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,**2
*
Edison Biotechnology Institute,
Department of Biomedical Sciences, College of Osteopathic Medicine and
**
Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701
2To whom correspondence should be addressed. E-mail: chenx{at}ohiou.edu.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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2 (PPAR2) mRNA and glucose
transporter-4 (GLUT4) protein in cells induced from preadipocytes with
IS-IBMX-DEX in the presence of BE. The unique combination of a glucose
uptake stimulatory activity, the absence of adipocyte differentiation
activity and effective inhibition of adipocyte differentiation induced
by IS-IBMX-DEX in 3T3-L1 cells suggest that BE may be useful for
prevention and treatment of hyperglycemia and obesity in type II
diabetics.
KEY WORDS: • type II diabetes • banaba extract • insulin • adipocyte differentiation • glucose uptake
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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2
3
4
5)
. NIDDM is a complicated
disease, involving both genetic and nongenetic factors
(5
6
7)
. Although the causes of NIDDM are not completely
known, obesity, hyperinsulinemia, hyperglycemia and insulin resistance
are closely associated with NIDDM (8
9
10
11)
. Insulin plays
multiple physiologic roles in the human body, including the reduction
of blood glucose levels and the promotion of lipid biosynthesis in
adipocytes (12
13
14)
. It is highly desirable to find
antidiabetic agents that induce glucose uptake in cells, but, unlike
insulin, do not simultaneously up-regulate lipogenesis.
Leaves of the tropical plant Lagerstroemia speciosa L.
(banaba in the Tagalog dialect in the Philippines) have been used as a
folk medicine for treatment of diabetes and kidney diseases. The
extract from banaba significantly reduced blood glucose and insulin
levels in type II KK-Ay diabetic mice (15)
. It was
reported recently that the extract exhibited an antiadipogenic
activity by effectively reducing weight gain and parametrial adipose
tissue in female diabetic mice (16)
. However, no study has
reported the mechanisms of action by the extract at the cellular and
molecular levels, and it is not known how the extract exerts these
effects.
In this study, the ability of the banaba extract (BE) to stimulate
glucose uptake in 3T3-L1 adipocytes was examined and compared with that
of insulin. In addition, the effects of BE on differentiation of
preadipocytes into adipocytes, a process induced by an
insulin/3-isobutyl-1-methylxanthine/dexamethasone (IS-IBMX-DEX)
cocktail were also investigated. The expression of peroxisome
proliferator-activated receptor 2 (PPAR2), a nuclear protein
that turns genes on and off upon binding to molecules that belong to a
group of compounds called peroxisome proliferators and is essential for
adipocyte differentiation (17
,18)
, and of glucose
transporter-4 (GLUT4), a hallmark of adipocyte differentiation and the
molecule that mediates insulin-stimulated glucose transport
(12
,13)
, were studied in 3T3-L1 preadipocytes treated with
BE in the presence or absence of insulin, IBMX or DEX. These studies
were designed to characterize the effects of BE in 3T3-L1 cells at
cellular and molecular levels, and to identify an extract that may be
used for prevention and treatment of obesity and NIDDM without the
undesirable side effects of insulin therapy (19)
.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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3T3-L1 fibroblasts were purchased from American Type Culture Collection (ATCC, Rockville, MD). Banaba leaves were obtained as a gift from Huagen Pharmaceuticals (Hong Kong). Dulbecco’s modified Eagle’s medium (DMEM) and Dulbecco’s PBS (DPBS) were from Gibco Life Technologies (Grand Island, NY). Fetal bovine serum (FBS) was from Atlanta Biologicals (Norcross, GA). Bovine IS, IBMX and DEX were from Sigma Chemical (St. Louis, MO). 2-Deoxy-D-[3H] glucose and XK 50 column were from Amersham Pharmacia Biotech (Piscataway, NJ). Dianion HP-20 resin was from Mitsubishi Chemical (Tokyo, Japan). Anti-mouse GLUT4 monoclonal antibody was from Biogenesis (Brentwood, NH).
Banaba extract preparation.
Banaba extract was prepared by the method described previously
(15)
with modifications. Banaba hot water extract (BE) was
isolated by boiling 50 g of banaba tea in 1 L distilled water for
30 min, followed by ultracentrifugation at 30,000 x g for 30 min, filtration with a 0.4-µm
filter, concentration by heat evaporation and freeze-drying. The BE
was further separated by passage through a Dianion HP-20 resin column.
The BE was loaded on the column packed with Dianion HP-20 resin, then
washed with distilled water (BWE), and the absorbed fraction was eluted
with methanol (BME). These two eluted fractions from the column were
individually concentrated and freeze-dried. The powder of the
banaba extracts (BE and BME) was dissolved in sterile distilled
H2O, and then further sterilized with
0.2-µm filters for the adipocyte differentiation
study. Unless otherwise stated, BE was used in the study.
Cell culture and adipocyte differentiation.
3T3-L1 cells were maintained in DMEM and supplemented with 10% FBS at
37°C in a 10% CO2 cell incubator. Preadipocyte 3T3-L1
cells were grown in 12-well plates until 2 d postconfluence. The
differentiation was induced as previously described (20)
by addition of 1 mg/L IS, 0.5 mmol/L IBMX and 0.25
µmol/L DEX (IS-IBMX-DEX). Two days after induction,
the IS-IBMX-DEX–containing medium was replaced with medium containing
1 mg/L IS alone. The medium was subsequently replaced again with fresh
culture medium (DMEM supplemented with 10% FBS) after 2 d and
then every other day thereafter. To determine the roles of banaba
extract in adipocyte differentiation, BE was added to the medium either
to substitute for insulin (BE-IBMX-DEX) or to supplement IS-IBMX-DEX
(BE-IS-IBMX-DEX). The differently induced cells were assayed for
glucose uptake activity 9–12 d after the initiation of induction.
Glucose uptake activity assay.
Glucose uptake activity was analyzed by measuring the uptake of
2-deoxy-D-[3H] glucose as described
previously (21
,22)
. Briefly, confluent 3T3-L1 adipocytes
grown in 12-well plates were washed twice with serum-free DMEM and
incubated with 1 mL of the same medium at 37°C for 2 h. The
cells were washed 3 times with Krebs-Ringer-Hepes (KRP) buffer and
incubated with 0.9 mL KRP buffer at 37°C for 30 min. Insulin and/or
BE were then added and adipocytes were incubated at 37°C for 15 min.
Glucose uptake was initiated by the addition of 0.1 mL KRP buffer and
37 MBq/L 2-deoxy-D-[3H] glucose and 1 mmol/L
glucose as final concentrations. After 10 min, glucose uptake was
terminated by washing the cells 3 times with cold PBS. The cells were
lysed with 0.7 mL of 1% Triton X-100 at 37°C for 20 min. The
radioactivity retained by the cell lysates was determined by a
scintillation counter. Nonspecific glucose uptake was measured at a
glucose concentration of 100 mmol/L. Assay data were analyzed
statistically using Student’s t test by comparison of
experimental samples of the same treatment conditions as a group with
negative control (untreated) samples, or positive (insulin-treated)
samples, or with experimental samples with different treatment
conditions. To compensate for multiple t tests,
P < 0.01 was set as the level of significant
difference.
Adipocyte differentiation assay.
Undifferentiated 3T3-L1 preadipocytes were induced to
differentiate into adipocytes as described above. The degree of the
differentiation of the cells induced by different agents was evaluated
by microscopic observation of lipid accumulation, as well as by the
glucose uptake activities they exhibited at the end of the induction as
described above. The glucose uptake assay was chosen and performed here
for determination of the degree of adipocyte differentiation on the
basis of the observation that differentiated adipocytes can be induced
by insulin to take up glucose, whereas preadipocytes cannot
(23
,24)
.
Northern blot and Western blot analyses.
Total RNA or total protein was isolated with standard procedures from
3T3-L1 cells induced by different combinations of insulin, IBMX and
DEX, and BE. For detection of PPAR2 mRNA expression, a
32P-labeled fragment of 308 bp, corresponding to the
nucleotides from + 29 to + 336 of the coding region of the PPAR2
cDNA, was used as a probe and 10 µg of total RNA
(isolated 144 h postinduction) was used per sample. For Western
blot analysis, an anti-mouse GLUT4 monoclonal antibody was used and
100 µg of total protein (isolated 10 d post
induction) was loaded per lane.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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), suggesting that the effective component(s) with glucose
transport-inducing activity in the banaba extract are
water-soluble but relatively nonpolar. Also, the maintenance of the
activity through boiling and heat evaporation during extract
preparation indicated that the effective component(s) is heat stable
and is unlikely to be a protein(s).
|
) is very similar to that of insulin (Fig. 2
B). The
concentration range of BE that stimulated the greatest glucose uptake
was 
0.1–0.25 g/L (Fig. 2
A). The similarity between the
two dose-response curves and the observation that the induction
time required by BE for stimulating glucose uptake activity was similar
to that of insulin, i.e., no > 15 min (refer to the glucose uptake
activity assay in Materials and Methods), suggest that BE may stimulate
glucose uptake by a mechanism that is similar to that of insulin
(23
24
25)
and different from those utilized by other
chemicals (24
,26
27
28)
.
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), indicating that no additive or synergistic effects exist between BE
and insulin. To the contrary, in comparison to insulin alone (the
leftmost data point on the insulin + BE curve of Fig. 3
B),
reduction of the glucose uptake activity by addition of BE to insulin
was observed (Fig. 3
B). On the basis of the observations of
glucose uptake–inducing activity of BE and inhibitory activity of BE
on insulin-induced glucose uptake, a mechanism of action of BE may
be hypothesized. BE may interact with a protein factor that is directly
involved in the insulin-mediated glucose transport signaling
pathway that starts with the insulin receptor and terminates with
GLUT4, consequently activating glucose uptake. On the other hand, the
interaction between BE and the protein factor may structurally alter
the conformation of the factor, preventing it from properly receiving
the glucose uptake signal initiated from insulin-insulin receptor
binding. Further studies of insulin receptor binding and receptor and
intracellular protein phosphorylation are needed for the final
elucidation of the site of action and the glucose uptake induction
mechanism mediated by BE. BE apparently stimulates glucose uptake
through a mechanism that is very different from that used by other
common antidiabetic drugs such as the thiazolidinediones (TZD)
(29
,30)
. TZD stimulate glucose uptake using a slow and
indirect mechanism by activating PPAR, which in turn
up-regulates GLUT4 gene expression (29
30
31)
. In
contrast, the glucose uptake–stimulatory activity of BE seems to be
much faster and more direct. The effective compound(s) in BE may
represent a new group of chemicals that could be used as alternatives
to TZD to induce glucose uptake in both cells and animals.
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. However, when 1–100 mg/L BE was substituted for
insulin and added to preadipocytes in the presence of IBMX and DEX, no
adipocyte differentiation of 3T3-L1 cells was observed as revealed by
glucose uptake assays (Fig. 4
). This result indicates that BE does not induce adipocyte
differentiation in 3T3-L1 cells. Interestingly, both BE and BME, when
co-incubated with IS-IBMX-DEX, inhibited adipogenesis, whereas BWE
did not (Fig. 5
). This indicates that both the adipocyte differentiation inhibition
activity and the glucose uptake activity were due to BME (Fig. 1)
. The
inhibition of adipocyte differentiation by BE was time (Fig. 6A
) and concentration dependent (Fig. 6
B). These results are
consistent with the microscopic observations of fat accumulation (Fig. 5)
. The 3T3-L1 preadipocytes, whose differentiation was blocked by
co-incubation of BE and IS-IBMX-DEX, retained the capacity to
reenter the differentiation process when the IS-IBMX -DEX induction
cocktail was reintroduced into the cells (data not shown). It is
interesting to note that BE showed an insulin-like glucose
uptake–inducing activity in adipocytes but did not show an
insulin-like differentiation-inducing activity in preadipocytes.
This difference may be explained by the facts that these two activities
involve two distinct signaling pathways and that the insulin receptor
is involved in glucose transport in adipocytes, whereas the
insulin-like growth factor 1 receptor, which is homologous to the
insulin receptor, is used by insulin in preadipocytes for induction of
differentiation (18
,32
,33)
.
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2 and GLUT4,
were used to monitor the progress of differentiation in the
preadipocytes that were induced by either IBMX-DEX or IS-IBMX-DEX
in the presence or absence of BE. Northern blot analysis revealed that
BE greatly inhibited the mRNA expression of PPAR2 induced by either
IBMX-DEX or IS-IBMX-DEX in a dose-dependent manner (Fig. 7A
). Furthermore, as shown by a Western blot analysis, the protein
production of GLUT4 (65 kDa) was inhibited more in the cells induced
by IS-IBMX-DEX in the presence of BE than in the cells induced in the
absence of BE (Fig. 7
B). These results are consistent with
our other differentiation inhibition results studied with glucose
uptake assays (Figs. 4
and 6)
, and are not inconsistent with other
glucose uptake assays (Figs. 1
2
3)
because the glucose uptake–inducing
activity of BE was examined in fully differentiated adipocytes (Figs. 1
2
3)
, whereas the GLUT4 inhibitory effect of BE was observed in
undifferentiated cells (Fig. 7
B). GLUT4 expression was used
as an indicator of differentiation in this study to monitor the ability
of BE to induce differentiation in preadipocytes, not glucose transport
in adipocytes. All of these results suggest that the specific target of
the differentiation inhibition exerted by BE is PPAR2 or factor(s)
that directly or indirectly regulate the expression of PPAR2.
Further experiments are necessary to determine the site of the
inhibition. The identity and function of the 43-kDa protein (Fig. 7
B) are not known at this time. The presence of such a
protein band in the Western blot was likely due to the specific
monoclonal antibody, and possibly the cells used in this study.
|
We have demonstrated that BE stimulates glucose uptake activity and
inhibits the adipocyte differentiation activity of IS-IBMX-DEX in
3T3-L1 cells. These new findings are consistent with the previous
observations that BE lowered blood glucose levels in diabetic mice
(15)
and reduced weight gain and adipose tissue mass in
female diabetic mice (16)
.
Antidiabetic drugs such as insulin or TZD up-regulate both glucose
transport and lipid biosynthesis in adipocytes (29
,30)
.
Weight gain is a frequent side effect of insulin therapy in type II
diabetic patients (19)
. Therefore, drugs with
glucose-lowering activity, but lacking adipogenic activity are
highly desirable. The effective component(s) of BE seem to have such an
advantageous combination. A new polypeptide hormone, resistin, has
recently been found in adipocytes to be one of the potential links
between obesity and type II diabetes (34
,35)
. Resistin may
be responsible for insulin resistance, and its gene expression profile
appears to be very similar to that of PPAR (34)
, a gene
that BE down-regulates (Fig. 7
A). Thus, an understanding
of the mechanism of BE action will be valuable for the study,
prevention, and treatment of obesity, insulin resistance and type II
diabetes.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BE, banaba hot water
extract; BME, banaba HP-20 methanol eluent; BWE, banaba HP-20 water
eluent; DEX, dexamethasone; DMEM, Dulbecco’s modified Eagle’s medium;
DPBS, Dulbecco’s PBS; FBS, fetal bovine serum; GLUT4, glucose
transporter-4; IBMX, 3-isobutyl-1-methylxanthine; IS, insulin; KRP,
Krebs-Ringer-Hepes; NIDDM, noninsulin-dependent diabetes mellitus;
PPAR2, peroxisome proliferator-activated receptor 2; TZD,
thiazolidinedione.
Manuscript received March 12, 2001. Initial review completed May 3, 2001. Revision accepted June 23, 2001.
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