WO2017018500A1 - Glp-1分泌促進剤 - Google Patents
Glp-1分泌促進剤 Download PDFInfo
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- WO2017018500A1 WO2017018500A1 PCT/JP2016/072269 JP2016072269W WO2017018500A1 WO 2017018500 A1 WO2017018500 A1 WO 2017018500A1 JP 2016072269 W JP2016072269 W JP 2016072269W WO 2017018500 A1 WO2017018500 A1 WO 2017018500A1
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- QRMPKOFEUHIBNM-UHFFFAOYSA-N CC1CCC(C)CC1 Chemical compound CC1CCC(C)CC1 QRMPKOFEUHIBNM-UHFFFAOYSA-N 0.000 description 2
- 0 CC1*C(C)CC1 Chemical compound CC1*C(C)CC1 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N CC1CCCC1 Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a secretagogue for GLP-1, which is an incretin hormone, useful for treating impaired glucose tolerance or preventing diabetes.
- Glucagon-like peptide-1 (GLP-1) is a kind of incretin hormone that is secreted from the digestive tract by ingestion of food and has a function of promoting the secretion of insulin from the pancreas.
- GLP-1 is secreted from L cells, one of the endocrine cells of the gastrointestinal tract, in response to nutrient influx into the gastrointestinal lumen and binds to the GLP-1 receptor on the surface of the pancreatic ⁇ -cell And promotes insulin secretion from within the ⁇ -cell.
- GLP-1 suppresses the secretion of glucagon, a hormone that raises blood glucose levels, and has also been confirmed in animals to have effects such as protecting and promoting proliferation of pancreatic ⁇ cells.
- GLP-1 secretion Substances having an effect of promoting the above are extremely useful.
- the International Diabetes Federation has been exploding in the “Diabetes Atlas 6th edition UP2014 UPDATE”, which summarizes research on diabetes around the world.
- the number is 388.6 million (prevalence rate ⁇ 8.3%), and if it does not take effective measures, it is expected to increase to 591.9 million in 2035. In other words, it is clear that diabetes is a serious disease worldwide.
- Diabetes is diagnosed in the “Guidelines for Diagnosis of Diabetes” in the “Guidelines for Diagnosis of Diabetes Based on Scientific Basis 2013” published by the Japan Diabetes Society. Is determined by a combination of a fasting blood glucose level and a 75-g oral glucose tolerance test (OGTT) 2-hour value, and a determination based on HbAc1 (NGSP) value ⁇ 6.5%.
- OGTT oral glucose tolerance test
- NGSP HbAc1
- IFG equivalent fasting glucose
- IGT complementary glucose tolerance
- GIP glucose-dependent insulin secretion stimulating polypeptide
- GLP-1 glucagon-like peptide-1
- GIP is secreted mainly by stimulation to K cells existing in the upper intestine
- GLP-1 is an incretin hormone secreted by stimulation to L cells mainly present in the lower intestine as described above.
- Incretin hormones act on the pancreas to promote insulin secretion during hyperglycemia, and when it is not hyperglycemia, insulin secretion is not promoted, so there is little risk of causing hypoglycemia.
- incretin hormone has the disadvantage that it is rapidly degraded by incretin degrading enzyme (DPP-4), the action of “DPP-4 inhibitor” and DPP-4 that suppress the degradation of incretin "Incretin hormone analog” has been developed and is highly expected as having few side effects.
- DPP-4 inhibitor incretin degrading enzyme
- ⁇ -GI agents disaccharide-degrading enzyme inhibitors
- acarbose, voglibose and miglitol are known in addition to the above-mentioned DPP-4 inhibitors and incretin hormone analogs.
- these are synthesized and not cheap and can be taken orally with daily meals, but require a doctor's prescription.
- the object of the present invention is to promote secretion of GLP-1 without using sucrose as an essential active ingredient or separately administering sucrose, and is relatively inexpensive and excellent in safety. Another object is to provide a GLP-1 promoter that is an incretin hormone-related drug.
- Non-patent Document 1 Since D-psicose was known as an ⁇ -GI agent (Non-patent Document 1), the inventors initially used L-arabinose, D-xylose, or D-tagatose known as sucrose degrading enzyme inhibitors. Similarly, it was speculated that D-psicose would not promote GLP-1 secretion unless sucrose was ingested.
- GIP mentioned above is known as an incretin hormone that promotes insulin secretion like GLP-1, but unlike GLP-1, it is known to activate the fat synthesis system and induce fat accumulation. As a result, it was found that the GLP-1 secretion promoter of the present invention does not promote the secretion of GIP.
- a GLP-1 secretion promoter characterized by containing D-psicose as an active ingredient.
- the GLP-1 secretion promoter according to [1] above which does not contain sucrose.
- GLP-1 according to any one of [1] to [3] above, wherein D-psicose as an active ingredient is administered at a dose of 5 g or more at a time. Secretagogue.
- a GLP-1 secretion promoting composition comprising the GLP-1 secretion promoter according to any one of [1] to [5] and a water-soluble dietary fiber as active ingredients.
- the GLP-1 secretion promoter of the present invention contains D-psicose as an active ingredient, and the dietary experience and safety of the D-psicose have been confirmed, and no side effects such as drugs are observed. Since sucrose is not an essential component, it is very easy to use and can easily promote mammalian GLP-1 secretion. D-psicose has a sweetness of about 70% of that of sugar although it is 0 kilocalories, and has an excellent GLP-1 secretion ability without using sucrose as an essential ingredient, so it has a calorie of 2 kilocalories / g. In addition, it is useful in that the calorie intake can be greatly reduced as compared with D-tagatose, which requires sucrose for GLP-1 secretion.
- FIG. 1 is a diagram showing the results of GLP-1 secretion experiments in GLP-1 producing cells derived from mouse colon, with respect to 10 mM, 20 mM and 40 mM solutions of D-psicose or 10 mM solution of indigestible dextrin (Fibersol 2). is there.
- FIG. 2 shows active GLP-1 concentration (a), total GLP-1 concentration (b) and total GIP concentration (c) in portal vein over time after oral administration of 1 g / kg D-psicose to fasted mice. ).
- FIG. 3 shows that mice were orally administered with physiological saline, D-psicose 0.3 g / kg or 1.0 g / kg, D-tagatose 1.0 g / kg or D-glucose 1.0 g / kg. It is a figure which shows the active GLP-1 density
- FIG. 4 is a graph showing the effect of GLP-1 receptor inhibitors (Exendin-9, Ex-9) on the feeding suppression effect by oral administration of 1 g / kg D-psicose using fasted mice.
- FIG. 5 shows the amount of food consumed over a period of 1 to 6 hours after oral administration of 1 g / kg of D-psicose or D-tagatose to mice, relative to the amount of food consumed when physiological saline was orally administered.
- FIG. 5 shows the amount of food consumed over a period of 1 to 6 hours after oral administration of 1 g / kg of D-psicose or D-tagatose to mice, relative to the amount of food consumed when physiological saline was orally administered.
- FIG. 6 shows that 0.2 g / kg of D-psicose, indigestible dextrin (Fibersol 2), and dextrin (Matsutani Chemical Co., Ltd. product “Paindex # 2”) was administered to SD rats from 0 minutes to 240 minutes, respectively. It is a figure which shows the blood glucose level (a) and total GLP-1 density
- FIG. 7 shows that after humans ingested 200 ml of water or 5 g / 200 ml of D-psicose, 10 g / 200 ml or 15 g / 200 ml, 15 minutes, 30 minutes, 60 minutes, 120 minutes and 180 minutes after FIG. 3 is a graph showing the results of quantifying total GLP-1 in blood and calculating the area under the blood concentration-time curve (AUC).
- AUC blood concentration-time curve
- the drug of the present invention promotes the secretion of GLP-1, and improves various physiological functions and diseases / symptoms through the function of GLP-1 such as treatment of impaired glucose tolerance and prevention / treatment of diabetes. It is extremely useful.
- D-psicose which is an active ingredient of the GLP-1 secretion promoter of the present invention
- any conventionally known D-psicose can be used, and it is extracted from plants such as zina regardless of the degree of purification.
- Isomerized from D-glucose or D-fructose by the alkali isomerization method for example, “Rare Sugar Sweet” manufactured by Matsutani Chemical Industry Co., Ltd.
- enzymes obtained from microorganisms or recombinants thereof isomerase and epimerase) Etc.
- Alkali isomerization method for example, “Rare Sugar Sweet” manufactured by Matsutani Chemical Industry Co., Ltd.
- enzymes obtained from microorganisms or recombinants thereof isomerase and epimerase
- Etc. for example, “Astraea Allose” manufactured by Matsutani Chemical Industry Co., Ltd.
- the GLP-1 secretion promoter of the present invention In order for the GLP-1 secretion promoter of the present invention to exert its effect, it is important to take D-psicose orally, and at this time, it is not essential that sucrose is simultaneously present in the intestine. That is, it is not necessary to contain the GLP-1 secretion promoter of the present invention in a sucrose-containing food, and the GLP-1 secretion promoter of the present invention is taken together with sucrose or a sucrose-containing food or administered after ingestion. There is no need to do.
- the dosage form of the GLP-1 secretion promoter of the present invention is not particularly limited, and may be any of tablets, granules, powders, capsules, gels, and sols.
- the active ingredient D-psicose may be mixed with a pharmaceutically acceptable carrier such as starch or carboxymethylcellulose, and if necessary, stabilizers, excipients, binders, disintegrants, etc. Can be added.
- the GLP-1 secretion promoter of the present invention is preferably administered so that the active ingredient D-psicose is 0.07 / kg body weight or more at a time. 2.0 g / kg body weight is more preferable, and an amount of 0.1 to 0.6 g / kg body weight at a time is even more preferable.
- the GLP-1 secretion promoter of the present invention is preferably taken on an empty stomach. Specifically, it is preferably taken 5 minutes before a meal, and more specifically, it is more preferably taken 3 minutes after the previous meal and 10 minutes before the next meal.
- the present invention further provides a GLP-1 secretion promoting composition
- a GLP-1 secretion promoting composition comprising water-soluble dietary fiber as an active ingredient in addition to the GLP-1 secretion promoting agent.
- the water-soluble dietary fiber include high-viscosity dietary fibers such as pectin, konjac mannan, alginic acid, guar gum, and agar, and low-viscosity dietary fibers such as indigestible dextrin, polydextrose, and guar gum degradation products.
- indigestible dextrin, guar gum hydrolyzate, polydextrose and the like are particularly preferable from the viewpoint of effects.
- Low-viscosity dietary fiber is preferable from the viewpoint of handling and short travel time to the large intestine.
- Low-viscosity water-soluble dietary fiber is a dietary fiber material that contains 50% by mass or more of dietary fiber and dissolves in room temperature water to form a low-viscosity solution, generally a 5% by mass aqueous solution and a viscosity of 20 mPas or less Means. More specific examples of the low-viscosity dietary fiber include indigestible dextrin, guar gum hydrolysate, polydextrose (eg, lytes), and hemicellulose-derived material.
- the indigestible dextrin is a variety of starches such as potato starch, tapioca starch, corn starch, wheat starch, etc., which is thermally decomposed at 130 ° C or higher, further hydrolyzed with amylase, and decolorized and decolorized as necessary according to conventional methods. Made with salt.
- the average molecular weight of dietary fiber is about 500 to 3000, preferably 1400 to 2500, and more preferably around 2000.
- Glucose residues are ⁇ -1,4, ⁇ -1,6, ⁇ -1,2, ⁇ -1,3, ⁇ -1,6-glucoside bonds, and part of the reducing end is levoglucosan (1,6- Anhydroglucose) is a dextrin having a branched structure. It is marketed under the trade name of “Nutriose” (Rocket), “Pine Fiber”, “Fiber Sol 2” (Matsuya Chemical Industry Co., Ltd.) (“Food New Material Forum” NO.3 (1995, Foods) New Material Council))).
- the hydrolyzate of guar gum is obtained by hydrolyzing guar gum with an enzyme, and its properties are usually low viscosity and soluble in cold water, and the aqueous solution is neutral and colorless and transparent.
- Guar gum hydrolysates are commercially available under the trade names of “Sun Fiber” (Taiyo Kagaku) and “Fiberron” (Dainippon Pharmaceutical).
- the product derived from hemicellulose is usually produced by extracting from corn hulls with alkali and purifying it. The average molecular weight is as large as about 200,000, but the viscosity of a 5% aqueous solution is as low as about 10 cps. Become a clear liquid.
- D-psicose can be used alone, but in order to maintain GLP-1 secretion for a long time, it is possible to use indigestible dextrin together. preferable. This is because indigestible dextrin exerts a GLP-1 secretion promoting effect later than D-psicose, so that when used together, GLP-1 secretion can be maintained for a long time.
- the GLP-1 secretion promoter and indigestible dextrin of the present invention are preferably contained in a mass ratio of 1: 0.1 to 1: 100, and preferably 1: 0.5 to 1:50. More preferred.
- Glucagon-like peptide-1 (GLP-1) -producing cell line GLUTag derived from mouse colon was cultured in Dulbecco's modified Eagle's medium containing 10% FBS in the presence of 37 ° C. and 5% CO 2 .
- GLUTag cells were cultured in 48-well plates for 2-3 days until they were subconfluent. Before adding each sample (D-psicose or indigestible dextrin), Hepes buffer (140 mM NaCl, 4.5 mM KCl, 20 mM Hepes, 1.2 mM CaCl 2 , 1.2 mM MgCl 2 , 10 mM D-glucose,. The wells were washed with 1% BSA, pH 7.4), 80 ⁇ l of a sample solution dissolved in the same buffer was added, and incubated at 37 ° C. for 60 minutes.
- Hepes buffer 140 mM NaCl, 4.5 mM KCl, 20 mM Hepes, 1.2 mM CaCl 2 , 1.2 mM MgCl 2 , 10 mM D-glucose.
- the wells were washed with 1% BSA, pH 7.4
- the cells were precipitated by centrifugation (800 ⁇ g, 5 minutes, 4 ° C.), and 70 ⁇ l of the supernatant was stored frozen.
- the total GLP-1 in the supernatant was measured with a commercially available “Enzyme immuno assay kit” (manufactured by Yauchihara Laboratory Co., Ltd.).
- Example 1 C57BL / 6J male mice (9-11 weeks old) were used as experimental animals. Mice fasted for 16 hours from 18:00 on the day before the experiment were administered 1 g / kg of D-psicose intraorally at 10:00 am. The oral dose was 10 ml / kg. Portal vein blood was collected under isoflurane anesthesia before and 30 minutes after administration of D-psicose. A blood coagulation inhibitor (heparin (final concentration 50 IU / ml)) and a peptide degradation inhibitor (aprotinin (final concentration 500 KIU / ml) and vildagliptin (final concentration 10 ⁇ M)) were added in advance to the sampling syringe.
- heparin final concentration 50 IU / ml
- aprotinin final concentration 500 KIU / ml
- vildagliptin final concentration 10 ⁇ M
- D-psicose administered orally alone does not affect the secretion of GIP that promotes fat synthesis, but strongly induces the secretion of GLP-1 that has the effects of promoting insulin secretion, suppressing appetite and suppressing gastric emptying. It became clear to do.
- Example 2 C57BL / 6J male mice (9-11 weeks old) fasted for 16 hours from 18:00 the day before the experiment were treated with 0.3 g / kg or 1 g / kg of D-psicose at 10:00 am, D-tagatose or D -Glucose was administered at 1 g / kg each, or physiological saline was orally administered into the stomach.
- the oral dose was 10 ml / kg. 30 minutes after administration, the portal vein was collected under isoflurane anesthesia.
- a blood coagulation inhibitor (heparin (final concentration 50 IU / ml)) and a peptide degradation inhibitor (aprotinin (final concentration 500 KIU / ml) and vildagliptin (final concentration 10 ⁇ M)) were added in advance to the sampling syringe.
- the collected blood was cooled and centrifuged, and the plasma was stored at ⁇ 80 ° C. until analysis.
- Quantitative analysis of active GLP-1 and total GIP was performed using the kit described above.
- Statistical analysis was performed by one-way analysis of variance (no correspondence) followed by Dunnett's test using saline as a control. The results are shown in FIG. In FIG. 3, * is p ⁇ 0.05 and ** is p ⁇ 0.01.
- the numerical value in the bar graph in a figure shows the number of experiments.
- Example 3 C57BL / 6J male mice (9-11 weeks old) were preliminarily raised in individual cages for 1 week or more and handled by the experimenter to acclimatize to the breeding / experimental environment. After fasting for 16 hours from 18:00 on the day before the experiment, saline or GLP-1 receptor inhibitor (Exendin-9, Ex-9, 200 nmol / kg) was intraperitoneally administered from 9:45, immediately thereafter Then, physiological saline or D-psicose 1 g / kg was orally administered to the stomach. The doses for intraperitoneal administration and oral administration were 5 ml / kg and 10 ml / kg, respectively.
- CE-2 feed generally mouse feed with balanced nutrition, made by CLEA Japan
- CE-2 feed was freely fed to the mice, 0.5 hours, 1 hour, 2 hours, 3 hours and 6 hours. Later food intake was measured over time. The amount of food intake was calculated as an energy intake (kcal) with 0 kcal per gram of D-psicose administered orally in the stomach and 3.45 kcal per gram of CE-2 feed.
- energy intake kcal
- one-way analysis of variance was performed on the results at each time point, and all groups were compared by Tukey's test. The results are shown in FIG. In FIG. 4, * is p ⁇ 0.05, and ** is p ⁇ 0.01.
- control group saline intraperitoneal administration—saline oral administration, white
- D-psicose group saline intraperitoneal administration—D-psicose oral administration, halftone dot
- D-psicose 1 g / kg oral administration significantly reduced food intake from 30 minutes to 6 hours after administration.
- the “GLP-1 receptor inhibitor single administration group” (Ex9 intraperitoneal administration—oral saline oral administration, mesh hatching) has the same level of food intake in all time zones compared to the “control group” (FIG. 4), It was suggested that endogenous GLP-1 secreted by ingestion of CE-2 feed does not affect the amount of food intake.
- the amount of food intake after 1 hour after administration was not significantly different from that of the “control group” or “GLP-1 receptor inhibitor alone administration group”, and on the contrary, was significantly higher than that of the “D-psicose group”.
- the amount of food increased (Fig. 4). That is, it was shown that the feeding inhibitory effect of 1 to 6 hours after oral administration of D-psicose disappeared by intraperitoneal administration of a GLP-1 receptor inhibitor. From the above, it was clarified that oral administration of 1 g / kg of D-psicose suppresses food intake through promotion of GLP-1 secretion.
- Example 4 C57BL / 6J male mice (7-11 weeks old) were preliminarily raised in individual cages for 1 week or longer, handled by the experimenter, and acclimated to the breeding / experimental environment. After fasting from 18:00 on the day before the experiment for 16 hours, saline, D-psicose 1 g / kg or D-tagatose 1 g / kg was orally administered into the stomach from 9:50. The administration volume was 10 ml / kg. From 10:00, the CE-2 feed was freely fed to the mice, and the food intake after 1 hour, 2 hours and 6 hours was measured over time.
- the amount of food intake was calculated as an energy intake (kcal) of 2 kcal per gram of D-tagatose administered orally in the stomach and 3.45 kcal per gram of CE-2 feed.
- energy intake kcal
- kcal energy intake
- CE-2 feed 3.45 kcal per gram of CE-2 feed.
- one-way analysis of variance was performed on the results at each time point, and all groups were compared by Tukey's test. The results are shown in FIG. In FIG. 5, * is p ⁇ 0.05, and ** is p ⁇ 0.01.
- the “D-psicose group” (halftone dot) had significantly lower food intake than the “control group” (saline administration, white) from 1 to 6 hours after oral administration of D-psicose. (FIG. 5).
- the “D-tagatose administration group” hatchched line
- the amount of food consumed for 1 hour after administration was significantly lower than that of the “control group”, but was significantly higher than that of the “D-psicose group”.
- the “D-tagatose administration group” (diagonal line) the amount of food intake at 2 hours and 6 hours after D-tagatose administration was similar to that of the “control group”, which was significantly higher than the “psicose group”.
- Example 5 Blood was collected from the tail vein of Sprague Dawley rats (8-9 week old males) fasted overnight before sample administration (0 minutes). Using a feeding tube, 2 solutions of each of deionized water (control group), D-psicose, indigestible dextrin (DE10), and dextrin (Matsutani Chemical Co., Ltd. product “Paindex # 2” (DE10)) It was orally administered at g / kg body weight (10 mL / kg body weight). Thereafter, blood was collected from the tail vein 15 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, and 240 minutes later.
- the blood was collected in a tube to which a DPP-IV inhibitor (Millipore), aprotinin (Wako Pure Chemical Industries), and heparin (Nacalai Tesque) were previously added.
- Plasma was collected by centrifugation and stored frozen at -80 ° C.
- the total plasma GLP-1 concentration in the obtained plasma was measured by a commercially available ELISA kit (Multi Specials GLP-1 Total ELISA manufactured by Millipore).
- the plasma glucose concentration was measured with Glucose CII-Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.).
- FIG. 6 shows changes in blood glucose level and changes in blood total GLP-1 concentration.
- the blood glucose level increased with administration of dextrin, slightly increased with indigestible dextrin, and slight variation similar to that of the control group (water administration) was observed with D-psicose administration (FIG. 6 (a)). From this result, it was confirmed that D-psicose has no action to increase blood glucose level.
- the GLP-1 concentration increased significantly after administration from D-psicose, peaking from 60 minutes to 120 minutes after administration, whereas it increased after 90 minutes after administration by administration of indigestible dextrin.
- Example 6 After a rest period of 1 week or more in advance, 200 ml of water (control beverage) per one time for 6 healthy subjects (3 males and 3 females, weight 53.3 ⁇ 7.4 kg) Or D-psicose 5 g / 200 ml (in terms of body weight D-psicose 0.07 to 0.11 g / kg), 10 g / 200 ml (in terms of body weight D-psicose 0.14 to 0.22 g / kg) or 15 g / 200 ml ( (Test drink) (D-psicose 0.21 to 0.33 g / kg in terms of body weight) was ingested at random.
- D-psicose 5 g / 200 ml in terms of body weight D-psicose 0.07 to 0.11 g / kg
- 10 g / 200 ml in terms of body weight D-psicose 0.14 to 0.22 g / kg
- the designated dinner On the eve of the day of taking the control beverage or the test beverage (the test day), the designated dinner was taken, and the intake of food and drink other than water and tea drinks was prohibited from 21:00 on the previous night until 9:00 am on the test day.
- the designated meal is one of the menus (curry, oyakodon, beef bowl, Chinese rice bowl) that does not contain any substances that can be fermented by intestinal bacteria such as dietary fiber, lactic acid bacteria, and fermentable sugars. Selectivity.
- blood sampling at 9 am on the day of the test day blood was collected after 15 minutes, 30, 60, 120 and 180 minutes after intake of the control beverage or test beverage. During the blood collection, only the specified amount of water could be ingested.
- Blood collection was performed by collecting blood from each subject himself / herself with a hematocrit tube obtained by inserting a fingertip with a commercially available puncture device for diabetic patients.
- the collected blood was transferred to a microtube and subjected to a centrifuge, and the total amount of GLP-1 in the centrifuged plasma was measured using a product “Multi Specials GLP-1 Total ELISA”.
- the subjects were allowed to observe a regular life for about one month, which is the test period, to refrain from extreme exercise and heavy drinking and eating, and to spend calmly indoors during the test.
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Abstract
Description
〔1〕D-プシコースを有効成分として含有することを特徴とするGLP-1分泌促進剤。
〔2〕ショ糖を含有しないことを特徴とする前記〔1〕に記載のGLP-1分泌促進剤。
〔3〕空腹時に投与されることを特徴とする前記〔1〕又は〔2〕に記載のGLP-1分泌促進剤。
〔4〕有効成分であるD-プシコースが、一回に5g以上の量となるように投与されることを特徴とする前記〔1〕~〔3〕のいずれか一項に記載のGLP-1分泌促進剤。
〔5〕ショ糖あるいはショ糖含有食品を摂取することなく投与されることを特徴とする、前記〔1〕~〔4〕のいずれか一項に記載のGLP-1分泌促進剤。
〔6〕前記〔1〕~〔5〕のいずれか一項に記載のGLP-1分泌促進剤及び水溶性食物繊維を有効成分として含有することを特徴とするGLP-1分泌促進組成物。
本発明のGLP-1分泌促進剤は、空腹時に摂取されることが好ましい。具体的には、食前5分以前に摂取されることが好ましく、さらに具体的には、先の食後3時間経過後、かつ、次の食前10分以前に摂取することがより好ましい。
水溶性食物繊維としてはペクチン、コンニャクマンナン、アルギン酸、グアーガム、寒天などの高粘性食物繊維、あるいは難消化性デキストリン、ポリデキストロース、グアーガム分解物などの低粘性食物繊維が例示される。
これらの中で、効果の観点から、特に難消化性デキストリン、グアーガム加水分解物、ポリデキストロース等が好ましい。
ヘミセルロース由来の物は、通常コーンの外皮からアルカリで抽出し、精製して製造されたもので、平均分子量は約20万と大きいが、5%水溶液の粘度は10cps程度と低く、水に溶けて透明な液になる。ヘミセルロース由来の物は「セルエース」(日本食品化工社)の商品名で市販されている。
ポリデキストロース(ライテス)はブドウ糖とソルビトールをクエン酸の存在下で液圧加熱して重合させ、精製したものであり、水溶性で低粘性である。「ライテス」(ファイザー社)として市販されている。
これら低粘性の水溶性食物繊維の中でも、難消化性デキストリンが最も効果的で好ましい。
本発明のGLP-1分泌促進剤と難消化性デキストリンは、質量比で1:0.1~1:100の比で含まれることが好ましく、1:0.5~1:50であることがより好ましい。
活性型(アクティブ)GLP-1は、血中において、酵素であるDPP-4による非常に速やかな限定的分解を受けることで生理活性を失い、不活性型GLP-1となることが知られている。よって、活性型GLP-1を測定したい場合は、血液を即座にペプチド分解抑制剤(DPP-4阻害剤)入りのサンプリングシリンジに保存して測定したり、相当量の血液を採取するなどの工夫が必要である。そこで、活性型(アクティブ)GLP-1と不活性型GLP-1を合わせた、DPP-4による影響を受けない、血中のトータルGLP-1を定量することにより、その体内分泌量自体は知ることはできるため、原則、トータルGLP-1を定量することによりGLP-1分泌促進効果を確認することとし、実験によっては、参考のためにアクティブGLP-1も合わせて測定することとした。
GIPについては活性型と不活性型を合わせたトータルGIPを測定した。
<培養細胞>
マウス大腸由来のGlucagon-like peptide-1(GLP-1)産生細胞株GLUTagを、10%FBSを含むDulbecco’s modified Eagle’s medium にて、37℃、5% CO2存在下で培養した。
GLUTag細胞を、48ウェルプレートでサブコンフルエントになるまで2、3日間培養した。各試料(D-プシコース又は難消化性デキストリン)を添加する前に、Hepesバッファー(140mM NaCl、4.5mM KCl、20mM Hepes、1.2mM CaCl2、1.2mM MgCl2、10mMD-glucose、0.1%BSA、pH 7.4)にてウェルを洗浄し、同バッファーに溶解した試料溶液を80μl添加して、37℃にて60分間インキュベーションした。上清を回収後、遠心分離(800×g、5分間、4℃)により細胞を沈殿させ、その上清70μlを凍結保存した。この上清中のトータルGLP-1を、市販の「Enzyme immuno assay kit」(株式会社矢内原研究所製)にて測定した。
D-プシコースの10mM、20mM、40mMの各溶液または難消化性デキストリン(松谷化学工業株式会社製品「ファイバーソル2」(DE10))10mM溶液を加え、上記GLP-1分泌試験を行ったところ、難消化性デキストリンがGLP-1分泌を顕著に促進した一方、D-プシコースにおいては、わずかに分泌促進傾向が見られる程度であった(図1)。すなわち、D-プシコースが、GLP-1産生細胞株への直接作用によりGLP-1分泌を促進する効果は観察されなかった。
実験動物として、C57BL/6J雄性マウス(9-11週齢)を用いた。実験前日の18時00分から16時間絶食させたマウスに、午前10:00にD-プシコースを1g/kg経口胃内投与した。経口投与量は10ml/kgとした。D-プシコース投与前及び投与してから30分及び60分後にイソフルラン麻酔下で門脈採血した。なお、サンプリングシリンジには血液凝固抑制剤(ヘパリン(終濃度50IU/ml))とペプチド分解抑制剤(アプロチニン(終濃度500KIU/ml)及びビルダグリプチン(終濃度10μM))を予め加えておいた。採取した血液は冷却遠心し、得られた血漿を分析するまで-80℃で保存しておいた。アクティブGLP-1、トータルGLP-1及びトータルGIPの定量分析は、ELISAキット(ミリポア社製。各々EGLP-35K、EZGLP1T-36K及びEZRMGIP-55K)を用いて行った。また、統計解析は、一元配置分散分析(対応あり)を行い、次いでD-プシコース投与前(0分)を対照としたDunnett検定を行った。結果は図2に示す。なお、図2中、*はp<0.05、**はp<0.01である。また、図2中の棒グラフ内の数値は実験数を示す。
実験前日の18時00分から16時間絶食させたC57BL/6J雄性マウス(9-11週齢)に、午前10:00にD-プシコースを0.3g/kg若しくは1g/kg、D-タガトース若しくはD-グルコースを各1g/kg、又は生理食塩水を経口胃内投与した。経口投与量は10ml/kgとした。投与してから30分後にイソフルラン麻酔下で門脈採血した。なお、サンプリングシリンジには血液凝固抑制剤(ヘパリン(終濃度50IU/ml))とペプチド分解抑制剤(アプロチニン(終濃度500KIU/ml)及びビルダグリプチン(終濃度10μM))を予め加えておいた。採取した血液は冷却遠心し、血漿は分析するまで-80℃で保存した。アクティブGLP-1及びトータルGIPの定量分析は、前述したキットを用いて行った。また、統計解析は、一元配置分散分析(対応なし)を行い、次いで生理食塩水を対照としたDunnett検定により行った。結果は図3に示す。なお、図3中、*はp<0.05、**はp<0.01である。また、図中の棒グラフ内の数値は実験数を示す。
C57BL/6J雄性マウス(9-11週齢)を個別ケージ内で1週間以上予備飼育し、実験者によるハンドリングをして、飼育・実験環境に順化させた。実験前日の18時00分から16時間絶食させた後、9時45分から生理食塩水又はGLP-1受容体阻害剤(Exendin-9,Ex-9,200nmol/kg)を腹腔内投与し、その直後に生理食塩水又はD-プシコース1g/kgを経口胃内投与した。腹腔内投与及び経口投与の各投与容量はそれぞれ5ml/kg及び10ml/kgとした。10時00分から、CE-2飼料(栄養バランスの摂れた一般的なマウス用飼料、日本クレア製)をマウスに自由摂食させ、0.5時間、1時間、2時間、3時間及び6時間後の摂食量を経時的に測定した。摂食量は、経口胃内投与したD-プシコース1g当たりを0kcal、CE-2飼料1g当たりを3.45kcalとしたエネルギー摂取量(kcal)として算出した。統計解析は、各時点における結果に対して一元配置分散分析(対応なし)を行い、Tukey’s検定による全群比較を行った。結果は図4に示す。なお、図4中、*はp<0.05、**はp<0.01である。
一方、「GLP-1受容体阻害剤+D-プシコース群」(Ex9腹腔内投与-D-プシコース経口投与、斜線)について比較すると、投与後30分の「GLP-1受容体阻害剤+D-プシコース群」の摂食量は、「対照群」若しくは「GLP-1受容体阻害剤単独投与群」と比較して、有意に減少し、「D-プシコース群」と同レベルの摂食量であった。したがって、投与後30分後のD-プシコースによる摂食抑制作用は、GLP-1以外の摂食抑制作用であることが示唆された(図4)。投与後1時間以降の摂食量は、「対照群」や「GLP-1受容体阻害剤単独投与群」の摂食量と有意な差はなく、逆に、「D-プシコース群」より有意に摂食量が増加した(図4)。すなわち、D-プシコース経口投与後1時間から6時間の摂食抑制作用が、GLP-1受容体阻害剤の腹腔内投与によって消失することが示された。以上より、D-プシコース1g/kgの経口投与は、GLP-1分泌促進を介して摂食量を抑制することが明らかとなった。
C57BL/6J雄性マウス(7-11週齢)を個別ケージ内で1週間以上予備飼育し、実験者によるハンドリングをして、飼育・実験環境に順化させた。実験前日の18時00分から16時間絶食させた後、9時50分から生理食塩水、D-プシコース1g/kg又はD-タガトース1g/kgを各々経口胃内投与した。投与容量は10ml/kgとした。10時00分からCE-2飼料をマウスに自由摂食させ、1時間、2時間及び6時間後の摂食量を経時的に測定した。摂食量は、経口胃内投与したD-タガトース1g当たりを2kcal、CE-2飼料1gが当たり3.45kcalとしたエネルギー摂取量(kcal)として算出した。統計解析は、各時点における結果に対して一元配置分散分析(対応なし)を行い、Tukey’s検定による全群比較を行った。結果は図5に示す。なお、図5中、*はp<0.05、**はp<0.01である。
従って、D-タガトース1g/kg経口投与には摂食抑制作用が認められるが、その作用は投与後1時間までの短期的なものであって、D-プシコース1g/kg経口投与と比較すると、その作用程度は弱いことが明らかとなった。D-タガトース1g/kg経口投与による摂食抑制作用が弱い理由としては、D-プシコースよりGLP-1分泌促進効果が弱い(図3)ことが推測された。
一夜絶食させたSprague Dawleyラット(8~9週齢の雄)の尾静脈より試料投与前(0分)の採血を行った。フィーディングチューブを用いて、脱イオン水(コントロール群)、D-プシコース、難消化性デキストリン(DE10)、デキストリン(松谷化学工業株式会社製品「パインデックス#2」(DE10))の各溶液を2 g/kg体重(10 mL/kg体重)にて経口投与した。その後、15分、30分、60分、90分、120分、150分、180分、210分、240分後に尾静脈より採血を行った。
血液は、あらかじめDPP-IV阻害剤(ミリポア社製)、アプロチニン(和光純薬工業社製)、ヘパリン(ナカライテスク社製)を添加したチューブに回収した。遠心分離により血漿を回収し、-80℃にて凍結保存した。得られた血漿中のトータルGLP-1濃度を市販のELISAキット(ミリポア社製 Multi Species GLP-1 Total ELISA)にて測定した。血漿中のグルコース濃度は、グルコースCII-テストワコー(和光純薬工業社製)にて測定した。
図6に血糖値の変化及び血中トータルGLP-1濃度の変化を示す。血糖値はデキストリン投与で上昇し、難消化性デキストリンではわずかに上昇し、D-プシコース投与ではコントロール群(水投与)と同様のわずかな変動が見られた(図6(a))。この結果から、D-プシコースには血糖値を上昇させる作用がないことが確かめられた。
一方、GLP-1濃度は、D-プシコース投与により投与後60分~120分をピークとして大きく上昇したのに対し、難消化性デキストリン投与では投与後90分以降に上昇したが、D-プシコースよりは弱い作用であり、GLP-1の分泌刺激として最もよく知られるグルコースから構成される消化性のデキストリン(パインデックス#2)の投与によってはGLP-1分泌を促進しなかった(図6(b))。この結果より、D-プシコースに強いGLP-1分泌促進作用があり、投与後60~120分をピークとした持続性のある作用であることが示された。
<試験方法>
1週間以上の休止期を予め設けた後、健常な被験者6名(男3名及び女3名。体重53.3±7.4kg。)に対して、1回につき、水200ml(対照飲料)又はD-プシコース5g/200ml(体重換算するとD-プシコース0.07~0.11g/kg)、10g/200ml(体重換算するとD-プシコース0.14~0.22g/kg)若しくは15g/200ml(試験飲料)(体重換算するとD-プシコース0.21~0.33g/kg)、をランダムに摂取させた。対照飲料又は試験飲料を摂取する日(試験日)の前夜は指定の夕食を摂取させ、前夜21時以降、試験当日の午前9時まで、水及び茶飲料を除く飲食物の摂取を禁じた。前記指定食は、食物繊維、乳酸菌、発酵性糖質といった腸内細菌が利用して発酵する可能性のある物質をほとんど含まないメニュー(カレー、親子丼、牛丼、中華丼)のいずれかの選択性とした。試験日当日の午前9時の空腹時に採血後、対照飲料又は試験飲料を摂取させ、その摂取後15分、30分、60分、120分及び180分後に採血をした。なお、その採血の間は、指定された分量の水のみ摂取可能とした。採血は、各被験者自身が糖尿病患者用に市販される穿刺器で指先を刺して得られる出血液をヘマトクリット管により採取することにより行った。採取した血液はマイクロチューブに移して遠心分離器に供し、遠心分離された血漿のトータルGLP-1量を、メルク(株)製品「Multi Species GLP-1 Total ELISA」を用いて測定した。なお、被験者には、試験期間である約1か月間は規則的な生活を心がけて過激な運動や暴飲暴食を慎むこと、及び、試験中は室内にて穏やかに過ごすことを遵守させた。
各血中のトータルGLP-1を縦軸に、上記D-プシコース摂取後15分~180分後の各時間を横軸にして折れ線グラフを描いたときの、血中トータルGLP-1濃度-時間曲線下面積(AUC)を算出し、得られた数値を図7に示す。D-プシコース摂取量に依存してAUC数値が大きくなっており、D-プシコースを1回に0.07g/体重kg以上摂取することにより、血中のトータルGLP-1分泌量を促進する効果が得られることがわかった。
Claims (6)
- D-プシコースを有効成分として含有することを特徴とするGLP-1分泌促進剤。
- ショ糖を含有しないことを特徴とする請求項1に記載のGLP-1分泌促進剤。
- 空腹時に投与されることを特徴とする請求項1又は2に記載のGLP-1分泌促進剤。
- 有効成分であるD-プシコースが、一回に0.07g/体重kg以上の量となるように投与されることを特徴とする請求項1~3のいずれか一項に記載のGLP-1分泌促進剤。
- ショ糖あるいはショ糖含有食品を摂取することなく投与されることを特徴とする、請求項1~4のいずれか一項に記載のGLP-1分泌促進剤。
- 請求項1~5のいずれか一項に記載のGLP-1分泌促進剤及び水溶性食物繊維を有効成分として含有することを特徴とするGLP-1分泌促進組成物。
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JP2019011257A (ja) * | 2017-06-29 | 2019-01-24 | 松谷化学工業株式会社 | D−プシコース及び大豆たんぱく質を有効成分とする生体機能改善用組成物 |
JP2020074695A (ja) * | 2018-11-06 | 2020-05-21 | 株式会社明治 | コプロコッカス属菌の増殖促進用組成物 |
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2016
- 2016-07-29 EP EP16830603.3A patent/EP3329922A4/en not_active Withdrawn
- 2016-07-29 US US15/747,827 patent/US20180214467A1/en not_active Abandoned
- 2016-07-29 WO PCT/JP2016/072269 patent/WO2017018500A1/ja active Application Filing
- 2016-07-29 CN CN201680044368.5A patent/CN108135918A/zh active Pending
- 2016-07-29 JP JP2017530931A patent/JP6896247B2/ja active Active
- 2016-07-29 KR KR1020187006014A patent/KR20180035878A/ko not_active Application Discontinuation
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Cited By (3)
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JP2019011257A (ja) * | 2017-06-29 | 2019-01-24 | 松谷化学工業株式会社 | D−プシコース及び大豆たんぱく質を有効成分とする生体機能改善用組成物 |
JP2020074695A (ja) * | 2018-11-06 | 2020-05-21 | 株式会社明治 | コプロコッカス属菌の増殖促進用組成物 |
JP7216260B2 (ja) | 2018-11-06 | 2023-02-01 | 株式会社明治 | コプロコッカス属菌の増殖促進用組成物 |
Also Published As
Publication number | Publication date |
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JPWO2017018500A1 (ja) | 2018-06-21 |
CN108135918A (zh) | 2018-06-08 |
EP3329922A4 (en) | 2019-03-27 |
JP6896247B2 (ja) | 2021-06-30 |
EP3329922A1 (en) | 2018-06-06 |
KR20180035878A (ko) | 2018-04-06 |
US20180214467A1 (en) | 2018-08-02 |
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