KR101737046B1 - Pharmaceutical Composition for Preventing or Treating Diabetes Comprising Linalyl Acetate - Google Patents

Abstract

The pharmaceutical compositions and health functional foods for the prevention or treatment of diabetes or diabetic complications comprising lignan acetate according to the present invention as an active ingredient can be used for controlling the fat metabolism by increasing the expression or activity of AMPK (AMP kinase) glucose uptake) and is useful for the treatment or prevention of diabetes.

Description

[0001] The present invention relates to a pharmaceutical composition for preventing or treating Diabetes comprising linalool acetate,

The present invention relates to a pharmaceutical composition for the prevention or treatment of diabetes comprising lignan acetate, and more particularly to a pharmaceutical composition for preventing or treating diabetes or diabetic complications comprising lignan acetate or lignyl acetate and anisole as an active ingredient ≪ / RTI >

Diabetes mellitus (diabetes) is a group of diseases characterized by chronic hyperglycemia due to lack of insulin action due to an absolute or relative deficiency of plasma insulin levels, and several characteristic metabolic abnormalities. Since insulin is mainly involved in carbohydrate metabolism, diabetes is a general metabolic disease, since the abnormality of carbohydrate metabolism is a fundamental problem, and all the nutrient metabolism in the body is affected thereby. Diabetes is one of the most important chronic diseases in modern times, especially in advanced countries. Diabetes is largely classified as type 1 diabetes and type 2 diabetes. Type 1 diabetes is a type 2 diabetes caused by insulin deficiency caused by a destructive lesion of the pancreatic β-cells, and is again divided into immune-mediated and unexplained forms. Type 2 diabetes is caused by decreased insulin secretion and insulin resistance (IR), and depending on the degree of involvement of these two factors, Insulin Secretion Superior Diabetes mellitus and insulin resistance superior diabetes mellitus.

Diabetes is a major cause of insulin deficiency or hyperglycemia due to cell resistance to insulin, which leads to metabolic changes as hyperglycemia persists. When the insulin action is decreased, the ability to maintain a constant blood glucose level is decreased when an excessive amount of the sugar is consumed, so that the blood sugar is increased and thus the glucose is excreted in the urine. Early symptoms of diabetes include polyuria, polydipsia, polyphagia, and weight loss. Clinical symptoms include glucosuria, hyperglycemia, abnormal glucose tolerance test, and asthenia through urinary excretion. Many type 2 diabetes mellitus in Korea occurs due to insulin resistance, which causes early symptoms of insulin secretion in the pancreas. However, when the pancreas has a limited ability, symptoms are delayed and diagnosis is delayed. Usually this period is known to be more than 5 years, so complications should be examined at the time of diagnosis of diabetes.

The causes of diabetes are food intake, lack of exercise, and genetic susceptibility. Diabetes has negative consequences for health and quality of life, such as type 2 diabetes, hypertension, hypercholesterolemia, and cardiovascular disease, and the social costs are gradually increasing. In the United States, diabetes deaths account for more than 300,000 deaths annually, making it the second leading cause of preventable deaths (McGinnis JM and Foege WH, JAMA 270: 2207-2212, 1993) (Colditz GA, Am. J. Clin . Nutr . 55: 503S-507S, 1992).

As such, various metabolic diseases such as lipid disorders in plasma due to diabetes, increased oxidative stress due to free radical generation, lipid peroxidation, and atherosclerosis are various and their seriousness is deepened, so prevention and treatment are urgently needed to prevent them. Drugs that regulate the blood glucose level of patients with type 2 diabetes mellitus are currently on the market, and drugs such as sulfonylurea, acetaminophen, alpha-glucosidease inhibitors, thiazolidinedione, meglitinide, etc. . On the other hand, concerns over the risk of pancreatitis and pancreatic cancer were raised in 2011 when long-term use of GLP-1 antidiabetics such as bieta, Researchers at the University of California, USA. According to the results of the study, patients treated with Bayeta and Januvia showed that GLP-1 antidiabetic agent acts on the exocrine pancreas to unnecessarily promote the proliferation of pancreatic duct cells, thereby partially blocking the passage of digestive enzymes, leading to local pancreatic inflammation, And pancreatic cancer are more common. Therefore, it is urgent to develop antidiabetic agents of natural products without such side effects because of concerns about side effects.

Anethole was prepared by reacting ( E ) -1-methoxy-4- (1-propenyl) benzene with ( E ) -1- As an ingredient that can be extracted from Eucalyptus globules, an acute lung injury model induced by LPS has been shown to have an anti-inflammatory effect in association with the inflammation mechanism (Kang et al. al., Life Sciences , 2013, 93 (24): 955-961), and it was confirmed that MMP9 was inhibited in prostate cancer cells by a consistent reaction with the antimetastatic effect (Ha et al ., 2014, Journal of Natural Products , 77 (1): 63-69). In addition, nonimmune acute inflammation has been shown to have an anti-inflammatory response (Domiciano et al ., 2013, Naunyn Schmiedebergs Arch Pharmacol . , ≪ / RTI > 386 (4): 331-338). (Ritter et al ., 2013, Inflammopharmacology , 21 (2): 187-197) in pain models due to acute chronic inflammation of mice. In addition, human keratinocytes have been shown to reduce inflammation-associated cytokine IL6 secretion (Sung et al ., 2012, Journal of Ethnopharmacology , 144 (1): 182-189). In addition, it is known that RAW 264.7 macrophages reduced NO production (Conforti et al., 2010; Journal of Medicinal Food , 13 (1): 137-141) none.

Linalyl acetate was prepared by reacting 3,7-dimethylocta-1,6-dien-3-yl acetate (3,7-dimethylocta-1,6-dien- Some of the components of BiRyuChe-bang used for allergic rhinitis, which can be extracted from Eucalyptus globules, are shown to be effective in inhibiting histamine secretion, among which the effect of linalyl acetate (Moon et al ., 2013, American Journal of Chinese Medicine , 41 (6): 1267-1282). In addition, linalyl acetate promoted colon cancer cell death through inhibition of NF kappa B activation in colon cancer cells. (Deeb et al ., 2011, Frontiers in Bioscience (Elite Ed.), 3: 410-420), and the association with the treatment or prevention of diabetes is known There is no way.

Accordingly, the present inventors have made intensive efforts to solve the above problems, and as a result, they have found that anethole and linalyl acetate are excellent in the effect of inhibiting diabetes through the expression or activity increase of AMPK (AMP kinase) , Thereby completing the present invention.

It is an object of the present invention to provide a composition for the treatment or prevention of diabetes comprising linalyl acetate or linalyl acetate and anethole as active ingredients and a health functional food for diabetes improvement.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating diabetic or diabetic complications comprising lignan acetate as an active ingredient.

The present invention also provides a health functional food for improving diabetes or diabetic complications comprising lignyl acetate as an active ingredient.

According to the present invention, linalyl acetate increases the activity of AMPK through phosphorylation of AMPK and is excellent in glucose uptake effect, and is useful for the treatment or prevention of diabetes.

FIG. 1 and FIG. 2 are graphs showing the effect of AMPK (AMP kinase) protein expression on the concentration and time of anethole (A) and / or linalyl acetate (LA) in muscle cells in an embodiment of the present invention (IB: immmunoblotting).
Figures 3 and 4 illustrate glucose uptake effects of anethole and / or linalyl acetate in one embodiment of the present invention.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.

In the present invention, the proinflammatory activity of AMPK is increased in a concentration-dependent manner by lignan acetate and anesol and the activity of AMPK is increased by phosphorylation of AMPK, And the glucose uptake effect is excellent. Thus, it can be used as an active ingredient of a composition for treating or preventing diabetes and a health functional food for improving diabetes.

Thus, in one aspect, the present invention relates to a pharmaceutical composition for preventing or treating diabetes or diabetic complications comprising linalyl acetate as an active ingredient.

In another aspect, the present invention relates to a health functional food for improving diabetes or diabetic complications comprising lignyl acetate as an active ingredient.

As used herein, the term "improvement" is meant to include preventing, ameliorating, treating, or delaying the onset of such symptoms.

As used herein, the term "diabetic improvement" means any action that improves or alters the symptoms of diabetes by administration of the composition.

As used herein, the term "functional food" means food prepared and processed using raw materials or ingredients having functionality useful to the human body according to Law No. 6727 on health functional foods, and " And function of the nutrient for the purpose of obtaining a beneficial effect in health use such as controlling the nutrient or physiological action.

The pharmaceutical composition for the prevention or treatment of diabetes or diabetic complication according to the present invention and the health functional food for improvement may further comprise an anthole.

The lignan acetate and the anesol of the present invention can be characterized in that the expression or activity of AMPK (AMP kinase) is increased to control lipid metabolism.

In one embodiment of the present invention, the activity of AMPK was analyzed by treating the progenitor cells with anesol and linalool acetate, and the phosphorylation of AMPK was increased in a concentration-dependent manner by anesol and linalool acetate.

The pharmaceutical composition of the present invention has an effect of preventing or treating complications due to diabetes as well as diabetes, and the complications include hyperglycemia, hyperinsulinemia, hypertriglyceridemia, (s), hypertriglyceridemia, insulin resistance, dyslipidemia, impaired fasting glucose, impaired glucose tolerance, obesity, atherosclerosis, microangiopathy, kidney disease, heart disease, Foot ulcers, arthritis, osteoporosis, diabetic retinopathy, and one or more other ophthalmic diseases.

Herein, diabetes includes all kinds of diabetes such as type 1 diabetes, type 2 diabetes, adult type diabetes mellitus, seizure autoimmune diabetes mellitus, and pancreatic diabetes mellitus. Diabetic complications include glomerulosclerosis , Erectile dysfunction, diabetic neuropathy, premenstrual syndrome, vascular restenosis, ulcerative colitis, coronary heart disease, hypertension, angina pectoris, myocardial infarction, stroke, skin and connective tissue diseases, metabolic acidosis, .

In addition, the above-mentioned ophthalmic diseases include diabetic retinopathy, diabetic retinopathy, all ophthalmic diseases caused by diabetes such as cataract, macular degeneration, optic neuritis, iridocyclitis, optic neuritis, glaucoma, retinal degeneration, .

The pharmaceutical composition according to the present invention may be provided as a pharmaceutical composition containing the active ingredient alone or in combination with one or more pharmaceutically acceptable carriers, excipients or diluents.

Further, the pharmaceutical composition of the present invention may be provided by mixing with conventionally known therapeutic substances for diabetes or complications thereof. That is, the pharmaceutical composition of the present invention can be administered in combination with a known compound having an effect of preventing or treating diabetes mellitus or its complications.

Accordingly, the pharmaceutical composition for preventing or treating diabetes or diabetic complications of the present invention may further comprise a known anti-diabetic compound.

Examples of such anti-diabetic compounds include nateglinide, repaglinide, glitazone, sulfonylurea, metformin, glymepride, thiazolidinedione, biguanide, alpha-glucosidease inhibitor, meglitinide, etc. But is not limited thereto.

Meanwhile, in the present invention, the route of administration of the pharmaceutical composition is not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, Ministerial, topical, sublingual or rectal.

The composition of the present invention may be administered orally or parenterally, and it is preferable to select parenterally when injecting parenterally or intraperitoneally, intramuscularly, subcutaneously, intravenously, intramuscularly or intrasternally , But is not limited thereto.

The preferred dosage of the composition of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the composition is preferably administered at a daily dose of 0.0001 to 1 g / kg, preferably 0.001 to 200 mg / kg, but is not limited thereto. The above administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.

In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose ), Lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Propyleneglycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.

The health food of the present invention can be used as it is or in combination with other food or food ingredients, and can be suitably used according to conventional methods.

There is no particular limitation on the kind of the food. Examples of the food include dairy products including drinks, meat, sausage, bread, biscuits, rice cakes, chocolates, candies, snacks, confectionery, pizza, ramen noodles, other noodles, gums, ice cream, various soups, And a combination thereof, all of which include health foods in a conventional sense.

The lignyl acetate according to the present invention can be added directly to the food or can be used together with other food or food ingredients, and can be suitably used according to conventional methods. The amount of the active ingredient to be mixed can be suitably determined according to its use purpose (for prevention or improvement). Generally, the amount of the linalool acetate in the health food may be 0.01 to 15% by weight of the total food, and the health beverage composition may be added in a proportion of 0.02 to 5 g, preferably 0.3 to 1 g, have. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

The health functional beverage composition of the present invention is not particularly limited to other ingredients other than the lignan acetate as an essential ingredient in the indicated ratios and may contain various flavors or natural carbohydrates as additional ingredients such as ordinary beverages have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above .

In addition to the above-mentioned foods, the food of the present invention may contain flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and heavies (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like.

In addition, the lignan acetate of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so important, but is generally selected in the range of 0 to about 20 parts by weight based on 100 parts by weight of the lineryl acetate of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are for illustrative purposes only and that the scope of the present invention is not limited by these embodiments.

[Example]

Example  One: AMPK  (AMP kinase ) Phosphorylation experiments

To investigate the effects of linalyl anethole and linalyl acetate on AMPK, an important protein in lipid metabolism, C2C12 muscle precursor cells (ATCC, US) were anethole, The amount of phosphorylated protein was measured by treating linalyl acetate. C2C12 was cultured in Dulbecco's modified Eagle medium (DMEM) and treated with concentrations of 0 μM, 50 μM, 100 μM, 125 μM, 300 μM anethole and linalyl acetate for 60 min each. Western blotting analysis was performed to measure changes in the activity of AMPK in muscle precursor cells. AMPK phosphorylated antibody (Threonine 172, Millipore-Upstate, US) was used for the detection of phosphorylated AMPK protein. As a result, the amount of phosphorylated AMPK protein increased together with the concentration of the treated anesole and linalyl acetate, so that anethole and linalyl acetate increased the amount of AMPK protein (Fig. 1).

C2C12 cells were treated with 0, 10, 30, 1, 3, 6, 12 and 24 hours, respectively, at a concentration of 300 μM and 125 μM of linalyl acetate The amount of pAMPK protein was analyzed by western blotting.

As a result, as shown in FIG. 1, the degree of phosphorylation of AMPK gradually increased after treatment with 300 μM of anethole and 125 μM of linalyl acetate, and it was confirmed that the maximum was reached at 12 hours.

After treatment with C2C12 cells for 1 hour each with 30 μM of anethole, 1000 μM of linalyl acetate, 30 μM of anethole and 1000 μM of linalyl acetate, the pAMPK protein Was analyzed by Western blotting.

As a result, as shown in Fig. 2, in the degree of AMPK phosphorylation after treating with lanyl acetate and / or anesol, 30 μM of anethole and 1000 μM of linalyl acetate were simultaneously treated The degree of phosphorylation of AMPK was significantly higher than that of AMPK after treatment with 30 μM anethole or 1000 μM linalyl acetate, respectively.

From the above results, it can be seen that there is a synergistic effect between anethole and linalyl acetate in activating AMPK protein.

Example  2: Anesol ( anethole ), Rinanal  acetate( linalyl  acetate) Tonic  Effect on ability

In order to confirm the effect of anethole and linalyl acetate on blood glucose control ability, differentiation of muscle cell line was induced first. Differentiation was induced by culturing for 7 days while changing 2 days with 2% FBS. The glucose uptake ability was measured by adding isotope labeled glucose to the culture medium and reacting for 15 minutes, and then measuring the amount of isotope sugar transferred into the cell.

As shown in FIG. 3, in the experimental group treated with anethole or linalyl acetate for 11 hours, the isotope-labeled sugar level in the cells was increased as compared with the control group. Anethole showed maximum sugar uptake ability at 100 μM concentration and linalyl acetate at 125 μM concentration.

In addition, as shown in FIG. 4, compared to the experimental group treated with 30 μM of anethole and 1000 μM of linalyl acetate for 1 hour, the isotopically labeled sugar And it was confirmed that the numerical value was increased.

Therefore, anethole and linalyl acetate were found to promote the glucose uptake ability, which is the most important mechanism for controlling glucose.

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereto will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (8)

A pharmaceutical composition for preventing or treating diabetes comprising lignan acetate as an active ingredient.
The pharmaceutical composition for preventing or treating diabetes according to claim 1, further comprising an anthole.
The pharmaceutical composition for preventing or treating diabetes according to claim 1 or 2, wherein the expression or activity of AMP kinase is increased to control fat metabolism.
delete The pharmaceutical composition for preventing or treating diabetes according to any one of claims 1 to 3, further comprising an anti-diabetic compound.
6. The method of claim 5, wherein the anti-diabetic compound is selected from the group consisting of nateglinide, repaglinide, glitazone, sulfonylurea, metformin, glymepride, thiazolidinedione, biguanide, alpha-glucosidease inhibitor acarbose, And at least one member selected from the group consisting of ritinides.
A health functional food for improving diabetes comprising linalool acetate as an active ingredient.
The health functional food for diabetes according to claim 7, further comprising an anthole.

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