Effectiveness of Herbal Medicines Containing Kudzu Root as a<br /> Principal Ingredient in Patients with Diabetes Mellitus

Abstract : Background : Puerarin, the main component of kudzu root, has been shown to lower blood glucose levels in vivo and in vitro. However, no clinical trials were performed in diabetic patients. The purpose of this study was to determine whether kudzu root lowers blood glucose or hemoglobin A1c in diabetic patients.

Methods : We performed a retrospective study to evaluate whether the use of daily herbal medicine including kudzu root with conventional therapy lowers fasting blood glucose, as compared to conven-

회원학술보고

갈근 함유탕제의 혈당 강하 효과

김종윤, 김진숙

, 정지현

, 김정태

, 윤현옥

, 유기연

서울대학교병원 약제부, 한국한의학연구원

, 동덕여자대학교 약학대학

, 경희대학교 약학대학 강동경희대학교병원

, 경상대학교 약학대학

Effectiveness of Herbal Medicines Containing Kudzu Root as a Principal Ingredient in Patients with Diabetes Mellitus

Jong Yoon Kim, Jin Sook Kim

, Ji Hyun Chung

, Jung Tae Kim

, Hyon Ok Yoon

and Ki Yon Rhew

Seoul National University Hospital, Seoul, Korea

Korea Institute of Oriental Medicine Herbal TKM-Based Herbal Drug Research Group, Daejeon, Korea

College of Pharmacy, Dongduk Women’s University, Seoul, Korea

College of Pharmacy, Kyung Hee University Hospital at Gangdong, Seoul, Korea

College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Korea

투고일자 2014.10.27; 심사완료일자 2014.11.17; 게재확정일자 2014.11.28

�교신저자 유기연 Tel:02-940-4519 E-mail:[email protected] 윤현옥 Tel:055-772-2422 E-mail:[email protected]

As the worldwide diabetic rate rises, the search for dietary adjuncts to treat this life- altering disease has become extensive. Also the mortality of lifestyle-related diseases such as diabetes and cardiovascular disease has con- siderably increased in many countries.

Diabetic Mellitus (DM) is the fifth-leading cause of death all over the world and con- tributes to the leading causes of death, cancer and cardiovascular disease (CVD). In addition, glycemic management still remains a corner- stone of DM care, although the co-manage- ment of atherosclerosis, cardiovascular risk reduction, and prevention of long-term conse-

quences associated with DM are now well rec- ognized to improve long-term survival.

Besides pharmacological interventions, life style modification is also important in diabetes management. The use of complementary and alternative medicine is expected to play a criti- cal role in effectively managing diabetes.

Complementary and alternative medicine (CAM) is defined as the medical practices, products, and health care systems that are not considered as parts of conventional care by the National Institutes of Health (NIH).

In spite of the advanced conventional medicine, the use of CAM in the United States has increased signif- tional therapy alone. 65 patients with diabetes were included in the study. 20 patients consumed 32- 48 g of kudzu root extract daily for at least 20 days (median 34 days) with conventional therapy, and 45 patients received conventional diabetic care alone. Fasting blood glucose level was obtained at baseline and after the administration of herbal medicine. Hemoglobin A1c, cholesterol profiles [LDL(Low-density lipoprotein), HDL(High-density lipoprotein, TG(Triglyceride)] and AST(Aspartate transaminase), ALT(Alanine transaminase) were measured.

Results : The difference between basal and index day fasting glucose level was 14.1 mg/dL (±24.65, p= 0.011) in the kudzu root group was statistically significant. Hemoglobin A1c data were obtained from 27 participants and there was a significant improvement in both, the kudzu root treatment group and the control group, with p values of 0.004 and 0.022, respectively. Cholesterol profiles and liver enzymes did not reveal significant changes.

Conclusion : The study findings suggested that kudzu root intake might help to lower serum fasting blood glucose levels in diabetic patients when combined with conventional therapy.

[Key words] Blood glucose, Puerarin, Kudzu root, Diabetic mellitus, Glucose lowering effect

icantly between 2002 and 2007

Naturopathic medicine, a part of CAM, is a unique whole system of medicine that focuses on patient wellness through the delivery of health-pro- motion counseling in clinical practice and has shown improvement in health care outcome in diabetes.; However, these improvements were not explained in detail by which herbal medi- cine contribute to the effectiveness because of limited availability of laboratory data.

Radix Puerariae, also known as Gegen, Yegen or kudzu root, is the dried root of Pueraria lobata. Kudzu root is native to South East Asia and has been used to treat fever, diarrhea, diabetes and cardiovascular diseases over 2000 years.

Puerarin, the most abundant is of flavonoid of kudzu, has shown blood glucose lowering effects in vitro and in vivo. Co-incu- bation of puerarinin high glucose-treated preadipocytes potentiated the glucose uptake considerably in a dose-dependent manner.

Also in an in vivo study, puerarin (15 mg/kg, i.v.) decreased blood glucose level and increased endorphin content in the absence of insulin stimulation in streptozotocin (STZ) induced diabetic rats.

The mechanism of action is known as the activation of peroxisome prolif- erator-activated receptor gamma (PPAR-γ ), the glucose transporter subtype 4 (GULT-4), and α 1-adrenogenic pathways elucidate the hypoglycaemic effect of puerarin.

Kudzu root is also used for lowering choles- terol.

The publication by Zheng and colleagues proposed that administration of puerarin (400 mg/kg/day) has dropped the hepatic total cho- lesterol and triglyceride concentrations in liver of Wistar rats.

Diabetic patients have increased risk of cardiovascular disease and hyperlipidemia is risks factor either.

Yer-dahan-so-tang, Chungpye-sagan-tang,

and Galgeun-haegi-tang are examples of CAM remedies that originated from Sasang consti- tutional medicine theory of Lee Je-ma.

This theory is widely used to diagnose and treat diseases in Korea, and represents an individu- alized Korean traditional medical approach.

The CAM remedies mentioned above contains dried kudzu roots and prescribed to treat a dis- ease symptomized by thirst and polyuria which are similar to the symptoms of contemporary DM. Also, as shown above, kudzu root has been shown to be effective in lowering blood glucose level in previous studies.

Therefore, we hypothesized that kudzu root could be used for diabetes as an adjuvant therapy. The objective of this study was to investigate the effect of kudzu root on lowering blood glucose level in hospitalized diabetics in South Korea.

MATERIALS AND METHODS Settings

This was a retrospective chart review study of diabetic patients who were admitted to the naturopathy clinic and conventional clinic of the Stroke and Neurological Disorders Center of Kyung Hee University Hospital at gangdong, Korea, between June 1st 2006 and December 31th, 2011. Medication chart review was per- formed to collect demographic characteristics, past medical history, medications, and blood workup including fasting blood glucose, hemo- globin A1c, and cholesterol profile. CAM group includes patients who received CAM, contain- ing kudzu root as a principle ingredient, with conventional medicine (CM) and patients who CM only were assigned to control group.

Patients can choose the CAM therapy based on

patients’preference by themselves. The pri-

mary indication of the CAM or CM treatment was to prevent secondary stroke after ischemic attack. Patients in both groups received opti- mal treatment of other disease including dia- betes through the cooperative care with other department when necessary. The study was conducted after protocol approval by the Kyung Hee University Hospital at gangdong Institutional Review Board (KHNMC-OH-IRB 2012-046).

Subjects

The overall cohort included sixty-five patients with diabetes who were hospitalized at the naturopathy clinic and conventional clinic of the Stroke and Neurological Disorders Center in the Kyung Hee University Hospital at gangdong between June 1, 2006 and December 31, 2011. The patients in the center could select the medication therapy method either including Korean traditional medicine (CAM group) or only western medicine (CM group), when they admitted in. The patients usually are not medically urgent or severe.

Therefore, patients were categorized to two groups, control group and CAM group. Twenty patients were assigned to CAM group and con- sumed 32-48 g of kudzu root extract daily for at least 20 days (median 34 days). In control group, forty-five patients received conven- tional diabetic care only. Patients were eligible for inclusion in the study if they were 18 years of age or older; and if they had documented diagnosis by conventional physician of DM.

Inclusion criteria were: (1)currently diabetes mellitus (2)hospitalization for at least 20 days, (3)administration of selected CAM with Conventional Medicine (CM) or CM only during his/her hospitalization. Exclusion criteria

were: (1)patients on CM lowering or raising blood glucose except oral hypoglycemic agents or insulin(i.e. steroids, beta-blockers), (2) patients who need an operation or are in a critical condition.

Medical charts were identified through data warehouse software (Hyperion) which can be searched by Korean Standard Classification of Diseases 5th version code (KCD-5) till 2010 or KCD-6 (2011).

Quality control and process of CAM components

Kudzu root was prepared in three different ways, Yer-dahan-so-tang, Chungpye-sagan- tang, and galgeun-haegi-tang. Each prepara- tion has 7-8 ingredients including Pueraria Radix. For better quality control, all prescrip- tions were prepared by Kyung Hee Herb Pharm Co Ltdand under supervision of Korea Food &

Drug Administration in accordance with quali- ty assurance criteria of Korean pharma- copoeia. Herbal extracts were added to water to obtain final products of 360 ml solution and patient ingested 120 ml per dose three times a day. Table 1 represents components of each preparation.

Efficacy outcomes

Fasting blood glucose (FBG) was defined as

the first morning blood glucose of the day

without continuous tube feeding or parenteral

nutrition. Also we collected FBG level, choles-

terol profiles (LDL, HDL, TG) on index day,

defined as day 20 after CAM administration in

patients whose hospitalization is 20 days or

greater but less than 30 days or day 30 in

patients who were admitted hospital for at

least 30 day. The glycated hemoglobin A1c

(HbA1C) was monitored in patients who were admitted for at least 4 weeks.

Safety outcomes

Adverse effects of kudzu root were monitored with aspartate transaminase (AST) and alanine transaminase (ALT). Reference ranges for AST

and ALT are 0-40 IU/L. Drug-induced liver injury was defined as: (1)a rise of over two times the upper limit of reference range in ALT or (2)a combined rise in AST, provided above 2 times upper limit of reference range.

Statistical analyses

Dose (g) Raw material codea

Name of CM intervention Name of herb Table 1. Constituents of interventions per dose

Pueraria Radix Angelicae Temissimae Radix

Scutellariae Radix Angelicae Dahuricae Radix

Platycodi Radix Raphani Semen Cimilifugae Rhizoma

KHHP001 KHHP053 KHHP047 KHHP022 KHHP009 KHHP010 KHHP032

16 8 8 4 4 4 4 Yer-dahan-so-tang

Pueraria Radix Angelica Temissimae Radix

Scutellariae Radix Angelicae Dahiricae Radix

Rei Rhizoma Platycodi Radix Raphani Semen Cimilifugae Rhizoma

KHHP001 KHHP053 KHHP047 KHHP022 KHHP058 KHHP009 KHHP010 KHHP032

16 8 8 4 4 4 4 4 Chungpye-sagan-tang

Pueraria Radix Cimilifugae Rhizoma

Scutellariae Radix Armeniacae Semen Angelicae Dahiricae Radix

Platycodi Radix ZizyphiSpinosi Radix

KHHP001 KHHP032 KHHP047 KHHP194 KHHP022 KHHP009 KHHP030

12 8 6 6 4 4 4 Galgeun-haegi-tang

a Approved and regulated by Korea Food & Drug Administration

Differences between the treatment groups were evaluated by using the paired t-test for continuous variables. For categorical variables, Chi squared test and Fisher’s exact test were performed. All reported p values are two-

sided; a p value under 0.05 was considered to show statistical significance. SPSS software, version 20.0 (Chicago, USA), was used for sta- tistical analysis.

RESULTS

Table 2 represents demographics characteris- tics of the participants. There was no signifi- cant difference in age between two groups with a median of 66.5 years in CAM and with a median of 69.67 years in CM. 14 males (70%) were included in CAM and 25 males (44%) were included in CM. Majority of participants were diagnosed with type 2 diabetes. CAM cohort group has lower FBG than CM cohort at base- line. HbA1c was higher in CAM with a median of 8.39 but it was statistically not significant.

Either new medication or dose increase in anti-diabetic medication was initiated in 3 patients (15%) in CAM group and 10 patients (22.2%) in control group on observations and it was statistically insignificant (p= 0.594).

Fasting Blood Glucose (FBG)

As shown in the Table 3, FBG decreased from 117.45±23.46 to 103.35±20.22 in CAM group and it was statistically significant with P value of p= 0.011. On the other hand, the control group did not show a significant change in FBG (p= 0.252). Due to different preparations of kudzu root, 5 subjects consumed 32 g of kudzu root daily and 14 patients received 48 g of kutzu root daily. There was only one patient prescribed 36 g of kudzu root daily. Mean FBG drop (FBG index day - FBG baseline ) in 32 g of kudzu root group was 7 mg/dL and 48 g of kudzu root group showed a mean FBG drop with 25.5 mg/dL (Fig. 1). The patient consumed P -

value

Feature The CAM

cohort (n=20)

The CM cohort (n=45)

Table 2. Baseline features of subjects in the selected CAM and the CM cohorts

Age (years)* 66.50±11.89 69.67±11.71 0.32 Sex

Males 14 (70%) 25 (56%)

Females 6 (30%) 20 (44%) 0.004 Type of DM

T2DM 19 (95%) 45 (100%)

IDDM 1 (5%) -

FBG(mg/dL) 117.45±23.46 160.91±56.05 0.001 HbA1c(%)* 8.39±1.80(n=13) 7.67±1.52(n=14) 0.686

* Plus-minus values are means ± standard deviation.

�Analysis by unpaired t test (with Welch’s correction when variances are unequal).

T2DM= Type 2 diabetes mellitus; IDDM= Insulin-Dependent Diabetes Mellitus; FBG= Fasting Blood Glucose; HbA1c = Hemoglobin A1c

P - value Day 0 Index Day Table 3. FBG and HbA1c changes in each cohort

The CAM

cohort (n=20) 117.45±23.46 103.35±20.22 0.011 The CM

cohort (n=45) 160.91±56.05 148.40±55.30 0.252 FBG

The CAM

cohort (n=13) 8.39±1.80 6.87±1.18 0.004 The CM

cohort (n=14) 7.67±1.52 6.69±1.15 0.022 Hb-

A1c

FBG= Fasting Blood Glucose; HbA1c = Hemoglobin A1c; CAM = Complementary and Alternative medicine; CM = Conventional Medicine

36 g of kudzu root dropped 6 mg/dL of FBG during the kudzu root intake.

HbA1c

HbA1c analysis only included patients whose baseline and index day HbA1c data were avail- able. Hemoglobin A1c analysis showed signifi- cant improvement in both kudzu root treat- ment group and control group with p value of 0.004 and 0.022 respectively.

Lipid Panels

There was no significant improvement in LDL, HDL and TG observed in the experimental group and the control group.

Safety outcomes

One patient in CAM group showed high ALT as 135 during the kudzu root intake with base- line 100, but no changes in AST with baseline 64. The others showed no significant changes

compared with their baseline in AST and ALT.

Discussions

This study confirms the previous in vivo and in vitro study, which showed the blood glucose lowering effects in kudzu root, and extends to clinical use in human subjects. The publication by Peng and colleagues proposed that supple- mentation of 0.2% of kudzu root in normal diet for two months has dropped fasting blood glu- cose and insulin levels in stroke prone sponta- neously hypertensive rats.

As shown in Fig. 1, the results from this analysis have shown dose dependent blood sugar lowering effects sup- porting kudzu root as the key factor for blood glucose lowering effect.

Recent study has proposed that administra- tion of puerarin (400 mg/kg/day) dropped the hepatic total cholesterol and triglyceride con- centrations in liver of Wistar rats.

Although this was an animal model based study, the result was obtained by administering the 4 times higher dose of medication than that of Song, et al (2004) which reported the hypo- glycemic effect when administering puerarin 100 mg/kg/day to Male SD rats.

Therefore, when taking herbal medications containing kudzu root as a major component, the hypo- glycemic effect was produced as anticipated from the literature, while the lipid lowering effect was not produced; however, the lipid lowering effect may be expected to be pro- nounced in case of long-term treatment with medication containing higher level of kudzu root.

Liver toxicity is known as a potential adverse effect of herbal medicines. The prevalence of concurrent medicine-induced liver injury was reported 0.5~1.4% prevalence of drug-induced Fig. 1 FBG variations depending on the amount

of Kudzu root intake a day

Drop in FBG = FBG index day - FBG day0

liver injury in larger population studies.

Although there was one patient presented increased ALT compared to the reference ranges, the baseline data was also high and AST escalating was not accompanied. Moreover hepatotoxicity caused by CM medication could not be excluded. More precise study should be conducted to prove the probability whether the CAM treatment caused the adverse event or not.

Although it is suggested that FBG improve- ment was observed in the CAM group, this study has several limitations. Given it was a retrospective study, we could not randomize patients and treatments were initiated by patients’preference. Majority of participants were of the elderly Korean population and the sample size was small. Therefore, findings from this study may not be generalizable to the general population. Lastly, herbal medicines including kudzu root may have drug interac- tion with diabetic medications.

There are limited data available in drug-herbal interac- tions between kudzu roots and conventional.

CYP 1A2 expression induction and CYP 2D6 activity inhibition were reported in eighteen healthy Chinese male volunteers.

In vivo studies, puerarin enhanced the activity of CYP 1A1/2, 2A1, 2C11 and inhibited the activity of CYP 2B1, 2E1 and 3A in Wistar rats.

However, further systemic studies are required to prove this potential interaction.

A description of glycemic control that occurred during naturopathic treatment based on kudzu root is provided in this study. It was confirmed that FBG on index day dropped sig- nificantly in the CAM group. This result was dependent on the amount of kudzu root per day included in CAM intervention. This study was a retrospective pilot trial; therefore, a

prospective, long term follow-up trial is required to determine more definitely the hypoglycemic effect of kudzu root containing herbal medicines.

ACKNOWLEDGEMENT

This work was supported by Korea Institute of Oriental Medicine, Herbal TKM-Based Herbal Drug Research Group (K12040).

AUTHOR DISCLOSURE STATEMENT

The authors declare that there is no conflict of interests regarding the publication of this article.

REFERENCES

1) The Statistics Korea : Statistics of Cause of Death in Korea, 2011. http://www.kostat.

go.kr/portal/korea/kor_nw/2/6/2/index.boar d?bmode=read&bSeq=&aSeq=260046&page No=1&rowNum=10&navCount=10&currPg=

&sTarget=title&sTxt. Accessed 26 July, 2013 2) Shiyovich A., Shlyakhover V., and Katz A.:

Sitting and cardiovascular morbidity and mortality. Harefuah., 152(1), 43-8 (2013) 3) Wang C., and Reusch J.: Diabetes and car-

diovascular disease: changing the focus from glycemic control to improving long- term survival. Am J Cardiol., 110(9), 58-68 (2012)

4) National Center for Complementary and Alternative Medicine (NCCAM). http://

nccam.nih.gov/health/whatiscam#defin- ingcam, Accessed 30 July, 2013

5) Okoro C., Zhao G., Li C., and Balluz L. :

Has the use of complementary and alterna-

tive medicine therapies by U.S. adults with

chronic disease-related functional limita- tions changed from 2002 to 2007. J Altern Complement Med., 19(3), 217-23 (2013) 6) Garrow D., and Eqede L.: Association

between complementary and alternative medicine use, preventive care practice, and use of conventional medical services among adults with diabetes. Diabetes Care., 29(1), 15-9 (2006)

7) Bradley R., and Oberg E.: Naturopathic medicine and type 2 diabetes: A retrospec- tive analysis from an academic clinic.

Altern Med Rev., 11(1), 30-9 (2006)

8) Bradley R., Kozura E., Buckle H., Kaltunas J., Tais S., and Standish L.: Description of clinical risk factor changes during naturo- pathic care for type 2 diabetes. J Altern Complement Med., 15(6), 633-8 (2009) 9) Qicheng F.: Some current study and

research approaches relating to the use of plants in the traditional Chinese medicine.

J Ethnopharmacol., 2(1), 57-63 (1980) 10) Yan B., Wang D., Xing D., Ding Y., Wang

R., Lei F., and Du L.: The antidepressant effect of ethanol extract of radix puerariae in mice exposed to cerebral ischaemia reperfusion. Pharmacol Biochem Behav., 78(2), 319-25 (2004)

11) Hsu F., Liu I., Kuo D., Chen W., Su H., and Cheng JT : Anti hyperglycemic effect of puerarin in streptozotocin-induced dia- betic rats. J of Nat Prod., 66(6), 788-92 (2003)

12) Xu M., Xiao S., Sun Y., Zheng X., Ou- Yang Y, and Guan C : The study of anti- metabolic syndrome effect of puerarin in vitro. Life Sci., 77(25), 3183-96 (2005) 13) Cheng J., Liu I., Kuo D., and Lin M.:

Stimulatory effect of phenylephrine on secretion of beta-endorphin from rat

adrenal medulla in vitro. Auton Neurosci., 93(1-2), 31-5 (2001)

14) Chiarelli F., and Marzio D.: Peroxisome proliferator-activated receptor-gamma agonists and diabetes: current evidence and future perspectives. Vasc Health Risk Manag., 4(2), 297-304 (2008)

15) Sheepers A., Joost H., and Shurmann A.:

The glucose transporter families SGLT and GLUT: molecular basis of normal and aberrant function. J Parenter Enteral Nutr., 28(5), 364-71 (2004)

16) Zheng P., Ji G., Ma Z., Liu T., Xin L., Wu H., Liang X., and Liu J.: Therapeutic effect of puerarin on non-alcoholic rat fatty liver by improving leptin signal transduction through JAK2/STAT3 path- ways. Am J Chin Med., 37(1), 69-83 (2009) 17) Sivaprasad S., Gupta B., Crosby-Nwaobi

R., and Evans J.: Prevalence of diabetic retinopathy in various ethnic groups: a worldwide perspective. SurvOphthalmol., 57, 347-370 (2012)

18) Lee J.: Donguisusebowon [Longevity and Life Preservation in Oriental Medicine]

Seoul (1894)

19) Chen W., Hayakawa S., Yamamoto T., Su H., Liu I., and Cheng J.: Mediation of beta-endorphin by isoflavone puerarin to lower plasma glucose in streptozotocin- induced diabetic rats. Planta Med., 70(2), 113-6 (2004)

20) Benichou C.: Criteria of drug-induced liver disorders-report of an international consensus meeting. J Hepatol., 11(2), 272- 6 (1990)

21) Peng N., Prasain J., Dai Y., Moore R.,

Arabshahi A., Barnes S., Carlson S., and

Wyss J.: Chronic dietary kudzu isoflavones

improve components of metabolic syn-

drome in stroke-prone spontaneously hypertensive rats. J Agric Food Chem., 57(16), 7268-73 (2009)

22) Song C., and Bi H.: Effects of puerarin on plasma membrane GLUT4 content in skeletal muscle from insulin-resistant Sptague-Dawley rats under insulin stim- ulation. China J Chinese MateriaMedica., 29(2), 172-5 (2004)

23) Meier Y., Cavallaro M., Roos M., Pauli- Magnus C., Folkers G., Meier P., and Fattinger K.: Incidence of drug-induced liver injury in medical inpatients. Eur J ClinPharmacol., 61(2), 135-43 (2005) 24) Kim N., Jung H., Cho S., Park S., Park J.,

and Ko C.: Liver enzyme abnormalities during concurrent use of herbal and con- ventional medicines in Korea: a retro- spective study. Phytomedicine, 18(14), 1208-13 (2011)

25) Yi S., Cho J., Lim K., Kim K., Kim J., Kim B., Hong J., Jang I., Shin S., and Yu K.:

Effects of Angelicaetenuissima radix, Angelicaedahuricae radix and Scutellariae radix extracts on cytochrome P450 activi- ties in healthy volunteers. Basic Clin Pharmacol Toxicol., 105(4), 249-56 (2009) 26) Hu Z., Yang X., Ho P., Chan S., Heng P.,

Chan E., Duan W., Koh H., and Zhou S.:

Herb-drug interactions: a literature review. Drugs, 65(9), 1239-82 (2005) 27) Zheng J., Chen B., Jiang B., Zeng L., Tang

Z., Fan L., and Zhou H.: The effects of puerarin on CYP2D6 and CYP1A2 activi- ties in vivo. Arch Pharm Res., 33(2), 243- 6 (2010)

28) Guerra M., Speroni E., Broccoli M., Cangini M., Pasini P., Minghett A., Crespi-Perellino N., Mirasoli M., Cantelli- Forti G., and Paolini M.: Comparison

between chinese medical herb Puerarialo-

bata crude extract and its main isoflavone

puerarin antioxidant properties and

effects on rat liver CYP-catalysed drug

metabolism. Life Sci., 67(24), 2997-3006

(2000)