The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial.

Abstract

Oxidative stresses are increasingly implicated in the pathogenesis of diabetic complications which may either cause direct pancreatic beta-cell damage or lead to metabolic abnormalities that can induce or aggravate diabetes. The valuable effect of antioxidant nutrients on the glycemic control of diabetic patients has been reported in experimental and clinical studies. The present study was designed to investigate the effects of the herbal medicine, Silybum marianum seed extract (silymarin), which is known to have antioxidant properties on the glycemic profile in diabetic patients. A 4-month randomized double-blind clinical trial was conducted in 51 type II diabetic patients in two well-matched groups. The first group (n = 25) received a silymarin (200 mg) tablet 3 times a day plus conventional therapy. The second group (n = 26) received the same therapy but a placebo tablet instead of silymarin. The patients were visited monthly and glycosylated hemoglobin (HbA(1)c), fasting blood glucose (FBS), insulin, total cholesterol, LDL and HDL, triglyceride, SGOT and SGPT levels were determined at the beginning and the end of the study. The results showed a significant decrease in HbA(1)c, FBS, total cholesterol, LDL, triglyceride SGOT and SGPT levels in silymarin treated patients compared with placebo as well as with values at the beginning of the study in each group. In conclusion, silymarin treatment in type II diabetic patients for 4 months has a beneficial effect on improving the glycemic profile.

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SILYBUM MARIANUM FOR DIABETES
1
Copyright © 2006 John Wiley & Sons, Ltd.Phytother. Res. (in press)
DOI: 10.1002/ptr
Copyright © 2006 John Wiley & Sons, Ltd.
PHYTOTHERAPY RESEARCH
(www.interscience.wiley.com) DOI: 10.1002/ptr.1988
Diabetes: A Randomized, Double-blind,
Phytother. Res. (in press)
(Silymarin) in the Treatment of Type II
Published online in Wiley InterScience
The Efficacy of Silybum marianum (L.) Gaertn.
Placebo-controlled, Clinical Trial
H. Fallah Huseini1*, B. Larijani2, R. Heshmat2, H. Fakhrzadeh2, B. Radjabipour2, T. Toliat3
2Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Tehran, Iran
and Mohsin Raza4
3School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
1Department of Pharmacology, Institute of Medicinal Plants, ACECR Tehran, Iran
4Department of Physiology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran
Oxidative stresses are increasingly implicated in the pathogenesis of diabetic complications which may either
in experimental and clinical studies. The present study was designed to investigate the effects of the herbal
type II diabetic patients in two well-matched groups. The first group (n = = = = = 25) received a silymarin (200 mg)
fasting blood glucose (FBS), insulin, total cholesterol, LDL and HDL, triglyceride, SGOT and SGPT levels
pared with placebo as well as with values at the beginning of the study in each group. In conclusion, silymarin
cause direct pancreatic β β β β β-cell damage or lead to metabolic abnormalities that can induce or aggravate diabe-
medicine, Silybum marianum seed extract (silymarin), which is known to have antioxidant properties on the
tablet 3 times a day plus conventional therapy. The second group (n = = = = = 26) received the same therapy but a
were determined at the beginning and the end of the study. The results showed a significant decrease in
treatment in type II diabetic patients for 4 months has a beneficial effect on improving the glycemic profile.
Keywords: silymarin; herbal medicine; antioxidant; diabetes.
tes. The valuable effect of antioxidant nutrients on the glycemic control of diabetic patients has been reported
glycemic profile in diabetic patients. A 4-month randomized double-blind clinical trial was conducted in 51
placebo tablet instead of silymarin. The patients were visited monthly and glycosylated hemoglobin (HbA1c),
HbA1c, FBS, total cholesterol, LDL, triglyceride SGOT and SGPT levels in silymarin treated patients com-
Copyright © 2006 John Wiley & Sons, Ltd.
Received 11 October 2005
Revised 22 May 2006
Accepted 29 June 2006
* Correspondence to: H. Fallah Huseini, Institute of Medicinal Plants,
Contract/grant sponsor: Endocrinology and Metabolism Research Center,
ACECR, No. 97, Bozorgmehr St. Ghods St. Enghelab Ave, Tehran, Iran.
Tehran University of Medical Sciences Tehran Iran; contract/grant number:
E-mail: huseini_fallah@yahoo.com
R507/2003.
INTRODUCTION
Asteraceae family and its seed extract contains large
1999). Silymarin has powerful antioxidant properties
viral hepatitis and mushroom poisoning (Sonnenbichler
problem, which causes substantial morbidity, mortal-
The favorable effect of antioxidants in the treatment
Silybum marianum (L.) Gaertn. is a member of the
flavonolignans collectively known as silymarin (Pepping,
including hepatotoxicity secondary to acute and chronic
Diabetes mellitus is a continuously growing health
countries.
reported in several experimental studies (Rudich et al.,
numbers of chemical constituents including several
and has a beneficial effect on various hepatic disorders,
et al., 1986; Flora et al., 1998; Parish and Doering, 1986).
ity and long-term complications even in developed
of oxidative metabolic derangement in diabetes has been
1999; Packer et al., 2000; Maddux et al., 2001). In addi-
vitamin E, vitamin C, or glutathione improves insulin
Goldfine, 2000). Two placebo-controlled clinical trials
insulin resistance and the need for exogenous adminis-
the effects of 4 months silymarin administration on the
tion, several clinical trials, albeit of short duration, have
sensitivity in insulin-resistant individuals and/or patients
have also reported that Silybum marianum seed extract
tration of insulin (Velussi et al., 1993; Velussi et al.,
glycemic state in type II diabetes patients.
METHODOLOGY
diabetes from the Diabetes Clinic of Shariati Hospital
and Metabolism Research Center of Shariati Hospital
demonstrated that treatment with antioxidants such as
with type II diabetes (Jacob et al., 2000; Evans and
administration to diabetic cirrhotic patients reduces
1997). The present study was undertaken to evaluate
A total of 51 patients (19 male, 32 female) with type II
approved by the Ethics Committee of the Endocrinology
patient prior to study.
were enrolled in this study. The research protocol was
and written informed consent was obtained from each

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Copyright © 2006 John Wiley & Sons, Ltd.Phytother. Res. (in press)
DOI: 10.1002/ptr
2
H. FALLAH HUSEINI ET AL.
Statistical analysis. The statistical analysis of the
t-test employing SPSS statistical software for quantita-
recorded data at the beginning and after 4 months was
tive variables. A value of p < 0.05 was considered as
RESULTS
dropouts. The patients’ demographic characteristics are
(silymarin and placebo) were compared with each other
except for the triglyceride levels that were higher in the
Glucose
group at the beginning of the study was 156 ± 46 mg/
at the beginning of the study was 167 ± 47 mg/dL, which
HbA1c
beginning of the study was 7.82 ± 2.01%, which de-
performed using independent and paired Student’s
statistically significant.
All 51 patients completed the study and there were no
The baseline findings of patients in the two groups
enzymes. The two groups were completely comparable,
summarized in Table 1.
regarding FBS, HbA1c, lipid profile, insulin and liver
silymarin group (Table 2).
The average fasting blood glucose level in the silymarin
39 mg/dL after 4 months of silymarin treatment. The
increased significantly (p < 0.0001) to 188 ± 48 mg/dL
dL, which decreased significantly (p < 0.001) to 133 ±
after 4 months of placebo treatment.
average fasting blood glucose level in the placebo group
The average HbA1c level in the silymarin group at the
months silymarin treatment. The average HbA1c level
creased significantly (p < 0.001) to 6.78 ± 1.05% after 4
All the patients who participated were aged between
tes Association, 2003). The patients had a fasting blood
controlled exclusively by diet. The exclusion criteria
were then randomly allocated to two groups using a
clinical and paraclinical assessments were unaware of
and kindly provided by the Institute of Medicinal Plants
tinued in the two groups. The compliance was assessed
silymarin tablet three times a day before meals. The
The blood levels of HbA1c and fasting blood glucose,
and after 4 months of the study in both groups.
the glucose-oxidase method using a Beckman Glucose2
hemoglobin levels were determined by a D-10 Hemo-
an auto analyzer Hitachi 902 using commercial kits.
of the fasting blood glucose level.
Table 2. Paraclinical characteristics of the two groups at the beginning of study
40 and 65 years, and had a confirmed diabetes type II
glucose level less than 250 mg/dL, the duration of dia-
were insulin therapy, cardiovascular disease, infectious
balanced randomization method.
the treatment groups and type of medication. Silymarin
(Tehran, Iran). The conventional oral hypoglycemic
indirectly using a pill count method.
control group (26 patients) received a placebo tablet
insulin, total cholesterol, LDL and HDL, triglyceride,
Blood samples were drawn after an overnight fast-
Analyzer immediately after blood sampling at the
globin testing system (Bio-Rad Laboratories, Inc.). All
Patients were visited and examined every month and
diagnosis according to ADA criteria (American Diabe-
betes was more than 2 years, and their diabetes was not
diseases, pregnancy and breast-feeding. The patients
The patients and the investigators who carried out
(200 mg) and placebo tablets were of the same shape
agent (metformin and glibenclamide) treatment con-
The first group (25 patients) received a 200 mg
three times a day before meals.
SGOT and SGPT were determined at the beginning
ing (12 h). Fasting glucose levels were determined by
Endocrine Research Center laboratory. Glycosylated
the other blood sample parameters were measured by
the efficacy of treatment was checked by determination
Group
Silymarin
(mean ± SD)
Placebo
(mean ± SD)p value
FBS (mg/dL)
HbA1c (%)
Insulin (ng/mL)
Cholesterol (mg/dL)
HDL (mg/dL)
LDL (mg/dL)
Triglyceride (mg/dL)
SGOT (U/L)
SGPT (U/L)
156 ± 46
7.8 ± 2.0
0.4 ± 0.3
225 ± 64
140 ± 47
70 ± 33
284 ± 206
22 ± 5
19 ± 9
167 ± 47
8.3 ± 1.9
0.3 ± 0.2
211 ± 46
130 ± 47
94 ± 60
185 ± 78
22 ± 5
17 ± 9
0.39
0.39
0.43
0.38
0.08
0.44
0.02
0.396
0.041
Table 1. The demographic characteristics of patients in placebo and silymarin treated groups
GroupSilymarin (n = 25)Placebo (n = 26)Total
Age (year) (mean ± SD)
Sex (male/female)
Duration of disease (year) (mean ± SD)
Weight (kg) (mean ± SD)
53.0 ± 6.6
14M/11F
7.6 ± 4.9
77.2 ± 14.8
54.1 ± 6.0
5M/21F
11.7 ± 6.1
69.9 ± 10.9
53.5 ± 6.3
19M/32F
9.6 ± 5.9
73.4 ± 13.1

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SILYBUM MARIANUM FOR DIABETES
3
Copyright © 2006 John Wiley & Sons, Ltd. Phytother. Res. (in press)
DOI: 10.1002/ptr
of hyperglycemia (Rudich et al., 1999; Jacob et al., 2000;
cal quenching enzymes such as superoxide dismutase,
potent inhibitory effects on enhanced lipid peroxida-
silymarin reduces insulin resistance and the need for
levels increase. Silymarin, as an inhibitor of this
reported that silymarin inhibits insulin secretion in
insulin resistance.
et al., 2004). Silymarin is a powerful inhibitor of lipo-
et al., 1999).
(Soto et al., 1998; Soto et al., 2004; Von Schonfeld et al.,
Furthermore, silymarin is a well-known hepatoprotec-
istration may positively influence lipid and glucose
ment has a beneficial effect in reducing the glycemic
type II diabetes patients needs further investigation in
Acknowledgements
from the Endocrinology and Metabolism Research Center, Tehran
ing staff of the Diabetic Center of Shariati Hospital for their support
Maddux et al., 2001). Silymarin has been shown to
glutathione peroxidase and catalase in alloxan-induced
tion seen in diabetes. Two clinical studies (Velussi
exogenous administration of insulin in diabetic cirrhotic
enzyme, inhibits its deleterious effect on the nerves and
response to glucose stimulation (Lirussi et al., 2002).
In addition, there is evidence that lipoperoxidation
peroxidation that may counteract its deleterious effect
Silymarin also inhibits the toxic effect of alloxan and
1997). This effect may protect pancreatic cells from
tive herbal medicine (Velussi et al., 1993). Thus the
metabolism.
state in type II diabetic patients. The use of antioxi-
large multi-centre studies.
increase and normalize the pancreatic levels of free radi-
diabetic animals (Soto et al., 2003). This can exert
et al., 1993; Velussi et al., 1997) also reported that
patients. In diabetic patients, aldose reductase enzyme
red blood cells (Zhang et al., 1993). It has also been
This effect may inhibit hyperinsulinemia and subsequent
may negatively affect patients with diabetes (Tsuzura
on the glucose profile in diabetic patients (Skottova
cyclosporin on pancreatic cells in experimental animals
harmful metabolic products in hyperglycemic patients.
correction of liver function following silymarin admin-
In conclusion, the results showed that silymarin treat-
dants such as silymarin as a complementary therapy in
This study was supported by a research grant number R507/2003
tration of the Institute of Medicinal Plants and the Medical and Nurs-
University of Medical Sciences Tehran Iran. We thank the adminis-
in providing the necessary facilities for conducting this study.
Table 3. The average serologic parameters at the beginning and after 4 months of the study in placebo and silymarin treated groups
Silymarin (mean ± SD) Placebo (mean ± SD)
Group Beginning After 4 monthsp value BeginningAfter 4 months p value
FBS (mg/dL)
HbA1c (%)
Insulin (ng/mL)
Total cholesterol (mg/dL)
LDL cholesterol (mg/dL)
HDL cholesterol (mg/dL)
Triglyceride (mg/dL)
SGOT (U/L)
SGPT (U/L)
in the placebo group at the beginning of the study was
Silymarin treatment also significantly lowered blood
at the beginning and after 4 month of the study are
systolic and diastolic blood pressure in patients on
were no changes in therapy or surgical intervention in
treatment.
DISCUSSION AND CONCLUSION
on the glucose profile in patients with type II diabetes.
between the two groups of patients at the beginning
diabetic patients at the end of the study.
marianum seed extract that contains a wide number
cellular membrane stabilizing properties (Flora et al.,
type II diabetic patients the elevation of glucose and
2001; McGarry, 2002). These metabolic abnormalities
insulin secretion (Boden, 1997). Silymarin, with its
diabetic metabolic abnormalities. In support of this
favorable effects on oxidative metabolic derangement
156 ± 46
7.8 ± 2.0
0.4 ± 0.3
225 ± 64
140 ± 47
70 ± 33
284 ± 206
22 ± 5
19 ± 9
133 ± 39
6.8 ± 1.1
0.3 ± 0.2
198 ± 41
123 ± 30
61 ± 19
211 ± 136
17 ± 3
12 ± 6
0.001
0.001
0.123
0.0001
0.005
0.027
0.004
0.008
0.0001
167 ± 47
8.3 ± 1.9
0.3 ± 0.2
211 ± 46
130 ± 47
94 ± 60
185 ± 78
22 ± 5
17 ± 9
188 ± 48
9.5 ± 2.2
0.3 ± 0.2
215 ± 50
130 ± 44
85 ± 91
207 ± 93
20 ± 5
18 ± 9
0.0001
0.0001
0.396
0.565
0.933
0.392
0.127
0.039
0.283
8.29 ± 1.88%, which increased significantly (p < 0.0001)
SGPT. The results of the clinical findings in both groups
Finally a slight but non-significant decrease in weight,
treatment were reported during the study and there
silymarin-treated patients wished to continue the same
to 9.45 ± 2.16% after 4 months of placebo treatment.
summarized in Table 3.
silymarin was found. In addition, no side effects of the
either group. At the end of the study, many of the
levels of total cholesterol, LDL, triglyceride, SGOT and
The present study investigated the effect of silymarin
cally significant differences in the main parameters
lowered the HbA1c and fasting blood glucose levels in
effect of silymarin is not clear. Silymarin is a Silybum
oxidants, that increases cellular glutathione levels and
1986; Von Schonfeld et al., 1997; Pepping, 1999). In
reactive oxygen species and oxidative stress (Brownlee,
to insulin resistance, β-cell dysfunction and impaired
hypothesis, several experimental and clinical studies
The results show that although there were no statisti-
of study (Table 2), silymarin treatment significantly
The mechanism underlying the glucose lowering
of active constituents including flavonoids with anti-
1998; Sonnenbichler et al., 1986; Parish and Doering,
free fatty acid (FFA) levels leads to the generation of
not only induce late diabetic complications but also lead
powerful antioxidant properties, is active against
indicate that substances with antioxidant properties have
oxidative stress and may induce a positive effect on

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Copyright © 2006 John Wiley & Sons, Ltd.Phytother. Res. (in press)
DOI: 10.1002/ptr
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H. FALLAH HUSEINI ET AL.
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