JP2008195630A - Adiponectin production promoting agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a safe and excellent adiponectin production promoting agent expectable to achieve preventing or ameliorating effect on arteriosclerosis or diabetes and metabolic syndrome by the increase of adiponectin concentration in blood and free from side actions on mammals, and to provide an agent for the prevention or amelioration of arteriosclerosis, diabetes or metabolic syndrome by using the production promoting action. <P>SOLUTION: The above agents contain 1,5-D-anhydrofructose and/or 1,5-D-anhydroglucitol. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an adiponectin production enhancer and an agent for preventing or improving arteriosclerosis, diabetes and the like.

1,5-D-anhydrofructose (hereinafter referred to as 1,5-AF) is an α-1,4-glucan lyase, which is an enzyme derived from certain ascomycetes and red algae. It can be biosynthesized enzymatically by acting on 4-glucan.
1,5-D-anhydroglucitol (hereinafter referred to as 1,5-AG) is a structure in which 1,5-AF is reduced, and NADPH-dependent reductase present in E. coli and mammals in vivo. 1,5-AF is reduced, and when 1,5-AF is orally ingested by mice, it is reduced in vivo to produce 1,5-AG, and further, Oral ingestion of a certain oligoglycated 1,5-AF to a mouse also causes the oligosaccharide to be decomposed in the gastrointestinal tract to produce 1,5-AF, which is absorbed from the gastrointestinal tract to produce 1,5-AG. Has also been reported (public results presentation in technology development projects such as the promotion of supply of branded and processed Japanese foods on H17 / 3/11). From these facts, 1,5-AG can be biosynthesized in vivo by orally administering 1,5-AF or a 1,5-AF derivative. It has been reported that 1,5-AG can be chemically synthesized by hydrogenating 1,5-AF in the presence of a metal catalyst and reducing it (Non-patent Document 1). Although there are few reports on the physiological functionality of 1,5-AG,
It has been reported that it has an action of enhancing the amount of insulin secretion from pancreatic islets of Langerhans (Non-patent Document 2).

Physiologically active substances secreted from adipose tissue are collectively referred to as adipocytokines, and it is considered that the function and production regulation of adipocytokines in obesity, particularly visceral fat obesity, are largely involved in the onset and progress of metabolic syndrome. Among adipocytokines, adiponectin has been found to have a function of suppressing various cellular phenomena such as inflammation that causes arteriosclerosis in blood vessels. Adiponectin has also been confirmed to be associated with diabetes. When diabetic, the blood concentration of adiponectin decreases, and when the concentration of adiponectin increases, the blood glucose level decreases. This is presumed to be due to increased insulin sensitivity. As the concentration of adiponectin is increased, the prevention of arteriosclerosis, the prevention / amelioration effect of diabetes or the anti-obesity effect can be expected. Therefore, in recent years, a search for substances that increase the production of adiponectin has been actively conducted. Compositions containing an extract as an active ingredient (Patent Document 1), soybean saponin (Patent Document 2), rice bran extract (Patent Document 3) and the like have been proposed as production enhancers of adiponectin.
JP2004-315379 JP 2006-143609 A JP 2005-68132 A Carbohydrate Research 337 (2002) 873-890 Biochimica et Biophysica Acta 1623 (2003) 82-87

  An object of the present invention is to provide a safe and excellent adiponectin production enhancer that can be expected to prevent or ameliorate arteriosclerosis or diabetes and metabolic syndrome by increasing the concentration of adiponectin in blood, and has no side effects on mammals, and its An object of the present invention is to provide an agent for preventing or improving arteriosclerosis, diabetes or metabolic syndrome using production enhancing action.

  Still other objects and advantages of the present invention will become apparent from the following description.

As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention further contain 1,5-AF and / or 1,5-AG, preferably a PPAR-γ agonist or a PPAR-γ endogenous ligand. As a result, it was found that adiponectin production was enhanced, and the present invention was completed.
That is, the present invention has the following contents.
1. An adiponectin production enhancer comprising 1,5-AF and / or 1,5-AG.
2. An adiponectin production enhancer comprising 1,5-AF and / or 1,5-AG and a PPAR-γ agonist or a PPAR-γ endogenous ligand.
3. A preventive or ameliorating agent for arteriosclerosis or diabetes caused by adiponectin secretion deficiency, which contains 1,5-AF and / or 1,5-AG as an active ingredient 4. A preventive or ameliorating agent for metabolic syndrome, comprising 5-AG as an active ingredient.
5. Use of 1,5-AF and / or 1,5-AG as an adiponectin production enhancer.

  The active ingredient of the present invention, 1,5-AF and / or 1,5-AG, is safe and enhances adiponectin production by itself or further containing a PPAR-γ agonist or a PPAR-γ endogenous ligand To do.

The adiponectin production enhancer of the present invention can be used for the purpose of preventing or treating obesity, hypertension, hyperlipidemia, diabetes, arteriosclerosis, liver fibrosis, and cancer.
The adiponectin production-enhancing agent of the present invention can be administered according to its dosage form by various methods known per se, and the dose, administration site, administration interval, period, etc. are determined depending on the age and weight of the patient. It can be determined in consideration of a medical condition or a combination with other drugs or treatments. The administration method can be, for example, oral administration, direct injection into the body such as intravenous, subcutaneous, intraperitoneal, or external use by injection or infusion, and is not particularly limited.

The dose of the agent in the present invention varies depending on the dosage form, administration method, or symptoms to be prevented or treated. For example, the dose per kg body weight is 1,5-AF and / or 1,5-AG. The dose may be 0.1 μg to 1,000 mg, preferably 1 mg to 1,000 mg, and may be administered at an appropriate dosing frequency such as once or several times a day or once every several days. Is possible.
Examples of the form of the adiponectin production enhancer of the present invention include, but are not particularly limited to, tablets, capsules, granules, injections and the like. Moreover, components necessary for preparing a preparation, for example, a preparation carrier, an excipient, a stabilizer and the like can be contained.

Furthermore, as long as the effects of the present invention are exhibited, other anti-atherosclerotic agents, anti-diabetic agents, other pharmacological components, or nutritional components such as glucose can also be included.
In addition, the use of the adiponectin production enhancer of the present invention is not limited to pharmaceutical applications, and can be blended in quasi drugs, foods, beverages and the like. For example, 1,5-AF and / or 1,5-AG can be added to food to take the form of a functional food intended for the treatment of arteriosclerosis.
The adiponectin production enhancer of the present invention can be administered to mammals other than humans. That is, in that case, obesity, hypertension, hyperlipidemia, diabetes, arteriosclerosis, liver fibrosis, and cancer can be prevented or treated by administering an appropriate amount of an adiponectin production enhancer to a mammal.

  Hereinafter, the present invention will be described in more detail by way of examples. The present invention is not limited to the embodiment.

Example 1
10T1 / 2 and 3T3-L1 were used as adipocyte progenitor cells targeted for insulin. Using a known adipocyte differentiation inducing ability evaluation system, oil-red-0 staining method and adiponectin secretion ability to the culture supernatant were examined. A specific method is shown below.
3T3-L1 or 10T1 / 2 cells were seeded on a plate of 24well1 (1 × 10 ⁴ cells / well) and cultured under conditions of 37 ° C. and 5% CO ₂ until becoming confluent {medium: fetus D-MEM (Low glucose)} containing 10% serum (hereinafter referred to as FBS) and 2% penicillin / streptomycin. When cells become confluent, the supernatant is removed and adipocyte differentiation media (IBMX 0.5 mM, Dexamethasone 1 μM, F-BS 10% and penicillin / streptomycin 2% D-MEM (High glucose) ) Medium} was added and cultured under conditions of 37 ° C. and 5% CO ₂ for 48 hours or more. After culturing, the supernatant is removed, and adipocyte differentiation media containing a predetermined amount of 1,5-AG and a thiazolytin derivative (drug name: pioglitazone) (Insulin 10 μg / ml, FBS 10% and penicillin. The medium was replaced with D-MEM (High glucose) medium containing 2% streptomycin} and cultured for 5 days under conditions of 37 ° C. and 5% CO _2. The supernatant was adiponectin-secreting ability, and the cells adhered to the plate were oil-red. Subjected to −0 staining. The adiponectin content in the cell culture supernatant was measured using a mouse / rat adiponectin ELISA kit (manufactured by Otsuka Pharmaceutical Co., Ltd.).

  1,5-AG acted somewhat positively on adipocyte maturation in response to induction of adipocyte differentiation and insulin / glucose stimulation (A in FIG. 1). Furthermore, in this experimental system, adipocyte-derived anti-arteriosclerotic secretory protein adiponectin was measured, and 1,5-AG has an effect of enhancing adiponectin secretion from adipocytes induced by pioglitazone. Was found (B in FIG. 1). From these results, although biochemical mechanisms and pathways are still unclear for 1,5-AG, antidiabetic action based on increasing insulin sensitivity of various cells and increasing energy consumption, An anti-arteriosclerotic effect was indirectly expressed, and it became clear that there was a preventive or therapeutic effect on lifestyle-related diseases.

Example 2
Serum 1,5-AG and adiponectin content were measured when 1,5-AF was orally administered to cynomolgus monkeys once daily for 2 weeks. A specific method is shown below.
1,5-AF solution {water for injection (Otsuka Pharmaceutical Co., Ltd.) once a day for 2 weeks to cynomolgus monkeys (age: 3 years old, body weight: about 3 kg, 5 males) after habituation (2 weeks before start of administration) Made to 60 mg / kg} using a 5 ml nasogastric sonde and forcibly administered into the stomach {dose: 300 mg / kg / day}. Blood collection was performed twice 4 days before administration and 6 days after administration during the acclimatization period, and the obtained serum was subjected to measurement of 1,5-AG and adiponectin content. 1,5-AG and Adiponectin were measured using an animal 1,5-AG kit (manufactured by Nippon Kayaku Co., Ltd.) and a human adiponectin ELISA kit (manufactured by Otsuka Pharmaceutical Co., Ltd.).
The 1,5-AG content in serum was 1.14 ± 0.8 μg / ml before administration and 29.52 ± 16.2 μg / ml after administration, and was significantly increased by 1,5-AF. (A in FIG. 2). That is, 1,5-AF is rapidly metabolized to 1,5-AG in vivo. On the other hand, the value of adiponectin in serum was increased except for one case by administration of 1,5-AF (B in FIG. 2). These facts suggested that 1,5-AF promotes adiponectin production via 1,5-AG in vivo.

Effect of 1,5-AG on adiponectin production in adipocyte differentiation induction Relationship between 1,5-AG content (A) and adiponectin content (B) in serum before and after 1,5-AF administration

Claims (5)

An adiponectin production enhancer comprising 1,5-D-anhydrofructose and / or 1,5-D-anhydroglucitol. The production enhancer according to claim 1, further comprising a PPAR-γ agonist or a PPAR-γ endogenous ligand. Use of 1,5-D-anhydrofructose and / or 1,5-D-anhydroglucitol as an adiponectin production enhancer. 1. Prevention or improvement of arteriosclerosis or diabetes caused by adiponectin secretion deficiency, comprising 1,5-D-anhydrofructose and / or 1,5-D-anhydroglucitol as an active ingredient Agent. An agent for preventing or improving metabolic syndrome, comprising 1,5-D-anhydrofructose and / or 1,5-D-anhydroglucitol as an active ingredient.

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