Arterial stiffness increase inhibitor

Abstract

The present invention relates to an arterial stiffness increase inhibitor, which contains isomaltulose as an active ingredient, and which is used such that isomaltulose is administered to a human at least once a day and continuously for at least four weeks.

Description

Technical Field

[0001] The present invention relates to inhibitors of increased arterial stiffness. Background Art

[0002] In Japan, vascular diseases (cardiovascular diseases), such as heart disease and cerebrovascular disease, are among the leading causes of death. Therefore, preventing cardiovascular disease is a crucial issue. Arterial stiffness, the physical hardness of the arterial wall, has been reported to be a predictor of cardiovascular disease independent of blood pressure. Therefore, in addition to blood pressure, controlling arterial stiffness is also crucial for preventing cardiovascular diseases, including arteriosclerosis (aging of blood vessels) and early vascular disease.

[0003] By inhibiting the increase in arterial stiffness, cardiovascular disease is expected to be improved or prevented. Therefore, various studies have been conducted on ingredients that can inhibit or improve arterial stiffness. For example, Patent Document 1 discloses that cocoa polyphenols are useful as an active ingredient in a composition for improving arterial stiffness.

[0004] Prior art literature

[0005] Patent Literature

[0006] Patent Document 1: International Publication No. 2017 / 026471 Summary of the Invention

[0007] Problems to be solved by the invention

[0008] Postprandial hyperglycemia caused by a carbohydrate-rich diet is considered a risk factor for cardiovascular disease. One of the causes is believed to be a decrease in endothelial function caused by the increase in blood insulin concentration associated with a glucose load. This decrease in endothelial function due to a glucose load results in increased arterial stiffness, a risk factor for cardiovascular disease. Therefore, to prevent cardiovascular disease, it is important to suppress the increase in arterial stiffness associated with postprandial hyperglycemia.

[0009] An object of the present invention is to provide an inhibitor of increased arterial stiffness that can suppress an increase in arterial stiffness even in the presence of a glucose load.

[0010] Means for solving problems

[0011] The inventors of the present application have discovered that continuous ingestion of isomaltulose over a specific period of time can suppress an increase in arterial stiffness even after ingestion of sugar that causes a rise in blood sugar levels, thereby completing the present invention.

[0012] One aspect of the present invention provides an arterial stiffness enhancement inhibitor comprising isomaltulose as an active ingredient, wherein the isomaltulose is administered to a human once a day or more for four weeks or more.

[0013] Another aspect of the present invention provides a pulse wave velocity increase inhibitor comprising isomaltulose as an active ingredient, wherein the isomaltulose is administered to a human once a day or more for four weeks or more.

[0014] The above-mentioned inhibitor is preferably used in an amount of 20 g or more of isomaltulose administered per administration.

[0015] A transient effect of suppressing increased arterial stiffness is difficult to maintain; generally, after a certain period of time, arterial stiffness decreases (worsens) to a level equivalent to the initial value. On the other hand, the inhibitor of increased arterial stiffness according to the present invention, through continuous administration, can suppress increased arterial stiffness even after ingestion of sugars (non-isomaltulose sugars) that increase blood sugar levels at a different time than when the inhibitor of increased arterial stiffness is ingested. This is believed to produce functional and structural changes in the arterial wall.

[0016] Effects of the Invention

[0017] According to the present invention, it is possible to provide an inhibitor of increased arterial stiffness that can suppress increased arterial stiffness even in a state of glucose load. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] [ Figure 1 ] is a graph showing changes in arm-ankle pulse wave velocity (baPWV) in a test according to an embodiment.

[0019] [ Figure 2 ] is the result obtained by statistically analyzing the changes in the upper arm-ankle pulse wave velocity (baPWV) in the experiment involved in the embodiment. DETAILED DESCRIPTION

[0020] Hereinafter, embodiments of the present invention will be described. However, the present invention is not limited to the following embodiments.

[0021] The arterial stiffness enhancement inhibitor according to the present embodiment contains isomaltulose as an active ingredient, and isomaltulose is administered to a human once a day or more for four weeks or more.

[0022] In this specification, "arterial stiffness" refers to the physical hardness (physical flexibility) of the arterial wall. While the arterial wall is composed of three layers: the intima, media, and adventitia, arterial stiffness refers to the overall hardness of the arterial wall, encompassing all three layers, rather than being assessed based on the hardness of any one layer. Furthermore, arterial stiffness, which represents the physical hardness of the arterial wall, is an indicator distinct from the arteriosclerosis index, which is calculated based on blood cholesterol levels.

[0023] Arterial stiffness can be assessed, for example, by measuring pulse wave velocity (PWV) and cardio-ancle vascular index (CAVI), indicators of cardiovascular risk. PWV can be brachial-ancle pulse wave velocity (baPWV) or heart-brachial pulse wave velocity (hbPWV). The greater the degree of arterial stiffness, the higher the PWV and CAVI values.

[0024] That is, the present invention can also provide an inhibitor of an increase in pulse wave velocity containing isomaltulose as an active ingredient, and an inhibitor of an increase in the cardio-ankle vascular index containing isomaltulose as an active ingredient. Furthermore, the present invention can also provide an inhibitor of an increase in arm-ankle pulse wave velocity and an inhibitor of an increase in heart-upper arm pulse wave velocity containing isomaltulose as an active ingredient.

[0025] Isomaltulose is a compound formed by an α-1,6 bond between glucose and fructose. It is also known as 6-O-α-D-glucopyranosyl-D-fructose. It is also known as palatinose. Please note that "Palatinose" is a registered trademark of Mitsui Sugars Co., Ltd.

[0026] Isomaltulose is found naturally in honey. It is also present in the transfer products produced when α-glycosyltransferases (isomaltulose synthases) derived from bacteria and yeast act on sucrose. Industrially, isomaltulose is produced by allowing α-glycosyltransferases derived from bacteria such as Protaminobacter rubrum and Serratia plymuthica to act on sucrose.

[0027] As isomaltulose, isomaltulose derived from nature may be used, or isomaltulose synthesized by enzyme action or the like may be used.

[0028] Isomaltulose can be included in the inhibitor of increased arterial stiffness in the form of crystals or granules. Granular particles can be, for example, aggregates of multiple isomaltulose crystals and amorphous sugar components, with the sugar components contained within the aggregates (spherical particles). Such granular particles can be obtained, for example, by precipitating isomaltulose crystals from a sugar solution containing both isomaltulose and amorphous sugars and spray-drying the sugar solution containing the crystals. Alternatively, granular particles containing isomaltulose can be obtained by heating the sugar solution while applying shear force to precipitate isomaltulose nuclei and then cooling the mixture containing the nuclei. The sugar solution can be obtained, for example, by allowing an enzyme to act on sucrose. In this case, the sugar solution and the resulting granular particles contain trehalose, fructose, glucose, sucrose, and isomaltulose as amorphous sugar components. The granular particles may be solid substances described in Japanese Patent Application Laid-Open No. 2012-179045 or the like.

[0029] In addition, commercially available isomaltulose may be used. Examples of commercially available products include crystalline palatinose (trade name "Crystalline Palatinose PST-N", manufactured by DM Mitsui Sugar Co., Ltd.), powdered palatinose (trade name "Powdered Palatinose PST-NP", manufactured by DM Mitsui Sugar Co., Ltd.), and palatinose syrup (trade names "Palatinose Syrup-ISN" and "Palatinose Syrup-TN", manufactured by DM Mitsui Sugar Co., Ltd.).

[0030] The arterial stiffness inhibitor according to this embodiment only needs to contain isomaltulose as an active ingredient and may be composed solely of isomaltulose or may be a composition containing isomaltulose. When the arterial stiffness inhibitor is a composition, the isomaltulose contained therein may be contained in the form of isomaltulose alone or in the form of a commercially available isomaltulose preparation containing certain sugars. Isomaltulose preparations may also contain other ingredients in addition to isomaltulose.

[0031] Other ingredients may be materials that can be used in foods, quasi-drugs, or pharmaceuticals. Materials that can be used in foods, quasi-drugs, or pharmaceuticals are not particularly limited, and examples thereof include amino acids, proteins, carbohydrates, fats, sweeteners, minerals, vitamins, flavorings, excipients, binders, lubricants, disintegrants, emulsifiers, surfactants, bases, solubilizers, and suspending agents.

[0032] Examples of proteins include casein, whey, soy protein, wheat protein, and egg white. Examples of carbohydrates include corn starch, cellulose, α-starch, wheat starch, rice starch, and potato starch. Examples of oils and fats include salad oil, corn oil, soybean oil, safflower oil, olive oil, and palm oil. Examples of sweeteners include sugars such as glucose, sucrose, fructose, glucose-fructose syrup, and fructose-glucose syrup; sugar alcohols such as xylitol, erythritol, and maltitol; artificial sweeteners such as sucralose, aspartame, saccharin, and acesulfame K; stevia sweeteners; and the like. Examples of minerals include calcium, potassium, phosphorus, sodium, manganese, iron, zinc, and magnesium, as well as their salts. Examples of vitamins include vitamin E, vitamin C, vitamin A, vitamin D, B vitamins, biotin, and niacin. Examples of excipients include dextrin, starch, lactose, and crystalline cellulose. Examples of binders include polyvinyl alcohol, gelatin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, and polyvinyl pyrrolidone. Examples of lubricants include magnesium stearate, calcium stearate, and talc. Examples of disintegrants include crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, and dextrin. Examples of emulsifiers or surfactants include sucrose fatty acid esters, citric acid, lactic acid, glycerol fatty acid esters, polyglycerol fatty acid esters, sorbitol fatty acid esters, propylene glycol fatty acid esters, and lecithin. Examples of matrices include cetearyl alcohol, lanolin, and polyethylene glycol. Examples of solubilizers include polyethylene glycol, propylene glycol, sodium carbonate, and sodium citrate. Examples of suspending agents include glyceryl monostearate, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxymethylcellulose, and sodium alginate. These ingredients can be used alone or in combination of two or more.

[0033] Isomaltulose has a sweetness approximately half that of sucrose. Therefore, the inhibitor of increased arterial stiffness according to this embodiment can primarily contain isomaltulose as a sweetener. Since isomaltulose has a slow hydrolysis rate, only one-fifth that of sucrose, it can suppress increases in blood sugar levels after ingestion. Therefore, by making a substance primarily containing isomaltulose as a sweetener, blood sugar control can be facilitated.

[0034] When the inhibitor of increased arterial stiffness contains ingredients other than isomaltulose, the content of isomaltulose can be appropriately set depending on the form of the inhibitor of increased arterial stiffness, the intended use, etc., and may be, for example, 10% by mass or more, 20% by mass or more, or 30% by mass or more, or 70% by mass or less, 60% by mass or less, or 50% by mass or less, based on the total amount of the inhibitor of increased arterial stiffness.

[0035] Arterial stiffness increase inhibitors can be used as food compositions or pharmaceutical compositions. The food compositions or pharmaceutical compositions according to this embodiment can be provided in the form of, for example, health foods, foods for specified health uses, functional foods, nutritional functional foods, supplements, quasi-drugs, or pharmaceuticals. The food compositions according to this embodiment can be labeled with, for example, a claim to inhibit increased arterial stiffness or a claim to improve increased arterial stiffness. Furthermore, the dosage form can be any of solids (powders, granules, etc.), liquids (solutions, suspensions, etc.), or pastes, and can be any of powders, pills, granules, tablets, capsules, lozenges, liquids, and suspensions.

[0036] The arterial stiffness-increasing inhibitor according to the present embodiment is used by administering isomaltulose to a human once a day or more for four weeks or more.

[0037] From the perspective of achieving an effect of suppressing the increase in arterial stiffness even under a glucose load, the arterial stiffness-increasing inhibitor is administered once or more per day. The arterial stiffness-increasing inhibitor may also be administered two or more times or three or more times per day. The arterial stiffness-increasing inhibitor may also be administered three or fewer times per day.

[0038] The time period for administering the inhibitor of increased arterial stiffness is not particularly limited, and for example, it may be administered on an empty stomach before breakfast, at the same time as breakfast, before lunch, or at the same time as lunch.

[0039] From the perspective of achieving an effect of suppressing the increase in arterial stiffness even under a glucose load, the arterial stiffness-increasing inhibitor is administered for a period of 4 weeks or longer. The arterial stiffness-increasing inhibitor may also be administered for 8 weeks or longer, or 12 weeks or longer. The arterial stiffness-increasing inhibitor may also be administered for 52 weeks or shorter.

[0040] The inhibitor of increased arterial stiffness is preferably used at a dosage of preferably 20 g or more, more preferably 22 g or more, and even more preferably 25 g or more of isomaltulose per dose. Alternatively, the inhibitor of increased arterial stiffness may be used at a dosage of less than 75 g, less than 72 g, or less than 70 g of isomaltulose per dose. The inhibitor of increased arterial stiffness is preferably used at a dosage of preferably 20 g or more, more preferably 22 g or more, and even more preferably 25 g or more of isomaltulose per day. Alternatively, the inhibitor of increased arterial stiffness may be used at a dosage of less than 75 g, less than 72 g, or less than 70 g of isomaltulose per day. Within this range, sufficient blood concentrations can be achieved, and the inhibitory effect on increased arterial stiffness can be more effectively exerted.

[0041] The inhibitor of increased arterial stiffness may be administered orally or parenterally such as intravenously. The inhibitor of increased arterial stiffness is preferably administered orally.

[0042] The subject to whom the inhibitor of increased arterial stiffness is administered may be a person who does not suffer from diabetes (healthy person), or an elderly person who is 60 years old or older, 65 years old or older, or 70 years old or older.

[0043] Specific aspects of the pulse wave velocity increase inhibitor and the cardio-ankle vascular index increase inhibitor according to one embodiment can be similar to those described above for the arterial stiffness increase inhibitor. Specifically, the pulse wave velocity increase inhibitor and the cardio-ankle vascular index increase inhibitor according to one embodiment can be described in conjunction with the arterial stiffness increase inhibitor by replacing "arterial stiffness increase inhibitor" with "pulse wave velocity increase inhibitor" or "cardio-ankle vascular index increase inhibitor."

[0044] One embodiment of the present invention can also be understood as a method for inhibiting increases in arterial stiffness, pulse wave velocity, or cardio-ankle vascular index, comprising administering an effective amount of an inhibitor of increased arterial stiffness, pulse wave velocity, or cardio-ankle vascular index containing isomaltulose as an active ingredient to a human being once or more daily for four weeks or more. The form, administration method, and dosage of the inhibitor of increased arterial stiffness, pulse wave velocity, or cardio-ankle vascular index can be the same as those described above. Furthermore, one embodiment of the present invention can be understood as isomaltulose for use in a method for inhibiting increases in arterial stiffness, pulse wave velocity, or cardio-ankle vascular index, wherein the isomaltulose is administered to a human being once or more daily for four weeks or more.

[0045] One embodiment of the present invention can also be understood as the use of isomaltulose for producing an inhibitor of increased arterial stiffness, an inhibitor of increased pulse wave velocity, or an inhibitor of increased cardio-ankle vascular index. The forms of the inhibitor of increased arterial stiffness, the inhibitor of increased pulse wave velocity, and the inhibitor of increased cardio-ankle vascular index can be the same as described above. Another embodiment of the present invention can also be understood as the use of isomaltulose for inhibiting increased arterial stiffness, pulse wave velocity, or cardio-ankle vascular index, wherein the isomaltulose is administered to a human once a day or more for at least four weeks.

[0046] Example

[0047] Hereinafter, the present invention will be described in more detail based on examples. However, the present invention is not limited to the following examples.

[0048] The effect of long-term isomaltulose ingestion on the increase in arterial stiffness associated with postprandial hyperglycemia was examined by the following method.

[0049] <object>

[0050] Fifty-four healthy middle-aged and elderly individuals (30 men and 24 women) were selected for the study. All subjects were assigned to either the isomaltulose (I) or sucrose (S) groups in a single-blind trial before the intervention, and each group underwent a 12-week intervention.

[0051] <Experimental Design>

[0052] All subjects were instructed to ingest a jelly with the composition listed in Table 1 once daily for 12 weeks. Group I ingested a jelly containing isomaltulose (Example 1), and Group S ingested a jelly containing sucrose (Comparative Example 1). The jelly was ingested every morning before breakfast, and all subjects were instructed to maintain the same dietary habits as before the intervention. A 75g oral glucose challenge test (75-g OGTT, details of which are described below) was performed before the 12-week intervention, and after 4, 8, and 12 weeks of intervention, at least one day after ingestion of the jelly. Arterial stiffness was assessed before, 60, and 120 minutes after the 75-g OGTT using the method described below.

[0053] [Table 1]

[0054] Jelly composition (g) Comparative Example 1 Example 1 Gelling agent 0.7 0.7 sucrose 25 Isomaltulose - 25 Acidulant (50% citric acid) 0.2 0.2 spices 0.2 0.2 defoaming agent 0.03 0.03 water 73.87 73.87 total 100 100

[0055] <75g oral glucose test (75-g OGTT)>

[0056] For the 75-g OGTT, under the instructions of a physician, Trelan G75g (Yoshido Co., Ltd.), which is commonly used in medical institutions and research, was used, and the usual volume (225 mL each time) was orally ingested within 5 minutes in accordance with the guidelines of the Japan Diabetes Society (Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H et al. Japanese Clinical Practice Guideline for Diabetes 2019. JDiabetes Investig 2020; 11: 1020-1076.).

[0057] <Evaluation of Arterial Stiffness>

[0058] Arterial stiffness is assessed by calculating pulse wave velocity (PWV) based on the pulse wave transit time between two arterial points and the distance measured using a gauge (PWV = arterial length / pulse wave transit time). Arm-ankle pulse wave velocity (baPWV) is assessed as an indicator of systemic arterial stiffness using a blood pressure pulse wave monitoring device (BP-203RPEII, FUKUDA COLIN Co., Ltd.) with oscillometric sensors attached to the left and right upper arms and ankles. The intra-rater and inter-rater coefficients of variation for PWV measurements were 3% and 4% respectively.

[0059] <Statistical Processing>

[0060] The changes in baPWV before and after the intervention in each group are expressed as mean values (95% confidence interval). The comparison of baPWV changes between the two groups before and after the 75-g OGTT used a two-factor repeated measures analysis of variance. The Bonferroni method was implemented in the comparison of changes in each intervention based on post hoc tests. The total area under the curve (baPWV AUC) for 90 minutes was calculated using the trapezoidal formula. IBM SPSS Statistics Ver.25 (manufactured by IBM) was used for statistical analysis. The statistical significance level in this experiment was set at 5%.

[0061] The changes of baPWV in each group before and after intervention are shown in Figure 1 . Figure 1 (a) shows the baPWV before the intervention, and shows the changes in baPWV before the 75-g OGTT, 60 minutes after the 75-g OGTT, and 120 minutes after the 75-g OGTT. Figure 1 (b), (c), and (d) are baPWV after 4 weeks, 8 weeks, and 12 weeks of intervention, respectively, showing the changes in baPWV before 75-g OGTT, 60 minutes after 75-g OGTT, and 120 minutes after 75-g OGTT.

[0062] The baPWV AUC of each group before and after intervention is shown in Figure 2 . Figure 1 (a), (b), (c), and (d) show the baPWV AUC of each group before intervention, after 4 weeks of intervention, after 8 weeks of intervention, and after 12 weeks of intervention, respectively.

[0063] baPWV after 4, 8, and 12 weeks of intervention was significantly increased in Group S at 60 minutes (p < 0.05) and 120 minutes (p < 0.05) after the 75-g OGTT compared to before the 75-g OGTT, but no significant changes were observed in Group I. On the other hand, baPWV after 60 minutes of the 75-g OGTT after 4, 8, and 12 weeks of intervention was significantly lower in Group I compared to Group S (p < 0.05). No changes were observed in baPWV before the 75-g OGTT in either group after the intervention compared to before the intervention. No between-group differences were observed in baPWV AUC before the intervention. However, baPWV AUC after 4, 8, and 12 weeks of intervention was significantly lower in Group I compared to Group S (p < 0.01). As described above, baPWV after 60 minutes and 120 minutes of the 75-g OGTT after 4, 8, and 12 weeks of intervention was lower in Group I than in Group S, indicating that the increase in arterial stiffness after glucose loading was suppressed.

Claims

1. An arterial stiffness enhancement inhibitor comprising isomaltulose as an active ingredient, wherein: The isomaltulose is administered to humans once a day or more for four weeks or more.

2. A pulse wave velocity increase inhibitor comprising isomaltulose as an active ingredient, wherein: The isomaltulose is administered to humans once a day or more for four weeks or more.

3. The inhibitor according to claim 1 or 2, wherein The above-mentioned isomaltulose was used so as to be administered in an amount of 20 g per time.

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