JOURNAL OF MEDICINAL FOOD

J Med Food 10 (3) 2007, 543547

Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition
DOI: 10.1089/jmf.2006.089

Short Communication
Silymarin as an Adjunct to Glibenclamide Therapy Improves Long-Term and
Postprandial Glycemic Control and Body Mass Index in Type 2 Diabetes
Saad Abdul-Rehman Hussain
Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq
ABSTRACT Oxidative stress is increased postprandially and during long-term hyperglycemia in type 2 diabetic patients
who present with poor response to glibenclamide. This study was designed to evaluate the effects of the antioxidant flavonoid
silymarin in improving long-term and postprandial glycemic and weight control in type 2 diabetic patients treated with glibneclamide. Using a randomized, double-blind, placebo-controlled design, 59 type 2 diabetic patients, previously maintained
on 10 mg/day glibenclamide and diet control, with poor glycemic control, were randomized into three groups: the first two
groups were treated with either 200 mg/day silymarin or placebo as adjuncts to glibenclamide, and the third group was maintained on glibenclamide alone for 120 days. Fasting and 4-hour postprandial plasma glucose, glycated hemoglobin (HbA1c),
and body mass index (BMI) were evaluated at baseline and after 120 days. Compared with placebo, silymarin treatment significantly reduced both fasting and postprandial plasma glucose excursions, in addition to significantly reducing HbA1c levels and BMI after 120 days. No significantly different effects were observed for placebo compared to glibenclamide alone.
In conclusion, adjunct use of silymarin with glibenclamide improves the glycemic control targeted by glibenclamide, during
both fasting and postprandially, an effect that may be related to increased insulin sensitivity in peripheral tissues.
KEY WORDS:

postprandial glucose excursions

silymarin

type 2 diabetes mellitus

ated with these spikes increase free radical synthesis and

worsen the oxidative stress.
Several trials have shown that improving glycemic control does not necessarily improve oxidative stress.8 One
might infer from such observations that specific therapy directed toward oxidative stress is needed. With few exceptions, large long-lasting trials have been performed using vitamin E alone or sometimes combined with vitamin C, but
so-called oxidative chain breakers failed to significantly improve glycemia in type 2 diabetic patients.9 Thus, vitamins
may have simply been the wrong choice. Alternatively, pharmacologic intervention with oxidant chain breakers may
prove insufficient, a proposal that highlights the need for interfering directly with production of free radicals.10
Silymarin, a flavonoid extracted from milk thistle, Silybum marianum, has demonstrated protective effects against
oxidative stress-induced damage in several experimental
models and in human hepatic injury.11 Moreover, it was previously demonstrated that silymarin prevented a rise in both
plasma glucose and pancreatic lipid peroxidation in alloxaninduced diabetic rats.12 This project was designed to evaluate the effects of the antioxidant dietary supplement silymarin on glycemic control and body mass index (BMI) in

INTRODUCTION

ONENZYMATIC, FREE RADICAL-MEDIATED

oxidation of biological molecules, membranes, and tissues is associated with a variety of pathological events such as cancer,
aging, and diabetes mellitus (DM).1 Among the causes of
enhanced free radical production, hyperglycemia and hyperinsulinemia seem to play a major role.2,3 The state of oxidative stress in diabetes is strictly influenced by glycometabolic control in both type 1 and type 2 diabetics,4,5
and this consequently impairs insulin action as demonstrated
in type 2 diabetes. This impairment might be due to several
factors, such as membrane fluidity alterations, decreased
availability of nitric oxide, and increased intracellular calcium content.6 In diabetes mellitus, the postprandial hyperglycemic spikes have been considered a critical event in the
pathogenesis of micro- and macroangiopathic complications.7 It is obvious that all the metabolic pathways associ-

Manuscript received 1 June 2006. Revision accepted 26 September 2006.

Address reprint requests to: Saad Abdul-Rehman Hussain, Department of Pharmacology
and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq, E-mail:
saad_alzaidi@yahoo.com

543

544

HUSSAIN

was measured. The test was performed before starting silymarin treatment and 120 days after.
Statistical analysis was performed utilizing Students
t test to compare between pre- and post-treatment, while
analysis of variance was used for multiple group comparison. Values with 95% confidence were considered significant (P  .05).

type 2 DM patients with insulin resistance and poor glycemic control with oral hypoglycemic agents.

PATIENTS AND METHODS

This multicenter, randomized, double-blind, placebocontrolled study was conducted on 59 patients (30 men and
29 women) 3558 years old (range 49.2  4.8 years) with
type 2 DM for at least 5 years. All patients were already
maintained on 10 mg/day glibenclamide (SDI, Samara,
Iraq) and on diet control; their fasting plasma glucose
(FPG) was 10.0 mmol/L, glycated hemoglobin (HbA1c)
was 8.0%, and BMI was 29 kg/m2. The patients were
informed about the nature of participation in the study and
involved in complete clinical and laboratory evaluation,
before and after the end of the study. The patients were
randomly allocated into three groups and treated as follows: group A (18 patients) received 200 mg/day silymarin
(Luna Co., Cairo, Egypt) orally as a capsule dosage form,
in addition to the oral hypoglycemic agent (10 mg/day
glibenclamide) for 120 days; group B (20 patients) received placebo capsules, in addition to 10 mg/day glibenclamide for 120 days; and group C (21 patients) received
10 mg/day glibenclamide only, serving as controls. The
laboratory measurements performed to evaluate the metabolic effects of silymarin included FPG and HbA1c analysis, where blood samples were obtained from each patient
after fasting for 12 hours before starting treatment and 120
days after; plasma glucose level was analyzed according
to the method of Barham and Trinder,13 and HbA1c was
measured according to the method of Winterhalter.14 BMI
was measured for each patient at day 0 and after 120 days
according to the formula BMI  body weight (in
kg)/height (in m2).15 The postprandial glucose excursions
test was performed by measurement of plasma glucose in
blood samples taken at zero-time before the patients were
given a solid standard meal containing 560 kcal and at 15,
30, 60, 120, and 240 minutes after; the area under the curve
(AUC) for the plots representing plasma glucose and time

TABLE 1.

EFFECTS

Patient group
Group A (n  18)
Pretreatment
Post-treatment
Group B (n  20)
Pretreatment
Post-treatment
Group C (n  21)
Pretreatment
Post-treatment

OF

TREATMENT

WITH

SILYMARIN

RESULTS
Treatment of type 2 DM patients with 200 mg/day silymarin in addition to the currently used oral hypoglycemic
agent (glibenclamide 10 mg/day) for 120 days produced a
significant reduction (P  .05) in FPG, HbA1c, and BMI
(20%, 16%, and 9%, respectively) compared to pretreatment
levels (Table 1). Treatment with placebo in addition
to glibenclamide (10 mg/day) resulted in a significant decrease only in the FPG level (4%), whereas HbA1c and BMI
values were not significantly changed compared to pretreatment values. In group C patients (negative controls) receiving only the currently used oral hypoglycemic agent,
glibenclamide 10 mg/day, FPG was slightly but significantly
elevated compared to the pretreatment value, but HbA1c and
BMI were not significantly altered after the 120-day treatment follow-up period. When the post-treatment data for
FPG, HbA1c, and BMI in the three groups were compared,
the silymarin-treated group exhibited significantly greater
improvement in those parameters compared to the other two
groups, which showed no significant differences with each
other.
The effects of treatment with silymarin on the postprandial glucose spikes (postprandial hyperglycemia) (Table 2
and Fig. 1) clearly showed that the area under the curve
(AUC04 h), which represents the change in postprandial
plasma glucose from baseline, was significantly decreased
(36.8%) after treatment with silymarin for 120 days compared to pretreatment values. However, in placebo-treated
patients and controls, no significant changes in the level of
postprandial hyperglycemia were observed after 120 days

ON

FPG, HBA1C,

AND

BMI

IN

TYPE 2 DM PATIENTS

FPG (mmol/L)

BMI (kg/m2)

HbA1c (%)

11.69  0.21
9.31  0.13*a

31.66  0.47
28.95  0.35*a

8.91  0.18
7.45  0.19*a

11.18  0.21
10.73  0.2*b

30.91  0.32
30.68  0.28b

8.76  0.15
8.71  0.14b

10.72  0.14
10.97  0.1*b

31.04  0.32
30.95  0.28b

8.78  0.11
8.74  0.1b

Data are mean  SE values (n  number of subjects).

*Significantly different with respect to pretreatment values (P  .05).
abValues with nonidentical superscripts among different groups post-treatment are considered significantly different (P  .05).

545

SILYMARIN IN TYPE 2 DIABETES

TABLE 2.

EFFECTS OF TREATMENT WITH SILYMARIN ON THE POSTPRANDIAL GLUCOSE

EXCURSION TEST (AUC04 H) IN TYPE 2 DM PATIENTS
AUC04 h (mmol/minute/L)

Patient group
Group A (n  18)
Group B (n  20)
Group C (n  21)

Pretreatment

Post-treatment

% change

632.04  78.63
619.65  91.31
618.19  55.49

399.05  55.86*a
735.45  81.72b
619.73  45.25b

36.8%
18.7%
0.25%

Data are mean  SE values (n  number of subjects).

*Significantly different with respect to pretreatment values (P  .05).
abValues with nonidentical superscripts among different groups post-treatment are considered significantly different (P  .001).

compared to pretreatment levels. When the post-treatment

results of all groups in this respect were compared, the silymarin-treated group showed significantly lower AUC04 h
values compared to the other groups, which were not significantly different from each other (Table 2 and Fig. 1).

DISCUSSION
There is strong support for the suggestion that reactive
oxygen species play a relevant role in the etiology and pathogenesis of DM and its long-term effects.16,17 Many investigators have demonstrated that silymarin successfully prevents alloxan-induced DM and induces recovery of
pancreatic function after alloxan damage in rats.12,18 In this
study, it was reported that adjuvant use of silymarin (200
mg daily for 120 days) in type 2 diabetic patients who
showed poor glycemic control with maximal doses of
glibenclamide resulted in a significant reduction in FPG levels and protein glycation, associated with significant reduc-

tion in BMI after 120 days, compared to pretreatment levels. All these effects were significantly were significantly
more pronounced than in patients treated with placebo or
glibenclamide alone (Table 1).
In view of the insulin sensitivity and glycemic control
data, it is likely that normoglycemic insulin-resistant subjects and those with obesity may already exist in a state of
oxidative stress,19 and even in healthy populations, variations in insulin sensitivity are related to lipid hydroperoxide
levels and reduction in many of the natural antioxidant defenses, including catalase and vitamin E.20 Moreover, a large
body of evidence for oxidative stress in insulin resistance
and diabetes has logically prompted the use of antioxidants
as a self-evident treatment.
Chronic activation of certain isoforms of protein kinase
C (PKC) may be of key importance in insulin resistance and
hyperglycemia.21 It has been recently shown that in vivo inhibition of PKC- expression with LY333531 leads to decreased hyperglycemia and albuminuria,22 and a number of

Changes in plasma glucose (mmol/L)

8
7

Group A-pre

Group B-pre

Group A-post
Group B-post

Group C-pre
Group C-post

4
3
2
1
0
0
-1

50

100

150
Time (minutes)

200

250

300

-2

FIG. 1.

Effects of treatment with silymarin on changes in plasma glucose levels after a meal challenge in type 2 DM patients.

546

HUSSAIN

phytochemicals, including silymarin, have the potential to

suppress downstream signaling during PKC activation and
have been found to modulate insulin sensitivity and regulate the glycemic state.23 The results presented in Table 1
are compatible with those reported by Velussi et al.,24 in
which treatment of some type 2 diabetic patients suffering
from hepatic cirrhosis for 4 months with 600 mg silymarin/day significantly improved glycemic control associated with a reduction in both fasting insulin and exogenous
insulin requirements. The data in both situations strongly
suggest an improvement in insulin sensitivity and a differential effect of silymarin on the endocrine function of the
pancreas, which may have a considerable therapeutic potential in improving response of peripheral tissues to the secreted or exogenously administered insulin.
Despite the important advances in the treatment of type
2 DM, few patients achieve satisfactory glycemic control.
Among the barriers to achieving satisfactory glycemic control with oral hypoglycemic agents, even when insulin is
added to the treatment, are excessive weight gain,25 failure
to adequately control postprandial glycemic excursions,26,27
and an increased risk of hypoglycemia.28 In this study, the
data presented in Table 2 and Figure 1 indicate that silymarin not only improved insulin sensitivity, but also was involved in the maintenance of normal glucose homeostasis
during the mealtime period, which is very important for
achieving normoglycemia,29 especially in the postprandial
period. Such a pattern of regulation is important to avoid
the emerging risk of severe hypoglycemia when the doses
of insulin and/or the oral hypoglycemic agents are increased,
in addition to preventing undesired weight gain, which negatively affects plasma lipids, blood pressure, and compliance with therapy.30
Most of the available treatment approaches of DM favor
insulin release or control blood glucose levels, but without
emphasis on recovering physiological regulation of the endocrine function of the pancreas. The data presented in this
study suggest that silymarin offers the possibility of a novel
treatment of diabetes mellitus, not only for enhanced -cell
recovery, but also for increasing sensitivity of peripheral targets to the available insulin. In conclusion, adjunct use of
silymarin with oral hypoglycemic agents has the ability to
provide glycemic control during mealtime and the long-term
fasting state, as a result of improved tissue responses to the
available insulin in type 2 diabetic patients.

ACKNOWLEDGMENTS
I thank the Luna Co., Egypt for providing crude standard
silymarin.

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