of water, an alcohol, . The bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate is prepared by reacting a choline base and succinic acid, wherein the molar ratio of choline base to succinic acid introduced in the reaction is about 2: 1 And the reaction molar ratio is less than 1.9: 1, but not more than 2.1: 1. The reaction takes place at room temperature and the reaction is quantitative. The preferred product prepared by this reaction is obtained as a white crystalline powder with reproducible properties.

The present invention also relates to pharmaceutical use of bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate, preferably mammalian insulin resistance, hyperlipidemia, dyslipidemia, to provide. A preferred effect in the treatment of insulin resistance according to the present invention is to lower pathologically elevated plasma insulin levels. A preferred effect in the treatment of hyperlipidemia according to the present invention is to lower pathologically elevated levels of plasma triglycerides and plasma cholesterol. In addition, according to the present invention, a preferable effect for the treatment of dyslipidemia is to lower the low density lipoprotein cholesterol level and the high density lipoprotein cholesterol level. In addition, a beneficial effect of the present invention in the treatment of diabetes is to lower pathologically elevated levels of glucose in the blood.

Hereinafter, the present invention will be described with reference to the following examples. However, the following embodiments are only examples of the present invention, and the scope of protection of the present invention is not limited to the following embodiments.

Example 1

This example demonstrates the synergistic effect of insulin resistance and diabetes treatment obtained by administering effective amounts of choline chloride and disodium succinate together in diabetic rats.

Analysis : Plasma insulin concentrations were measured using a kit (Dako, The Netherlands) as rat's insulin standard (Novo Research Institute, Bagsvard, Denmark). Plasma glucose concentrations were measured using a kit (Agat, Russia). Plasma triglyceride and cholesterol concentrations were measured with FS reagent (DiaSys, Germany), HDL cholesterol concentration with Cormay (Poland) and LDL cholesterol concentration with Boehringer Mannheim (Germany) reagents.

Animals : Male wistar rats, 8-10 weeks of age, weighing 210-230 g were used. The rats were bred at a temperature of 18 +/- 21 < 0 > C with a 12 hour light-dark cycle. The rats were fed free of water and fasted (carbohydrate 59%, protein 17%, fat 3% and minerals, moisture and 21% cellulose). Alkoxate (40 mg / kg body weight) was injected twice into the tail vein of male Wistar rats and allowed to stand for 48 hours to induce diabetes. Wistar rats were tested on the sixth day after the first injection of alloxan. In Table 1, the levels of fasting plasma glucose, insulin, total cholesterol (Ch), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL) and triglyceride (TG) (Mean ± SD), compared with healthy controls. The rats were tested for their characteristics against insulin resistance, hyperinsulinemia, hyperglycemia, hyperlipidemia and dyslipidemia in the same manner as described above.

On the sixth day after the first injection of alloxan, the fast plasma parameters Rat Glucose, mmol / l Insulin, μU / ℓ HDL, mmol / l LDL, mmol / l TG, mmol / l Ch, mmol / l Healthy rats (n = 10) 4.3 ± 0.7 2.0 ± 0.5 2.0 ± 0.3 0.8 ± 0.2 0.5 ± 0.1 1.7 ± 0.3 Diabetic rats (n = 10) 13.9 ± 2.3 ^* 4.8 ± 0.8 ^* 1.0 ± 0.3 ^* 1.0 ± 0.3 1.3 ± 0.3 ^* 2.5 ± 0.5 ^*

^* Significant difference from healthy control group (P <0.01)

Treatment: We distinguish between animals that diabetes is the negun, i.e. diabetes control group (n = 10) and, every day, choline chloride (240 ㎎ / ㎏ body weight, n = 10), di-sodium succinate (70 ㎎ / ㎏ body weight, n = 10) or a combination of choline chloride (240 mg / kg body weight) and disodium succinate (70 mg / kg body weight) was divided into three diabetic groups injected intravenously for 5 days.

On the 6th day of the treatment, the fasting plasma glucose of the animals was measured. The measured data are shown in Table 2. The average glucose level in the diabetic control group was 12.5 mmol / l. Δ glucose is the difference in each mean value of fasting plasma glucose for the control and treatment groups, calculated according to the equation (Δ glucose = 12.5-mean value (mmol / l)).

The effect of the combination appears to be 7.8 mmol / l reduction in the fasting plasma glucose level of the control. The sum of the effects of each administered choline chloride and disodium succinate decreased 2.8 mmol / l (-1.1 + 3.9 = 2.8) in the fasting plasma glucose level of the control group. The glucose abatement effect of the combination is greater than the sum of the glucose abatement effects of each administered choline and succinate, and the combination has a synergistic effect in lowering pathologically elevated plasma glucose levels.

On the 6th day after the first treatment, the fasted plasma glucose of Wistar rats process Glucose, mmol / l (Mean 占 SD) [Delta] Glucose, mmol / l Control group 12.5 ± 2.4 ^* 0 Choline chloride 13.6 ± 2.2 ^* -1.1 Disodium succinate 8.6 ± 1.8 ^{* t} +3.9 Combination 4.7 ± 0.8 ^t +7.8

^* Significant differences from the above combinations (P <0.01)

^t there is a control group and a significant difference (P <0.01)

Fasting plasma insulin levels were measured on the 6th day after the first treatment of the rats. The measured data are shown in Table 3. The average insulin level was found to be 5.7 μU / ℓ in the control group with diabetes. Δ Insulin is the difference in the mean value of fasting plasma insulin for the control and treatment groups, calculated according to the formula (Δ insulin = 5.7-mean value (μU / ℓ)).

The effect of the combination appears to be reduced to 4.1 μU / l in the fasting plasma insulin level of the control group. The sum of the effects of choline chloride and disodium succinate each administered was reduced by 2.1 μU / ℓ (0.9 + 1.2 = 2.1) in the fasting plasma insulin level of the control group. The insulin-reducing effect of the combination is greater than the sum of the insulin-reducing effects of each administered choline and succinate, and the combination is synergistic in lowering pathologically elevated plasma insulin levels.

On the 6th day after the first treatment, fasting plasma insulin process Insulin, μU / l (Mean ± SD) Δ insulin, μU / ℓ Control group 5.7 ± 1.1 ^* 0 Choline chloride 4.8 ± 0.7 ^* 0.9 Disodium succinate 4.5 ± 0.6 ^{* t} 1.2 Combination 1.6 ± 0.3 ^t 4.1

^* Significant differences from the above combinations (P <0.01)

^t there is a control group and a significant difference (P <0.01)

Example 2

Bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate is effective for insulin resistance, hyperlipidemia, dyslipidemia and diabetes for diabetic rats.

Animals : As described in Example 1 of the present invention, diabetic rats were used.

Treatment of the animals with diabetic rats (n = 10) as control and bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate (120 mg / Kg body weight, n = 10) were divided into two groups, each of which was injected intravenously for 3 days by the tail vein. (HDL), low density lipoprotein cholesterol (LDL) and triglyceride (TG) levels on day 7 of the test as shown in Table 4 below And the mean value ± standard deviation (Mean ± SD).

Seven days after the start of the experiment, the fasting plasma parameters Blood factor (Mean ± SD) Treatment Control group Treatment group Fasting plasma glucose, mmol / l 12.5 ± 2.4 4.2 ± 0.6 ^** Fasting plasma insulin, μU / ℓ 6.0 ± 1.0 1.3 ± 0.5 ^** Total cholesterol, mmol / l 3.0 ± 0.4 1.5 ± 0.3 ^** LDL cholesterol, mmol / l 1.1 ± 0.3 0.8 ± 0.2 ^* HDL cholesterol, mmol / l 0.8 ± 0.2 2.0 ± 0.2 ^** Triglyceride, mmol / l 1.4 ± 0.3 0.7 ± 0.1 ^**

^* Differences from control (P <0.05)

^** Significant difference from control (P <0.01)

Example 3

Method for producing bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate

59 g (0.5 mole) of succinic acid was added to a solution of 121 g (1 mole) of choline base dissolved in methanol and mixed. The reaction mixture was stirred at room temperature for 20 minutes, dried at a temperature of 40 to 50 &lt; 0 &gt; C and concentrated in vacuo. Thus, bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate, which is a white crystalline material in solid yield (melting point in tert-butanol: 135-137 DEG C) Lt; / RTI &gt;

NMR ¹ H (D ₂ O):? 2.24 (s, 4H), 3.07 (s, 18H), 3.38 (m, 4H), 3.93 (m, 4H); NMR ¹³ C (D ₂ O):? 34.5, 54.2, 56.0, 67.8, 182.6; C ₁₄ H ₃₂ N the analysis value calculated for a ₂ O _6: C, 51.83; H, 9.94. Found: C, 51.66; H, 9.86.

Claims (32)

CLAIMS What is claimed is: 1. A method of achieving a synergistic effect in the treatment of insulin resistance in a mammal in need thereof, (a) a choline base or a pharmacologically acceptable salt thereof; And (b) administering an effective amount of succinic acid or a pharmaceutically acceptable salt thereof to said mammal, The effective dose of (a) alone and the effective dose of (b) alone are insufficient to achieve the effect, Wherein the effective amount of (a) and the effective amount of (b) is greater than the sum of the effective amount of (a) and the effective amount of (b) A method of achieving synergistic effects in the treatment of insulin resistance in mammals. The method according to claim 1, Wherein said effect comprises lowering plasma insulin levels. As a method for achieving a synergistic effect on the treatment of diabetes in a mammal in need of diabetes treatment, (a) a choline base or a pharmacologically acceptable salt thereof; And (b) administering an effective amount of succinic acid or a pharmaceutically acceptable salt thereof to said mammal, The effective dose of (a) alone and the effective dose of (b) alone are insufficient to achieve the effect, Wherein the effective amount of (a) and the effective amount of (b) is greater than the sum of the effects obtainable by the amounts of (a) and (b) / RTI &gt; The method of claim 3, Wherein said effect comprises lowering plasma glucose levels. 5. The method according to any one of claims 1 to 4, Wherein the amount of choline base or a pharmacologically acceptable salt thereof and the amount of succinic acid or a pharmacologically acceptable salt thereof are administered simultaneously. 6. The method according to any one of claims 1 to 5, Wherein the pharmacologically acceptable salt of choline is choline chloride. 7. The method according to any one of claims 1 to 6, Wherein the pharmacologically acceptable salt of succinic acid is disodium succinate. 8. The method according to any one of claims 1 to 7, Wherein the effective amount of the choline base or a pharmacologically acceptable salt thereof is from 3 to 300 mg / kg of the mammalian body weight. 9. The method according to any one of claims 1 to 8, Wherein the effective amount of succinic acid or a pharmacologically acceptable salt thereof is from 1 to 250 mg / kg of the mammalian body weight. 10. The method according to any one of claims 1 to 9, Wherein an effective amount of said choline base or a pharmacologically acceptable salt thereof is administered orally, parenterally, topically or rectally. 11. The method of claim 10, Wherein an effective amount of said choline base or a pharmacologically acceptable salt thereof is administered parenterally. 12. The method according to any one of claims 1 to 11, Wherein an effective amount of the succinic acid or a pharmacologically acceptable salt thereof is administered orally, parenterally, topically, or rectally. 13. The method of claim 12, Wherein an effective amount of the succinic acid or a pharmacologically acceptable salt thereof is parenterally administered. 14. The method according to any one of claims 1 to 13, Wherein an effective amount of the succinic acid or a pharmacologically acceptable salt thereof is administered for a period of one or more days. 15. The method of claim 14, Wherein an effective amount of the succinic acid or a pharmacologically acceptable salt thereof is administered for a period of 3 days to 7 days. 16. The method according to any one of claims 1 to 15, Wherein an effective amount of said choline base or a pharmacologically acceptable salt thereof is administered for a period of one or more days. 17. The method of claim 16, Wherein the effective amount of the choline base or a pharmacologically acceptable salt thereof is administered for a period of from 3 days to 7 days. A composition for achieving a synergistic effect on the treatment of insulin resistance in mammals requiring treatment of insulin resistance, (a) a choline base or a pharmacologically acceptable salt thereof; And (b) an effective amount of succinic acid or a pharmacologically acceptable salt thereof, The effective dose of (a) alone and the effective dose of (b) alone are insufficient to achieve the effect, Is greater than the sum of the effective amount of (a) and the effective amount of (b), and (b) the effective amount of the effective amount, A composition for achieving a synergistic effect in the treatment of insulin resistance in a mammal, comprising a pharmacologically acceptable diluent or carrier. 19. The method of claim 18, Wherein said effect comprises lowering plasma insulin levels. A composition for obtaining a synergistic effect in the treatment of diabetes in a mammal in need of treatment for diabetes, (a) a choline base or a pharmacologically acceptable salt thereof; And (b) an effective amount of succinic acid or a pharmacologically acceptable salt thereof, The effective dose of (a) alone and the effective dose of (b) alone are insufficient to achieve the effect, Is greater than the sum of the effective amount of (a) and the effective amount of (b), and (b) the effective amount of the effective amount, A composition for achieving synergistic effects in the treatment of diabetes in a mammal, comprising a pharmacologically acceptable diluent or carrier. 21. The method of claim 20, Wherein said effect comprises lowering plasma glucose levels. 22. The method according to any one of claims 18 to 21, Wherein the pharmacologically acceptable salt of choline is choline chloride. 23. The method according to any one of claims 18 to 22, Wherein the pharmacologically acceptable salt of succinic acid is disodium succinate. 24. The method according to any one of claims 18 to 23, Wherein the effective amount of the choline base or a pharmacologically acceptable salt thereof is from 3 to 300 mg / kg / kg of mammalian body weight. 25. The method according to any one of claims 18 to 24, Wherein the effective amount of the succinic acid or a pharmacologically acceptable salt thereof is 1 to 250 mg / kg / kg body weight of the mammal. Bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate. Bis (2-hydroxy-N, N, N-trimethylethanaminium) succinate for pharmaceutical use. 28. The method of claim 27, Wherein the medicament is for the manufacture of a medicament for treating insulin resistance in a mammal in need of treatment for insulin resistance. 28. The method of claim 27, Wherein said medicament is for the manufacture of a diabetes therapeutic agent in a mammal in need of such treatment. 28. The method of claim 27, Wherein the medicament is for the manufacture of a medicament for the treatment of hyperlipidemia or dyslipidemia in a mammal in need of treatment for hyperlipidemia or dyslipidemia. (2-hydroxy-N, N, N-trimethylethanaminium) succinate comprising reacting a choline base with succinic acid. 33. The method of claim 32, Wherein the molar ratio of cholic base to succinic acid is in the range of about 2: 1, but in the range of 1.9: 1 to 2.1: 1.