Original Article

診療と新薬 2018; 55: 945‑948

Suppressive Eﬀect of Hyuga-touki Leaf on
Postprandial Blood Glucose Level in Healthy Japanese:

診療と新薬 WebA Randomized, Double-blind, Placebo-controlled Crossover Study

Masatomo NAJIMA1)／Akinobu MIYATA2)／Masahiro YAMAMOTO 3)● Abstract
Objectives: The objective of this study is to examine how the ingestion of Hyuga-touki leaf containing YN-1
(isoepoxypteryxin) and isopteryxin contributes to suppressing an increase in postprandial blood glucose level.
Methods: A single dose cross-over trial was conducted. We administered oral glucose tolerance test (OGTT)
and appraised the changes of postprandial blood glucose levels.
Results: As the result of intergroup analysis, 0.5h-OGTT and three point of AUC (0-0.5h, 0-1h, and 0-1.5h)
showed signiﬁcant diﬀerences. Moreover no adverse eﬀects were observed by the ingestion of the test food.
Conclusion: We found out that the ingestion of Hyuga-touki leaf containing YN-1 and isopteryxin could help
moderate the elevation of postprandial blood glucose level. Additionally, no safety-related matter occurred
during the study.
Key Words: Hyuga-touki, Angelica Furcijuga Kitagawa, YN-1, isoepoxypteryxin, isopteryxin, postprandial
blood glucose level, OGTT, AUC

INTRODUCTION
According to National Health and Nutrition Survey
2016 conducted by Ministry of Health, Labour andWelfare, the number of people suﬀering from diabetes has
exceeded 10 million, increased by 500 thousand from thesurvey in 2012, and it was estimated that prediabetics
were to be 10 million 1). Diabetes will not get cured once
it develops, and if not treated, diabetes can cause
complicated disorders such as retinopathy, nephropathy,
and neuropathy, and may require blindness and dialysis
treatment. Since diabetes promotes the pathogenesis ordevelopment of cardiovascular conditions such ascerebrovascular and ischemic cardiac disease, it not only
reduces the patient s QOL seriously but also places aburden on society heavily in terms of medical
economics 2). The residual glucose in the blood which is
not consumed as energy is transported to the fat tissues
and stored as fat, accordingly this can cause obesity 3).
Further, the condition of postprandial hyperglycemia isreported to rise in risk for dementia 4), therefore theincrease in the postprandial plasma glucose level canbring on various diseases.
Meanwhile, the traditional medicinal plant in northern
1) JACTA (Japan Clinical Trial Association)2) Nihonbashi M s Clinic3) Meigen Inc.

Miyazaki Prefecture named Hyuga-touki is called Nihonyamaninjin and has been eaten as it suppresses bloodpressure and blood glucose levels 5), prevent inﬂammation
and allergy 6). For modern Japanese, who tend to lead anirregular lifestyle and intake an excess of calories, wethink that it is beneficial to be able to prevent lifestylediseases by easily ingesting food as a supplement. In thisstudy, we examined the effect of Hyuga-touki leaf forblood glucose and the safety by a randomized, doubleblind, placebo-controlled, crossover study.

MATERIALS AND METHODS
1. Test material
The test product was NIHON-YAMANINJIN tablet(Nihon-yamaninjin also called Hyuga-touki, hereinafter
called Active ) containing YN-1 and isopteryxin,
prepared by Meigen Inc. The amount of daily intake (orsingle dose) was 6 tablets (1 tablet weighs 240 mg), which
include 8.0 mg of YN-1 and 1.4 mg of isopteryxin per day.
The placebo ( Placebo ) does not include Hyuga-touki,YN-1, nor isopteryxin. Both tablets wereindistinguishable in shape, color, smell, or taste, andwere managed by an identification symbol. All involved
were blinded.
2. Subjects
The inclusion criteria were set according to Japanese42 （946）

診療と新薬・第 55 巻

foods for specified health uses (FOSHU) 7); (1) healthy
Japanese aged between 30 and 59 years, (2) 125 mg/dL 侒FBG (fasting blood glucose levels) or 199 mg/dL 侒2h-OGTT (postprandial blood glucose levels 120 minutes
after glucose tolerance). The following exclusion criteria
were applied; (1) dyslipidemia, (2) food allergies, (3)pregnant or lactating, (4) medicinal products or functional
food intake that could affect the outcome of the study,and (5) judged as unsuitable for the study by the principle
investigator. Written informed consent before the study
begun was obtained from all subjects.
3. Ethics review board
This study was conducted in accordance with the ethicalprinciples of the declaration of Helsinki (1975, as revisedin 2013) and the Ethical Guidelines for Medical andHealth Research Involving Human Subjects (2014,as partially revised in 2017). The study protocol wasa p p r o ve d b y t h e I n s t i t u t i o n a l R e v i e w B o a r d o f
Pharmaceutical Law Wisdoms (Tokyo). This trial wasregistered at UMIN Clinical Trial Registry (Trial ID:UMIN000027204).
4. Test procedure
These trials were conducted with the aid of a fund from
Meigen Inc. (Kagoshima) at two centers (KUROSUHOSPITAL, Tokyo and Japan Clinical Trial Association;JACTA, Tokyo). All of the subjects in this study were
public volunteers who had enrolled in the monitor bank ofHUMA CORP (Tokyo). 20 candidates were screenedusing a pretest comprising a physician s interview. 2
subjects were eliminated due to inclusion/ exclusion
criteria, thus 18 subjects were finally selected for thisstudy. A randomized, placebo- controlled, double-blindcross-over trial was conducted in May 2018. The study
consisted of 2 days separated by a washout, the 1st and2nd intake were single dose each and the washout period
was 7days. On each test day, the subjects visited at thesame time without eating or drinking (except water) 12
hours prior to the visit. The subjects took a 15 minuterest before proceeding with the ﬁrst blood extraction tomeasure FBG, then the subjects consumed 6 tablets oftest food and drank 75 g of glucose solution, and had theirblood drawn 30, 60, and 90 minutes after glucose
tolerance to measure postprandial glucose levels. During
wash out period, subjects were instructed to maintaintheir usual lifestyles and habits, to avoid taking othersupplements, to maintain their usual lifestyles and habits,
to avoid excessive amounts of food, drink, or alcohol, andto avoid excessive intake of foods which may influence
blood glucose level.
5. Randomization
A person in charge of allocation, who was not otherwise
involved in the study, veriﬁed the indistinguishability of
the Active and the Placebo, and performed allocation

第 12 号（2018 年 12 月）

Table 1 Participant s characteristics
Item
Sex（number）
Age（year）
Body weight（kg）

Mean ± SD
men 11 / women 7
45.3 ± 8.1
57.6 ± 7.8（n ＝ 18）

using a random number table. The allocation list wassealed and strictly controlled in a safe deposit box ofJACTA until the end of the study.
6. Data analysis
All statistics were expressed as mean ± standard
deviation (SD). Student s t-test was used for comparisons
for intergroup analysis. Multiplicity according to theoccasions was not adjusted. Any subjects with missing
values were eliminated from the analysis. Statisticalanalyses were performed using Statcel 4 (Yanai, 2015),
and the results were considered significant at a < 5％level in the two-sided test.

RESULTS
The subject s characteristics (11 men, 7 women) areshown Table 1. The mean age45.3 ± 8.1 y.o. The blood
glucose levels measured over time are shown Figure 1,and incremental postprandial areas under the curve(AUC) are shown Figure 2. At 30 min after glucose
tolerance, the blood glucose level of Active remained
lower than that of Placebo significantly (p = 0.004), and60-min of Active indicate signiﬁcant tendency to suppress
the blood glucose level compared to the Placebo(p = 0.067). As for AUC, all time points of 30, 60, and 90min depicted significant differences between Active andPlacebo (p = 0.005, p = 0.003, p = 0.005, respectively).
Moreover, no adverse events associated with the test
product were observed in the course of the reporting.

DISCUSSION
This study examined the eﬃcacy of ingesting Hyuga-touki
leaf containing YN-1 and isopteryxin, a type of coumarincompound. The pre-meal intake of Hyuga-touki leaf
inhibited the rise in postprandial blood glucose levelsigniﬁcantly. The Hyuga-touki used in this study is one of
the Apiaceae plants, which grows naturally from thenorthern part of Miyazaki prefecture to the mountainousarea of Kagoshima prefecture, and has been used as anindigenous drug such as cordial medicine called the grassof God since ancient times. In 1971, it was announced asa new species, named Angelica Furcijuga Kitagawa ,and named Hyuga-touki as the Japanese name. The
Hyuga-toki is also called Nihon-yamaninjin , and it issaid that full-fledged cultivation spreading activity had

診療と新薬・第 55 巻

mg/dL

ActivePlacebo

第 12 号（2018 年 12 月）

mg・h/dL##200180

43 （947）

Active250‡

200160##140150120
AUC

Blood glucose

Placebo##100##

1008060

5040
2000030‡60

90time（min）

30

p < 0.1, ## p < 0.01 between-group diﬀerence

60##90time（min）

p < 0.01 between-group diﬀerence

Figure 1 Plasma glucose concentration

Figure 2 AUC of blood glucose

begun since the 1980s. The Hyuga-touki contains YN-1
(isoepoxypteryxin) and isopteryxin, a type of coumarinbased compound, and coumarin is said to haveantibacterial effects 8) , anticoagulant action 9) , anda l l e v i a t e s s w e l l i n g 10). I n a d d i t i o n , m a n y a n t i hyperglycemic effects of coumarin contained in plants
have also been reported 11)-13).
Postprandial hyperglycemia is regarded as animportant index to diabetes or pre-diabetes 14). It isthought the fact that the postprandial blood glucose levelis high means the state of impaired glucose tolerance(IGT) . This means that the amount or function of insulin
is decreased, glucose is not able to be metabolized
suﬃciently inside of the body, and the function to returnthe blood glucose level to normal is very weak. As IGT
promotes arteriosclerosis and causes coronary heartdisease and others 15), it is important for us to suppress
postprandial blood glucose level in order to extend
healthy life expectancy and to maintain and improve
QOL. Ninomiya (2011) reported that Hyuga-touki root
extract enhanced glucose consumption in hepatocytes.
Moreover, the khellactone type coumarin hyuganin A,
the coumarin glycoside apiosylskimmin, and isopteriyxin,
which are contained in the extract, also showed evidenceof promoting glucose consumption 16). Many studies havealso reported that coumarin inhibits α-glucosidase andreduces oxidative stress or inflammation 17)-19). Based onthese, we could consider that the coumarin contained in
Hyuga-touki suppressed the increase in postprandial
blood glucose level.
Hyuga-touki root was acknowledged as medicine by theMinistry of Health, Labour and Welfare in 2002 20). On theother hand, there are reports that the leaves and stems of
Hyuga-touki also contain YN-1 and isopteryxin similar tothe root 21). The test food used as an intervention in thistrial is a tablet made from drying leaves of Hyuga-touki
into powder, so it was thought that the similar eﬀect tothe root was obtained.
Through the ingestion of the test food, OGTT, andblood drawing, we observed no harmful incidences to thesubjects, and this result indicated the safety of theingestion of the test product. In this study we conducted
single intake trials targeted for normal blood sugar level,or FBG or OGTT is boundary type (FBG; 110-125 mg/dL, 2h-OGTT; 140-199 mg/dL) which standards regulatedby the Consumer Aﬀairs Agency 7). Future study such as
tests on subjects with IGT (impaired glucose tolerance)and long-term intake tests would be expected.

CONCLUSION
In conclusion, we found out that the ingestion ofNIHON-YAMANINJIN tablet containing YN-1
(isoepoxypteryxin) and isopteryxin suppressed theincrease in postprandial blood glucose level of healthy
Japanese. In addition, no safety-related matter occurred
during the study.
CONFLICT OF INTEREST
All parts of this study were funded by Meigen Inc. Masahiro Yamamoto is
the principal. All authors state that the study was conducted in theabsence of any other relationships that could be interpreted as a conﬂict ofinterest.

REFERENCES
1) 2016 National Health and Nutrition Survey. Ministry of Health,Labour and Welfare.
2) Health Japan 21. Diabetes . Ministry of Health, Labour and Welfare.
3) Blaak EE, Antoine JM, Benton D, et al. Impact of postprandial
glycaemia on health and prevention of disease. Obes Rev. 2012; 13(10): 923-84.

44 （948）

診療と新薬・第 55 巻4) Mukai N, Ohara T, Hata J, et al. Alternative Measures ofHyperglycemia and Risk of Alzheimer s Disease in the Community:
The Hisayama Study. J Clin Endocrinol Metab. 2017; 102 (8): 300210.
5) Mizuno S. Kobayashi N. et al. Clinical Usefulness of Hyugatouki(Angelica Furcijuga ). J. New Rem. & Clin. 2002; 51 (11): 1114-1121.
6) Kageura T, Matsuda H, Murakami T, et al. Inhibitory Effects ofConstituents from Angelica furcijuga on Nitric Oxide Production. J
Tradit Med . 1998; 15 (5): 300-1.
7) Notiﬁcation No. 259. Consumer Aﬀairs Agency, Government of Japan,
2014.
8) Chiji H, Kuroda M, Yamada J. Antimicrobial activity of chromone andcoumarin compounds against brown fungus［in Japanese］. Bull. Fuji
Women s College. 1991; 29 (ser. 2): 1-4.
9) Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanismof action, clinical eﬀectiveness, and optimal therapeutic range. Chest.
2001; 119 (Suppl. 1): 8S-21S.
10) Tamura-Norimatsu A, Mori H. Anti-edema Effect of a Drink
Containing Peucedanum Japonicum Thunb. in Healthy Japanese
Women. Nippon Shokuhin Kagaku Kogaku Kaishi. 2012; 59 (10): 50914.
11) Cristians S, Guerrero-Analco JA, Pérez-Vásquez A, et al.
Hypoglycemic activity of extracts and compounds from the leaves of
Hintonia standleyana and H. latiﬂora: potential alternatives to the useof the stem bark of these species. J Nat Prod. 2009; 72 (3): 408-13.
12) Guerrero-Analco J, Medina-Campos O, Brindis F, et al. Antidiabetic
properties of selected Mexican copalchis of the Rubiaceae family.
Phytochemistry. 2007; 68 (15): 2087-95.
13) Banskota A H, Li J, Tezuka Y, et al. Hypoglycemic effect of
Aemotoxylon campechanum on streptozotocin (STZ)-induced diabetic

第 12 号（2018 年 12 月）
rats. J Tradit Med. 2003; 20 (2): 57-61.
14) Seino Y, Nanjo K, Tajima N, et al. Report of the Committee on theClassiﬁcation and Diagnostic Criteria of Diabetes Mellitus (Revisionfor International Harmonization of HbA1c in Japan). Journal of theJapan Diabetes Society. 2012; 55 (7): 485-504.
15) Tominaga M, Eguchi H, Manaka H, et al. Impaired glucose tolerance
is a risk factor for cardiovascular disease, but not impaired fasting
glucose. The Funagata Diabetes Study. iabetes Care. 1999; 22 (6):920-4.
16) Ninomiya K. Search for anti-diabetic constituents from medicinal
foods -through the enhancement of glucose metabolism inhepatocytes-. working papers in Grants-in-Aid for Scientific
Research (KAKEN) , Japan Society for the Promotion of Science.
2011-3-31.
17) Prada AL, Amado JRR, Keita H, et al. Cassia grandis fruit extract
reduces the blood glucose level in alloxan-induced diabetic rats.
Biomed Pharmacother. 2018; 103: 421-8.
18) Li H, Yao Y, Li L. Coumarins as potential antidiabetic agents. J PharmPharmacol. 2017; 69 (10): 1253-64.
19) Nguyen PH, Zhao BT, Kim O, et al. Anti-inﬂammatory terpenylatedcoumarins from the leaves of Zanthoxylum schinifolium with α-glucosidase inhibitory activity. J Nat Med. 2016; 70 (2): 276-81.
20) Notiﬁcation. No.1115003 of the PFSB. the Director of Pharmaceuticaland Food Safety Bureau, Ministry of Health, Labour and Welfare.
2002-11-1521) Matsushita Y, Sugamoto K, Matsui T, et al. Isolation and Analysis ofComponents of Hyugatouki (Angelica furcijuga Kitagawa) Leaves andStems. Mem Fac Eng Univ Miyazaki . 2009; 38: 87-90.