Вы находитесь на странице: 1из 6

Complementary Therapies in Medicine (2013) 21, 447452

Available online at www.sciencedirect.com

journal homepage: www.elsevierhealth.com/journals/ctim

Capparis spinosa L. (Caper) fruit extract in


treatment of type 2 diabetic patients: A
randomized double-blind
placebo-controlled clinical trial
Hassan Fallah Huseini a, Shirin Hasani-Rnjbar b,c,,
Neda Nayebi c, Ramin Heshmat c, Farahnaz Khaliqi Sigaroodi d,
Maryam Ahvazi d, Behroz Abbasi Alaei e, Saeed Kianbakht a
a

Pharmacology and Applied Medicine Department of Medicinal Plants research Center, Institute of
Medicinal Plants, ACECR, Karaj, Iran
b
Obesity and Eating Habit Research Center, Endocrinology and Metabolism Molecular - Cellular Sciences
Institute, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran,
Iran
c
Endocrinology and Metabolism Research center, Endocrinology & Metabolism research institute, Tehran
University of Medical Sciences, Tehran, Iran
d
Department of Pharmacognosy, Research Institute of Medicinal Plants, ACECR, Karaj, Iran
e
Diabetic Patient Association, Karaj, Iran
Available online 7 August 2013

KEYWORDS
Capparis spinosa;
Diabetes;
Medicinal plants;
Clinical trial

Summary
Objectives: Capparis spinosa L. (Caper) fruit is traditionally used as an anti-hyperglycemic food
by Iranian diabetic patients. But yet, no controlled human study has determined its efcacy in
treatment of hyperglycemia in type 2 diabetic patients.
Design: The present study was undertaken to explore the possible anti-hyperglycemic effects
of the caper fruit extract in type 2 diabetic patients. A randomized clinical trial was conducted
in 54 type 2 diabetic patients. Two groups 28 and 26 patients on standard anti-diabetic therapy,
received 400 mg caper fruit extract and placebo capsules three times a day respectively for two
months.
Main outcome measures: The patients fasting blood glucose, glycosylated hemoglobin, lipids
levels, liver and renal function tests were determined at baseline and endpoint.
Results: Results showed signicant decrease in fasting blood glucose levels (p = 0.037) and glycosylated hemoglobin (p = 0.043) in caper treated patients compared to control group at the
end of the study. Triglyceride level also decreased signicantly (p = 0.29) in caper treated group
at the end of the study compared to baseline. No liver, kidney and other side effects were
observed in these two groups.

Corresponding author at: Endocrinology and Metabolism Research Center, 5th oor, Shariati Hospital, North Kargar Avenue,
Tehran 14114, Iran. Tel.: +98 21 88220037; fax: +98 21 88220053.
E-mail address: shirinhasanir@yahoo.com (S. Hasani-Rnjbar).

0965-2299/$ see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ctim.2013.07.003

448

H. Fallah Huseini et al.


Conclusions: Caper fruit extract may be a safe anti-hyperglycemic and anti-hypertriglyceridemic
agent for type 2 diabetic patients.
2013 Elsevier Ltd. All rights reserved.

Introduction
Diabetes mellitus type 2 is one of the most prevalent and
fastest growing diseases in most of the countries.1 Apart
from conventional anti diabetic therapy, several studies
have shown that diet, medicinal plants, complementary and
alternative medicine therapies have benecial effects and
improve glucose homeostasis in diabetic patients.2,3 Capparis spinosa L. (caper) belongs to family Capparidaceae and
probably originated from dry regions in west or central Asia.4
The caper fruits and ower buds pickles are used as a food
by diabetic patients due to the belief that they have hypoglycemic and hypolipidemic actions.57 The pickled fruits of
caper are eaten at the dose of 28 g daily as a remedy by
diabetic patients in Iran. Despite a few ethno-botanical surveys indicating use of caper in anti-diabetic formulations in
folk medicine.57 and few experimental studies conrmed
the blood glucose lowering and hypolipidemic properties
of caper,8,9 to our knowledge no clinical studies have been
conducted to determine the caper anti-hyperglycemic efcacy and safety in diabetic patients so far. This randomized,
double-blind, placebo controlled study, was designed to
investigate the anti-hyperglycemic effects of 1200 mg caper
fruit extract daily (5 g caper fruit average daily doses used
by diabetic patients) in type 2 diabetic patients.

0.3 ml of 5% (w/v) sodium nitrite was added to the ask.


After 5 min, 0.3 ml of 10% (w/v) AlCl3 was added and, then
after 6 min, 2 ml of 1 M NaOH was also added to the mixture, followed by the addition of 3.4 ml distilled water. The
absorbance of the pink color mixture was read at 510 nm
against prepared water blank and avonoids content was
expressed as milligram rutin equivalent per gram of extract.
Sample was analyzed in triplicate.
The concentration of total phenols in caper fruit extract
was measured by the method described by Kim et al. with
some modication.11 Briey, an aliquot (1 ml) of the appropriately diluted extract or standard solutions of Gallic acid
in water (50, 100, 150, 200 and 250 g/ml) was added to
a 25 ml volumetric ask containing 9 ml of distilled water.
A reagent blank using distilled water was prepared. One
milliliter of Folin & Ciocalteus phenol reagent was added
to the mixture and shaken. After 5 min, 10 ml of 7% Na2 CO3
solution was added by shaking. The solution was then immediately diluted to volume (25 ml) with distilled water and
mixed thoroughly. After incubation for 90 min at 23 C, the
absorbance versus prepared blank was read at 750 nm. Total
phenols contents of the extract were expressed as milligram
Gallic acid equivalent per gram extract. Sample was analyzed in 3 replications.

Materials and methods

Preparation of caper and placebo capsules

Plant extract

The caper and placebo capsules with identical appearance


were prepared in the Research Institute of Medicinal Plants
(Tehran, Iran). The caper capsules contained 400 mg of the
caper fruit extract powder. Toast powder was chosen as the
placebo and as the excipient in preparation of the caper
extract powder. The selected 1200 mg (6.6 mg/kg for average of 60 kg body weight/day) hydro-alcoholic caper fruit
extract, was equal to 5 g dry caper fruit, the average doses
of caper prescribed by 8 herbalists in Tehran city in the range
of 28 g dry fruit daily. Totally 90 capsules of placebo or
caper were packed in boxes marked as A or B.

Caper fruits were collected from the lands in the Alamoot


region of the Qazvein province of Iran at the end of May
and identied by a botanist (M. Ahvazi). A voucher specimen
of the plant (number 1482) has been deposited in the Central Herbarium of the Research Institute of Medicinal Plants
afliated with the ACECR (Iranian Academic Center for Education, Culture and Research). The fruits were washed and
dried in shade at room temperature.
Total 5585 g of dried caper fruits powder were extracted
with 32 l of 70% aqueous ethanol using percolation method
at room temperature. The extracts were ltered through
Whatman no. 1 lter paper and evaporated to dryness under
reduced pressure at a maximum of 40 C using a rotary evaporator instrument.

Standardization of the plant extract


The extract was standardized through determining the total
avonoids and phenolics content.
The avonoids content in caper fruit extract was measured using a colorimetric assay developed previously.10 One
milliliter of the aliquot of the appropriately diluted caper
fruit extract or standard solutions of rutin in methanol (50,
100, 150, 200 and 250 g/ml) were added to a 10 ml volumetric ask containing 4 ml of distilled water. At rst,

Patients
Sixty Iranian male and female type 2 diabetic patients (aged
4065 years) registered at the
Diabetic Clinic registry of Shariati Hospital Tehran Iran,
who was eligible according to the inclusion and exclusion criteria, participated in this study. The patients were
visited by investigators and informed about the rationale
and main aims of the study. Written informed consent was
obtained from the patients. The medical ethics committee of the Tehran University of Medical Sciences approved
the protocol. All the patients who participated had conrmed diabetes type 2 according to ADA criteria12 and were
on treatment for at least two months with diabetic food
regimen and had not taken any herbal medicine and did

Caper in treatment of type 2 diabetic patients


not change anti-diabetic drugs dosage during the last two
months.
The inclusion criteria were type 2 diabetes with fasting
blood glucose (FBG) below 250 and above 150 mg/dl and glycosylated hemoglobin (HbA1c) 79% with disease duration
of 28 years, normal blood pressure and blood lipid levels, taking no more than two 5 mg glibenclamide and two
500 mg metformine tablets per day. The exclusion criteria
were insulin therapy, liver, kidney and cardiovascular disease, infectious lung diseases, eye proliferative retinopathy,
any known drug allergy, tendency to change the exercise
or food regimen, active neoplasm, depressed or myocardial
infarction patients, alcohol consumption, cigarette smoking, pregnant and breastfeeding patients.

Design, main outcome parameters and statistics


All sixty patients were randomly assigned in two groups
of 30 patients. The study was double-blind and Block randomization was used for treatment allocation. Twenty-six
participants in each group was the sample size calculated
to estimate 26 mg/dl difference of FBG between the groups,
considering type 1 error = 0.05 and 80% power.
The patients and the investigators who carried out clinical and para clinical assessments were unaware of treatment
groups and type of medication.
The rst group of patients took 400 mg caper capsules and
second group took 400 mg placebo capsules three times a
day before meals. The conventional oral anti-hyperglycemic
agent treatments were continued in two groups.
The FBG, HbA1c, cholesterol, low-density lipoprotein
(LDL), high-density lipoprotein (HDL), triglyceride, serum
glutamic oxaloacetic transaminase (SGOT), serum glutamic
pyruvic transaminase (SGPT), alkaline phosphatase (ALP),
blood urea nitrogen (BUN) and creatinine levels were determined at the baseline and after 2 months of the study in
both groups.
Blood samples were drawn after an overnight (12 h) fasting. FBG levels were determined by the glucose-oxidase
method using a Beckman Glucose-2 Analyzer immediately
after blood sampling at the Endocrine Research Center Laboratory. HbA1c levels were determined by D-10 Hemoglobin
testing system (Bio-Rad Laboratories, Inc., Germany). All
other blood sample parameters were measured by auto analyzer Hitachi 902 using commercially available kits (Pars
Azmon).
Patients were given diaries to note incidence and severity
of symptoms and were in contact with the department for
any adverse effects. They underwent clinical examination
such as creatinine, liver enzymes and fasting blood glucose
levels after two months for assessment of herbal drug efcacy or any side effects due to treatment.
The statistical analysis of the recorded data at the baseline and after 2 months was performed using t-test. A value
of p < 0.05 was considered as statistically signicant.

Results
Caper fruits yielded 24% dried extract. The fruit extract
possessed total avonoids expressed as rutin equivalent

449
Table 1
group.

The demographic data of the patients in each


Groups

Age (year)
Duration of
Disease (year)
Weight (kg)
BMI

Caper (N = 28)

Placebo (N = 26)

53.3 5.6
6.4 2.34

54.5 5.4
7.3 3.2

73.1 11.9
26.3 2.1

70.8 10.8
25.7 2.3

Results are given as the mean values standard deviation.

33.33 mg/g as well as total phenol content expressed as


Gallic acid equivalent 32.60 mg/g of the dried extract.
The demographic and preclinical data of the patients are
summarized in Table 1.
Sixty patients were randomized to two groups of 30 each,
but 28 in caper group and 26 in placebo group completed the
study. The CONSORT owchart describing the progress of the
patients through the trial is shown in Fig. 1.
The results of patients blood parameters in two groups
at the baseline and after 2 months of the study are given
in Table 2. FBG level and HbA1c in caper group was signicantly decreased (p = 0.037 and p = 0.043, respectively)
compared with control group at the end of the study.
In caper group serum triglyceride level also decreased
signicantly (p = 0.29) at the end of the study compared with baseline. Laboratory evaluations revealed no
signicant difference in serum cholesterol, LDL, HDL,
SGOT, SGPT, ALP, BUN and creatinine levels in caper
group compared with control group upon completion of
study (Table 2).
No hepatic, renal or other adverse effects were observed
in the caper and control groups after two months.

Discussion
The results suggest that caper fruit safely improves
hyperglycemia and hypertriglyceridemia in type 2
diabetic patients. The ndings of the present study
agree with the traditional use of caper for treatment
of diabetes,7,56 and previous animal studies demonstrating its anti-hyperglycemic and hypolipidemic
effect.8,9
The exact mechanisms of caper blood glucose-lowering
and hypolipidemic effects are unknown. In a study it
was reported that caper had hypoglycemic activity without effect on insulin secretion in diabetic rats.7 In other
studies hypoglycemic and lipid lowering effect of caper
have been reported but their mechanisms have not been
determined.8,13
In diabetic patients elevation of glucose and free
fatty acid levels leads to generation of reactive oxygen
species and oxidative stress.14 These metabolic abnormalities not only induce late diabetic complications but
also lead to insulin resistance, cell dysfunction and
impaired insulin secretion.1517 The favorable effects of substances with antioxidant properties on diabetic prole have

450

Table 2

The fasting blood parameters at baseline and after 2 months (endpoint) of the study in caper (1) and placebo (2) groups.
Baseline mean (SD)

p-Value
compared to
placebo

Endpoint mean
(SD)

p-Value
compared to
placebo

Percent change
endpoint compared
to baseline

p-Value endpoint
compared to
baseline

0.037

1
2

11.19
4.17

0.005
0.351

0.043

1
2

4.81
2.04

0.313
0.367

1
2

6.16
1.73

0.105
0.282

0.240

1
2

23.99
16.12

0.029
0.129

1
2

HbA1c (%)

1
2

Cholesterol (mg/dl)

1
2

196.4 (40)
201.8 (37)

Triglyceride (mg/dl)

1
2

250.5 (110)
221.2 (130)

HDL (mg/dl)

1
2

42.4 (11.2)
45.8 (10.9)

0.371

1
2

41.9 (10.1)
43.9 (12.1)

0.540

1
2

1.17
2.35

0.675
0.165

LDL (mg/dl)

1
2

108.7 (24.4)
112.4 (21.3)

0.482

1
2

100.8 (27.7)
107.6 (20.6)

0.360

1
2

7.26
4.27

0.084
0.209

BUN (mg/dl)

1
2

13.7 (1.6)
13.7 (2.9)

0.982

1
2

14.2 (3.8)
16.6 (2.5)

0.381

1
2

3.64
4.30

0.525
0.318

Creatinine (mg/dl)

1
2

0.423

1
2

0.531

1
2

3.26
1.09

0.401
0.815

SGOT (U/L)

1
2

22.8 (9.8)
19.9 (5.4)

0.193

1
2

21.4 (3.7)
18.6 (4.6)

0.384

1
2

4.14
4.02

0.368
0.240

SGPT (U/L)

1
2

19.8 (3.6)
15.3 (7.0)

0.062

1
2

17.1 (7.5)
14.5 (7.1)

0.851

1
2

3.63
2.31

0.402
0.301

ALP (IU/L)

1
2

184.3 (65.3)
186.5 (47.4)

0.643

1
2

185.2 (54.0)
179.8 (45.5)

0.715

1
2

0.488
3.59

0.893
0.168

180.5 (31)
179.8 (37)
8.3 (2.1)
8.3 (1.2)

0.92 (0.21)
0.89 (0.15)

0.913

1
2

0.921

1
2

0.770

1
2

184.3 (41)
198.3 (38)

1
2

190.4 (126)
184.4 (101)

0.612

160.3 (36)
187.3 (50)
7.9 (1.9)
8.5 (1.3)

0.89 (0.20)
0.90 (0.17)

p < 0.05 was considered as statistically signicant. SD, standard deviation; decreased; increased.

0.320

H. Fallah Huseini et al.

FBG (mg/dl)

Caper in treatment of type 2 diabetic patients

451

Figure 1

CONSORT ow diagram of study patients.

been reported in other studies.1820 However, the antioxidant properties of caper fruits due to the presence of
appreciable levels of phenolic compounds, tocopherols,
carotenoids and vitamin C may explain caper effects on
diabetic patients.2124 Caper fruits also contains compound
such as rutin and lectin,25,26 with favorable effects on
glucose and insulin metabolism.27,28 Furthermore many
bioactive compounds such as saccharides, glycosides, alkaloids, terpenoids, volatile oils, fatty acids, steroids and
several minerals present in caper may directly or indirectly
inuence glucose or insulin metabolism.2931
Considering the present study and previous data, caper
can be used as an adjuvant agent for treatment of diabetic
patients but this requires more additional validation studies. However it should be also noted that small sample size
and lack of identication of the active constituent(s)
responsible for the effects of caper fruit extract
are limitations of the present study. In conclusion,
more clinical trials are recommended to evaluate
the long-term efcacy and safety of caper in diabetic
patients.

Conict of interest statement


No conict to disclose.

Acknowledgement
We are grateful to the Endocrinology and Metabolism
Research Center, Tehran University of Medical Sciences, and
Research Institute of Medicinal Plants for nancial and other
supports in conduction of the present study.

References
1. Gerstein HC, Miller ME, Byington RP, Goff DC, Bigger JT, Buse JB,
et al. Effects of intensive glucose lowering in type 2 diabetes.
New England Journal of Medicine 2008;358(24):254559.
2. Hasani-Ranjbar S, Larijani B, Abdollahi M. A systematic review
of Iranian medicinal plants useful in diabetes mellitus. Archives
of Medical Science 2008;4(3):28592.

452
3. Nahas R, Moher M. Complementary and alternative medicine for
the treatment of type 2 diabetes. Canadian Family Physician
2009;55(6):5916.
4. Inocencio CF, Alcaraz F, Caldern C, Obn D, Rivera R. The use
of oral characters in Capparis sect. Capparis to determine
the botanical and geographical origin of capers. European Food
Research and Technology 2002;214(4):3359.
5. Yaniv ZA, Dafni J, Friedman D, Palevitch B. Plants used for the
treatment of diabetes in Israel. Journal of Ethnopharmacology
1987;2:14551.
6. Bnouham M, Mekh H, Abdelkhaleq LA, Ziyyat A. Ethnopharmacology forum. Medicinal plants used in the treatment of
diabetes in Morocco. International Journal of Diabetes and
Metabolism 2002;10:3350.
7. A-Yazar FU, Kasabri V, Abu-Dahab R. Medicinal plants from
Jordan in the treatment of diabetes: traditional uses vs.
in vitro and in vivo evaluations part 2. Planta Medica
2011;77(11):121020.
8. Eddouks M, Lemhadri A, Michel JB. Caraway and caper: potential anti-hyperglycaemic plants in diabetic rats. Journal of
Ethnopharmacology 2004;94(1):1438.
9. Eddouks M, Lemhadri A, Michel JB. Hypolipidemic activity of
aqueous extract of Capparis spinosa L. in normal and diabetic
rats. Journal of Ethnopharmacology 2005;98(3):34550.
10. Yoo KM, Lee CH, Lee H, Moon B, Lee CY. Relative antioxidant
and cytoprotective activities of common herbs. Food Chemistry
2008;106:92936.
11. Kim DO, Jeong SW, Lee CY. Antioxidant capacity of phenolic
phytochemicals from various cultivars of plums. Food Chemistry
2003;81:3216.
12. American Diabetes Association. Screening for type 2 diabetes.
Diabetes Care 2003;26(S1):214.
13. Lemhadri A, Eddouks M, Sulpice T, Burcelin R. Antihyperglycaemic and antiobesity effects of Capparis spinosa
and Chamaemelum nobile aqueous extracts in HFD mice.
American Journal of Pharmacology and Toxicology 2007;2(3):
10610.
14. McGarry JD. Banting lecture 2001: dysregulation of fatty acid
metabolism in the etiology of type 2 diabetes. Diabetes
2002;51:718.
15. Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997;46:310.
16. Rosen P, Nawroth PP, King G, Moller W, Tritschler HJ, Packer
L. The role of oxidative stress in the onset and progression of
diabetes and its complications: a summary of a congress series
sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes/Metabolism
Research and Reviews 2001;17:189212.
17. Paolisso G, Giugliano D. Oxidative stress and insulin
action, is there a relationship? Diabetologia 1996;39:
35763.

H. Fallah Huseini et al.


18. Montonen J, Knekt P, Jrvinen R, Reunanen A. Dietary antioxidant intake and risk of type 2 diabetes. Diabetes Care
2004;27(2):3626.
19. Fallah Huseini H, Larijani B, Fakhrzadeh H, Radjabipour B, Toliat
T, Reza M. The efcacy of Silybum marianum (L.) Gaertn, (silymarin) in the treatment of type 2 diabetes: a randomized,
double-blind, placebo-controlled clinical trial. Phytotherapy
Research 2006;20(12):10369.
20. Ruhe RC, McDonald BR. Use of antioxidant nutrients in the
prevention and treatment of type 2 diabetes. Journal of the
American College of Nutrition 2001;20(5):3639.
21. Yang YU, Gao H, Tang Z, Song X, Lijun WU. Several phenolic acids
from the fruit of Capparis spinosa. Asian Journal of Traditional
Medicines 2006;1:34.
22. Yang T, Liu YQ, Wang CH, Wang ZT. Advances on investigation of
chemical constituents, pharmacological activities and clinical
applications of Capparis spinosa. Zhongguo Zhong Yao Za Zhi
2008;33(21):24538.
23. Yang T, Liu YQ, Chou CHG, Cheng X, Wang ZA. New antioxidant compound from Capparis spinosa. Pharmaceutical Biology
2010;48(5):58994.
24. Tlili N, Khaldi A, Triki S, Munn-Bosch S. Phenolic compounds
and vitamin antioxidants of caper (Capparis spinosa). Plant
Foods for Human Nutrition 2010;65(3):2605.
25. Ramezani Z, Aghel N, Keyghobadi H. Rutin from different parts
of Capparis spinosa growing wild in Khuzestan/Iran. Pakistan
Journal of Biological Sciences 2008;11(5):76872.
26. Lam SK, Han QF. Isolation and characterization of a lectin with
potentially exploitable activities from caper (Capparis spinosa)
seeds. Bioscience Reports 2009;29(5):2939.
27. Stanley MPP, Kamalakkannan N. Rutin improves glucose homeostasis in streptozotocin diabetic tissues by altering glycolytic
and gluconeogenic enzymes. Journal of Biochemical and Molecular Toxicology 2006;20(2):96102.
28. Kolb H, Oschilewski M, Schwab E, Greulich B, Roos P,
Kiesel U. Suppression of low-dose streptozotocin-induced
diabetes by immunomodulatory lectins. Diabetes Research
1986;3(4):1836.
29. Rajesh PP, Selvamani S, Latha A, Saraswathy V, Kannan
R. A review on chemical and medicobiological applications
of Capparidaceae family. Pharmacognosy Reviews 2009;3:
37887.
30. Ozcan MM. Investigation on the mineral contents of capers
(Capparis spinosa) seed oils growing wild in Turkey. Journal of
Medicinal Food 2008;11(3):5969.
31. Triggiani V, Resta F, Guastamacchia E, Sabb C, Licchelli B,
Ghiyasaldin S, et al. Role of antioxidants, essential fatty acids,
carnitine, vitamins, phytochemicals and trace elements in the
treatment of diabetes mellitus and its chronic complications.
Endocrine, Metabolic & Immune Disorders Drug Targets
2006;6(1):7793.