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Metabolic effects of the association Berberis aristata/Silybum marianum: a

preliminary double-blind, placebo-controlled study in obese patients with
type 2 diabetes

Article in Nutrafoods · December 2015

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Nutrafoods (2015)
DOI 10.1007/s13749-015-0052-7
Review
Metabolic effects of the association Berberis aristata/Silybum
marianum: a preliminary double-blind, placebo-controlled study
in obese patients with type 2 diabetes
Giuseppina Guarino, Teresa Della Corte, Morena Sofia, Lucia Carbone,
Giampiero Marino, Emilia Martedì, Sandro Gentile
Received: 3 September 2015 / Accepted: 20 October 2015
© Springer – CEC Editore 2015
Abstract
Berberine, a quaternary isoquinoline alkaloid pres-
ent in Berberis aristata, is well known in terms of
its cholesterol-lowering, hypoglycemic, and insulin-
sensitizer effects. Because of its low oral bioavail-
ability, it has been recently formulated along with
silymarin (Silybum marianum) to improve intestinal
absorption. The aim of our study was to evaluate,
versus placebo treatment, the possible effect of its
association with silymarin on abdominal fat in
overweight/obese patients affected by type 2 dia-
betes mellitus. Using bioelectrical impedance at en-
rolment and after 6 months of treatment, we have
evaluated the following clinical parameters: waist
circumference, trunk fat, and visceral fat. Our re-
sults seem to indicate a clinically significant effect
for the association berberine+silymarin.
Giuseppina Guarino (•), Teresa Della Corte, Morena Sofia,
Lucia Carbone, Giampiero Marino, Sandro Gentile
Department of Experimental and Clinical Medicine
Second University of Naples
Naples, Italy
+39 338 906 5742
giuseppina.guarino@unina2.it
Emilia Martedì
Diabetes Unit A.I.D. Portici
Naples, Italy
Correspondence to: Keywords:
Giuseppina Guarino
berberine-silymarin
abdominal fat
giuseppina.guarino@unina2.it type 2 diabetes mellitus
obesity
cholesterol
Introduction
Type 2 diabetes mellitus (T2DM) is increasing to
epidemic levels globally. The increase in obesity is
one of the main risk factors: more than 1 billion
people worldwide are actually overweight or af-
fected by overt obesity [1].
White adipose tissue, in particular around the ab-
domen, is not a simple tissue whose only task is to
store lipid molecules—it is actually a real endocrine
tissue which can produce a number of cytokines.
These cytokines affect a wide range of biological
functions: insulin sensitivity, inflammation, blood
pressure, lipid metabolism, and energy homeostasis
[2,3].
In diabetes, an impaired glucose profile (hyper-
glycemia) and impaired lipid profile (dyslipidemia)
are risk factors that, working alone or together, ac-
celerate atherosclerotic damage and diabetic com-
plications [4,5]. Many drugs are available to treat
hyperglycemia and dyslipidemia, but despite their
effectiveness, several factors prevent the achieve-
ment of therapeutic goals in up to 50% of patients
[6]. Moreover, the side effects are often the cause
of poor adherence to treatment [7].
During the last few years a relatively large number
of supplements and nutraceuticals have been in-
vestigated for their assumed or, at least in part,
demonstrated ability to improve metabolic profiles
13

in humans. Berberine, a quaternary isoquinoline
alkaloid present in Berberis aristata [8], a plant used
from ancient times in traditional Chinese medicine,
has been reevaluated for its cholesterol-lowering
action and anti-hyperglycemic effect [9-13].
As demonstrated by in vitro and in vivo studies,
berberine affects energy balance at multiple sites:
(1) it counteracts in vitro adipocyte differentiation
by decreasing cAMP response element-binding pro-
tein (CREB) transcriptional activity, thus playing an
anti-adipogenic role [14]; (2) it activates thermoge-
nesis in white and brown adipose tissue in obese
db/db mice [15]; (3) it exerts anti-adipogenic activity
on 3T3-L1 adipocytes in 3T3-L1 cells by downregu-
lating a specific transcription factor [16]; (4) it mod-
ulates gut microbiota in high-fat diet-fed rats [17,18];
(5) it inhibits peroxisome proliferator-activated re-
ceptors and positive transcription elongation factor
b expression in white adipocytes in diabetic rats
[19]; (6) it inhibits human white pre-adipocyte dif-
ferentiation [20]; (7) it controls central and periph-
eral AMP-activated protein kinase (AMPK) activity,
reducing liver weight, hepatic and plasma triglyc-
erides, and cholesterol in obese db/db and ob/ob
mice [21]; (8) it induces glucagon-like peptide-1
(GLP-1) secretion in human gut NCI-H716 cells [22];
and (9) it reduces glucose absorption by suppressing
intestinal disaccharidases in both streptozotocin-in-
duced diabetic rats and in Caco-2 cell culture [23].
Due to its mechanisms of action, berberine has
been extensively used in several clinical conditions,
such as in patients with high cardiovascular risk
factors [24], T2DM with or without obesity [25-
29], polycystic ovary syndrome [30], hyperlipi-
demia [27], hypertension, and breast cancer, or in
subjects with multiple chronic diseases [9,12] or
dysbiosis [31].
The main mechanism for the cholesterol-lowering
action includes induction of expression of the re-
ceptor for low density lipoproteins (LDL) in the
liver, through a post-transcriptional mechanism
that stabilizes the mRNA encoding the receptor [10].
The glucose-lowering activity and the insulin-sen-
13
Nutrafoods (2015)
sitizer effect are conversely due to direct action on
AMPK in adipose and muscle tissue [11,32].
Due its poor oral bioavailability, berberine from
Berberis aristata has been formulated with silymarin
(Silybum marianum extract) which, besides having
a favorable effect on the liver, is rich in flavolig-
nanes (60–80%) and optimizes enteric absorption
of the berberine [33].
The main endpoint of our placebo-controlled study
was to evaluate the effect of the association berber-
ine–silymarin (BS) on the extent and distribution
of fat tissue in a group of obese subjects with T2DM
subjected to a low-intake diet regimen. Secondary
endpoints were to study the effect of BS on: (1) an-
thropometric and biochemical parameters; and (2)
safety, tolerability, and the percentage of subjects
who dropped out.
Materials and methods
Patients, diet, and measures
This double-blind placebo-controlled study was
conducted in accordance with the Helsinki Decla-
ration and with local ethics board approval.
Fifty patients affected by T2DM were enrolled after
giving informed consent. Inclusion criteria were:
1. Age between 18 and 70 years;
2. Obesity (body mass index (BMI) >30 kg/m2);
3. Altered glucose profile (fasting glucose ≥126 mg/dl
and insulin resistance index (HOMA-R) >2.5);
4. Altered lipid profile (total cholesterol (TOT
CHOL) >220 mg/dl; LDL-cholesterol >100 mg/dl);
5. No treatment with glucose-lowering drugs or
cholesterol-lowering drugs;
6. Absence of chronic or severe liver, kidney, or
heart disease;
7. No planned pregnancy and use of pill;
8. No previous bariatric surgery; and
9. Agreement to participate in the study.
All enrolled subjects were randomized to receive
either treatment or placebo. Subjects under treat-
ment took a BS tablet twice a day (after lunch and
dinner) containing 500 mg of berberine and 150
mg of silymarin. Subjects in the placebo group (P)
Nutrafoods (2015)
were treated with tablets indistinguishable from BS
in terms of size, shape, color, smell, and taste. Both
were administered over a period of 6 months.
During the study all patients received a low-calorie
diet (20–25% lower than that required to maintain
current weight) containing foods with a low
glycemic index; the diet was based on a variable
percentage of proteins (10–20%), fat (20–30% with
less than 10% as saturated fat), and carbohydrates
(50–60% with less than 5% as sucrose). Diets were
individually prepared in an effort to satisfy the
taste and the wishes of the participants. Carbohy-
drate favorites were starches with a low glycemic
index and high in soluble fiber (35 g/day). At least
30 min per day of predominantly aerobic physical
exercise was prescribed.
The following were evaluated at baseline and after
6 months: fasting blood glucose, fasting serum in-
sulin, HOMA-R, TOT CHOL, liver enzymes, albumin
levels, blood cell counts, anthropometric measures
(weight, height, BMI), and bioimpedentiometric
measures (abdominal fat levels).
Product tested
The product, in agreement with Italian law number
169/2004, was notified as Berberol® to the Minister
of Health in 2010 (registration number: E10
40753Y) and registered by Pharmextracta (Pon-
tenure, PC, Italy) as a food supplement with both
its active ingredients (Berberis aristata and Silybum
marianum standardized extracts) on the positive
list of botanicals admitted as nutraceuticals, and
with all of its excipients being food grade.
Bioimpedentiometry
Abdominal fat was measured with an innovative
bioimpedentiometer tool (Bia-TANITA AB140 ViS-
can) [34-36], which consists of a band with four
electrodes placed directly on the abdomen of the
subject lying supine. The position of the band was
guided by a laser beam from the base unit indicat-
ing the navel. For high accuracy and repeatability,
waist circumference (WC) was measured by the
base unit with an infrared system. The following
parameters were evaluated: WC, trunk fat (TF), and
percentage of visceral fat (VF) at enrollment and
after 6 months of treatment.
Diet adherence
All subjects completed a questionnaire to evaluate
adherence to the diet during the treatment period.
The questionnaire consisted of five questions in-
cluding the frequency of breaches of nutritional ad-
vice and the type and amount of food eaten outside
the recommended values. Four or less variations a
week from the recommended diet and a caloric load
of no more than 250 calories for each violation were
considered to be acceptable. The questionnaire was
previously validated by a sample of 10 healthcare
workers over a 2-week period.
Statistical analysis
The data are expressed as means±SD and compar-
isons evaluated with Student’s t test for paired data
and Yates correction or ANOVA test, when indi-
cated, using the software SPSS-PC Plus (SPSS Inc.,
Chicago, IL, USA). The lower level of statistical sig-
nificance was for p<0.05.
Results
A total of 25 subjects received BS and 25 received P
(the general data of the two treatment groups are
described in Table 1).
All enrolled patients completed the study. Good ad-
herence to the diet was observed in both groups
(87% vs 89% in BS and P, respectively) and generally
few side effects were noted (Table 2) with comparable
values for alanine transaminase (ALT), aspartate
transaminase (AST), gamma-glutamyl transferase
(γGT) (Table 3), and blood pressure (data not shown).
We observed a significant reduction in BMI,
HOMA-R, TOT CHOL, WC, and glycosylated he-
moglobin levels (HbA1c) in both groups but a sig-
nificant reduction in TF% only in the BS group.
Although not significant, a reduction in VF% was
also observed in the BS group (Table 4).
13
 Nutrafoods (2015)

To better determine the differences between the

BS Group P Group p
two groups and for greater understanding of the
Subjects (n) 25 25 -
Male (n) 14 13 n.s. effects exerted by BS, we calculated the percentage
Age (year) 54±5 56±7 n.s. of variations for all parameters studied. As shown,
Glycemia (mg/dl) 137±22 141±19 n.s.
HOMA-R 3,1±0,5 3,3±0,5 n.s.
treatment with BS significantly improved variation
HbA1c (%) 7.5±05 7.6±0.4 n.s. pre-post treatment BS vs P (Δ; %): BMI (−10.0±0.9
Total cholesterol (mg/dl) 230±14 235±13 n.s. vs −5.6±0.7 kg/m2, respectively; p<0.05), HOMA-R
Waist circumference (cm) 117±8 114±11 n.s.
Trunk fat level (%) 48±5 45±5 n.s. (−28.5±2.1 vs −18.1±2.6; p<0.01), TOT CHOL
Visceral fat level (%) 23±8 21±8 n.s. (−9.9±0.7 vs −6.2±0.5 mg/dl; p<0.05), WC (−8.2±0.5
BMI (kg/m2) 34±3 34±2 n.s.
vs −4.9±0.6 cm; p<0.05), TF (−11.4±0.5 vs −6.9±0.7;
AST (IU/l) 21±7 22±6 n.s.
ALT (IU/l) 27±9 25±8 n.s. p<0.05), VF (−15.2±1.2 vs −6.7±0.6; p<0.01), and
γGT (IU/l) 19±4 21±6 n.s. HbA1c (−1.1±0.4 vs −0.4±0.2%; p<0.01). These re-
All values are expressed as M ± SD sults revealed a significant difference between
Table 1 General parameters of patients enrolled at baseline groups for all outcomes considered (Fig. 1).

Severity* Persistent** Cause of drop-out

BS P p BS P p BS P p
Abdominal discomfort 2/25 2/25 n.s. 1/25 0/25 n.s. 0/25 0/25 n.s.
Nausea 1/25 0/25 n.s. 0/25 0/25 n.s. 0/25 0/25 n.s.
Abdominal distension 0/25 0/25 n.s. 0/25 0/25 n.s. 0/25 0/25 n.s.
Diarrhea 0/25 0/25 n.s. 0/25 0/25 n.s. 0/25 0/25 n.s.
Constipation 0/25 0/25 n.s. 0/25 0/25 n.s. 0/25 0/25 n.s.
*Mild-moderate; **persisting beyond the third treatment week
Table 2 Side effects observed in the treatment and placebo groups. In any patient the treatment was discontinued due to side effects

BS Group P Group
Baseline 6 months p Baseline 6 months p
AST (IU/l) 21±7 20±8 n.s. 22±6 24±6 n.s.
ALT (IU/l) 27±9 26±6 n.s. 25±8 27±6 n.s.
γGT (IU/l) 19±4 22±5 n.s. 21±6 20±8 n.s.
Table 3 Mean values (±SD) of serum transaminases (ALT, AST) and gamma-glutamyl transferase (ϒGT) before and at the end
of treatment (BS or P)

BS Group
BMI HOMA-R TOT CHOL WC TF VF HbA1c
(kg/m2) (mg/dl) (cm) (%) (%) (%)
T0 34±3 3.3±0.5 235±13 117±8 48±5 23±8 7.5±05
T6 30±3 2.4±0.6* 200±17* 107±8 41±4 19±8 6.4±04
P <0.05 <0.05 <0.05 <0.05 <0.05 n.s. <0.05
P Group
T0 34±2 3.1±0.5 230±14 114±11 45±5 21±8 7.6±0.4
T6 31±3 2.6±0.6 207±14 108±11 43±5 20±8 7.2±0.4
P <0.05 <0.05 <0.05 <0.05 n.s. n.s. n.s.
p<0.05 vs baseline; T0=baseline; T6=after six month treatment

Table 4 Comparison between parameters (mean ± SD) studied in the two subject groups, after 6 months of treatment.
* p<0.05 vs baseline; T0=baseline; T6=after six month treatment

13
Nutrafoods (2015)
BMI HOMA TOT CHOL
(kg/m2) (mg/dl)
0
-5
-10
p < 0.05
-15
-20
-25
p > 0.01
-30
Figure 1 Comparison between changes (%) pre-post treatment observed in the two treatment groups where green bars are
subjects treated with BB and orange bars were subjects treated with placebo
Discussion
We investigated the clinical effects of oral treatment
with a nutraceutical combination of B. aristata ex-
tract (containing 85% berberine) and S. marianum
extract (containing 60–80% flavolignanes). The lat-
ter ingredient is included to enhance the oral
bioavailability of berberine, mostly by reducing P-
glycoprotein activity in the gut. Enrolled patients
were obese and had a diagnosis of T2DM with
HbA1c values above normal. According to interna-
tional guidelines, high HbA1c values are linked to
an increased risk of developing microvascular and
macrovascular complications, so medical efforts
should aim to reduce HbA1c below 7% [37]. Use of
BS in patients with suboptimal glycemic control re-
sulted in a reduction in HbA1c of about 0.85% after
3 months of treatment, which was maintained for
a further 6 months of therapy [38]. Such a reduction
is comparable with that normally obtained in pa-
tients treated with acarbose, dipeptidyl peptidase-4
inhibitors (sitagliptin, vildagliptin, saxagliptin), or
glitazones, used alone or as a adjunct to metformin,
to achieve optimal glycemic control. A possible
mechanism of action of BS could be its ability to
increase insulin sensitivity, as shown by the reduc-
tion in HOMA-R. Another possible mechanism of
WC TF VF
(cm) (%) (%)
p < 0.05
p < 0.05
6 BS group 6 Placebo group
action could be linked to the acarbose-like action
observed by some clinicians [24]. This hypothesis
would explain some of the gastrointestinal side ef-
fects (constipation, meteorism) observed in previous
studies [39]. In our study we observed a relevant re-
duction in total cholesterol. This result, already de-
scribed in the literature, is likely due to the hypoc-
holesterolemic activity of berberine and to an
additive effect of berberine when combined with
statin therapy [40-42]. Even though we observed a
neutral behavior of BS on transaminase (AST, ALT)
and γGT, berberine has been previously described
to decrease transaminase levels, reducing liver
necrosis in non-alcoholic steatosis and in steatosis
due to hepatitis C infection [43]. However, these
observations need to be confirmed by studies specif-
ically designed to demonstrate a protective effect
of berberine on the liver.
The innovative results of our study are the signifi-
cant change in the distribution of TF and VF, re-
sulting in a significant reduction in body weight
and therefore BMI. In previous studies weight loss
due to berberine was observed [38,44] but this re-
duction was never described in terms of the redis-
tribution of body fat, especially VF, which is cor-
related with high cardiovascular risk. In particular,
13

analysis of our results shows that BS is able to im-
prove insulin sensitivity and enhance the reduc-
tion of TF and WC. The percentage of TF is a pa-
rameter which can be evaluated in the short term,
in the early stages of weight loss, and is an actual
marker of weight loss. On the other hand, the per-
centage of VF is a parameter that has to be evalu-
ated in the long term. Starting with severe obesity,
like that of the patients enrolled in our study, it
seems unlikely that after 6 months of dietary treat-
ment patients could reach their minimum goal,
which is to reduce their body weight by at least
10% compared with their initial weight. Reassess-
ment of VF% at 12 or 18 months will surely pro-
vide more useful information than that assessed
in our study at 6 months. The improvement in in-
sulin sensitivity and cholesterol level seems to be
due both to weight loss and the action of BS. As
reported in our study, the effects of berberine on
insulin sensitivity and lipid profile are well docu-
mented in the literature [24,38,39-41,45], while
the fact that supplementation with BS in patients
with diabetes can help reduce abdominal fat and
WC is a new finding. The reduction in abdominal
fat in overweight or obese T2DM patients neces-
sarily represents the first therapeutic goal; therefore
BS can be considered, among the nutraceutical ap-
proaches, a very useful treatment option for pa-
tients with diabetes.
Conclusion
BS is a nutraceutical combination of highly stan-
dardized herbal extracts of B. aristata and S. mari-
anum titered, respectively, as 85% berberine and
60–80% flavolignanes. BS seems to have positive
effects in patients with T2DM and suboptimal
glycemic control when given orally in addition to
a conventional regimen (i.e., metformin, dipeptidyl
peptidase-4 inhibitors, glitazones, acarbose, or in-
sulin, alone or as multidrug therapy). BS seems to
improve the cholesterol-lowering properties of
statins, and has a positive effect on liver enzymes.
Treatment seems to be safe and tolerated at the
13
Nutrafoods (2015)
doses tested, with minimal unwanted effects re-
solving on cessation of treatment without further
consequences. The results of our pilot study per-
formed in 50 patients with T2DM and obesity need,
of course, further confirmation in larger trials but
seem to indicate a new possible clinical use aimed
at treating abdominal fat in overweight/obese pa-
tients affected by T2DM.
Conflict of interests
The authors declare they have no conflict of interest
Human and Animal rights
All procedures followed were in accordance with the ethical
standards of the responsible committee on human experimen-
tation (institutional and national) and with the Helsinki Decla-
ration of 1975, as revised in 2008.
Informed consent
Informed consent was obtained from all patients for being in-
cluded in the study.
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