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Herbal Extract of Gynostemma Pentaphyllum Decreases Hepatic Glucose

Output in Type 2 Diabetic Goto-Kakizaki Rats

Article in International Journal of Biomedical Science · July 2011

DOI: 10.59566/IJBS.2011.7131

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 International journal of Biomedical science

ORIGINAL ARTICLE

Herbal Extract of Gynostemma Pentaphyllum Decreases

Hepatic Glucose Output in Type 2 Diabetic Goto-Kakizaki Rats
K. Yassin1, V. T. T. Huyen1, 2, 3, K. N. Hoa4, C. G. Östenson1
1
Depatment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 2Department of Internal Medicine,
Hanoi Medical University, Hanoi, Vietnam; 3Department of Endocrinology and Diabetes, National Institute of Gerontology,
Hanoi, Vietnam; 4Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

Abstract

The aim of the study was to explore the effect of Gynostemma pentaphyllum (GP) extract on hepatic glu-
cose output (HGO) in spontaneously type 2 diabetic Goto-Kakizaki (GK) rats treated orally with GP or
placebo extract 1600 mg/kg daily, during three days or three weeks. The three-week treatment of GP, but
not three-day treatment, significantly reduced plasma glucose (PG) levels from 9.8 ± 0.6 to 6.8 ± 0.4 mmol/L
(p=0.027) in GK rats, whereas PG levels were not significantly decreased in the placebo rats. Glucose toler-
ance assessed by an intra-peritoneal glucose tolerance test was significantly improved in GP treated com-
pared to placebo treated group (areas under the glucose curves, AUCs, from 0 to 120 min were 1150 ± 200
vs. 1761 ± 87 mmol/L; p=0.013). The glucose response in an intra-peritoneal pyruvate tolerance test from
minute 15 to minute 120, the AUC (15-120) was significantly lower in the GP group (415.5 ± 68.0 vs. 641.5
± 41.8 mmol/L; p<0.05). In liver perfusions, the AUCs for HGO during 18 min (0-18 min) were signifi-
cantly decreased in GP treated rats compared with control rats (302.8 ± 36.5 vs. 423.5 ± 44.7 µmol, p<0.05).
The three-week GP treatment significantly reduced the hepatic glycogen content, but not glycogen synthase
activity compared to placebo group (p<0.007). In conclusion, three-week treatment of GP extract exerted
anti-diabetic effect in GK rats, reducing plasma glucose levels and HGO, suggesting that GP improves the
hepatic insulin sensitivity by suppressing gluconeogenesis. (Int J Biomed Sci 2011; 7 (2): 131-136)

Keywords: glucose tolerance; gynostemma pentaphyllum; herbal medicine; insulin sensitivity

INTRODUCTION cle and adipose tissue, decreases glucose utilization and

insulin resistance in liver increases glucose production.
Type 2 diabetes is a common disease that is charac- Therefore, the liver is an important organ in maintaining
terized by chronic hyperglycemia due to impaired insu- glucose homeostasis (2). Thus, hyperglycemia associated
lin secretion and decreased insulin action (1). Diminished with impairments in the regulation of fasting glucose pro-
insulin sensitivity in extra-hepatic tissues, such as mus- duction and glucose tolerance may be improved by thera-
peutics which target insulin resistance in the liver (3).
Plant extracts have been used in traditional medicine
for treatment of various diseases including diabetes (4).
Corresponding author: Kamal Yassin, Department of Molecular Medi- Gynostemma pentaphyllum (GP) has been used in tra-
cine and Surgery, Endocrine and Diabetes Unit, Karolinska Institute,
Karolinska University Hospital, SE 17176 Stockholm, Sweden. Tel: +46 8
ditional herbal medicine in Vietnamese and some other
51776200; Fax: +46 8 51773096; E-mail: [email protected]. Asian countries. GP extract reportedly has numerous ef-
Received December 24, 2010; Accepted February 16, 2011 fects, such as cholesterol-lowering, immune-potentiating,

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 GP extract decreases HGP in diabetic rats

anti-tumor, anti-oxidant, and anti-diabetic effect (5-8). Our This powder had a humidity of approximately 6.7%, and
previous studies revealed that phanoside, a gypenoside could be dissolved in water into brown liquid with a sweet-
isolated from the GP, reduced blood glucose in mice and bitter flavour. The extract contained flavonoids, as shown
rats (9, 10). Moreover, in a randomized placebo-controlled by a positive cyanidin reaction with base FeCl3 (5%) and
clinical trial in drug-naïve patients with type 2 diabetes, furthermore about 18% saponins, as indicated by a posi-
GP extract significantly improved HbA1c values and fast- tive foaming test (18, 19). Thus, the standardization of the
ing plasma glucose levels (11). The latter effect in addition GP extract included confirmation of its typical odour, state
to improvement in insulin sensitivity suggested that the and sweet-bitter flavour, approximately 7% in humidity,
main effect may reside in the liver. To further explore this, and positive reaction in the flavonoid (cyanidin reaction)
we have performed experiments in spontaneously type 2 and saponin (foaming) tests. The placebo was green tea
diabetic Goto-Kakizaki (GK) rats (11-16). The GK rat de- (Camellia sinensis), which was supplied at the same dose
velops hyperglycemia post-natally and maintains moder- and was similar to the GP extract in shape and packaging.
ately enhanced plasma glucose levels during its lifetime Both GP and placebo extracts were ground into a soluble
(17). This animal model of type 2 diabetes is character- powder that easily could be dissolved in water at room
ized by not only major impairment in beta cell function, temperature.
but also insulin resistance in muscle and liver. This study
aims to investigate the direct effect of GP extract on he- Oral administration of GP and placebo extracts
patic glucose output, using the perfused GK rat liver. GP and placebo extracts were given to unanesthetized
male GK rats by gavage through an enteral feeding tube
MATERIALS AND METHODS (polyvinyl chloride, sterile VYCON, Lab. Pharmaceutiques
Vycon, Ecouen, France) connected to a syringe with the so-
Animals lutions. The GK rats were divided into two groups in each
Altogether twenty one diabetic Goto-Kakizaki (GK) experiment; 800 mg/kg of GP extract or placebo extract
rats (200-300 g), originating from Wistar rats, were bred were given twice a day at 9:00 and 15:00 for three days or
in our department. The animals were kept at 22°C on a 12- three weeks. The treatment periods were chosen to reflect
hour light-dark cycle (6 am and 6 pm) with free access to short-term and long-term treatment, respectively. The dose
food and water before being anesthetized for liver perfu- was selected from our previous screening study in mice (20)
sion. The study was approved by the Laboratory Animal that showed an acute effect of GP with 1500 mg/kg body
Ethics Committee of the Karolinska Institutet (N367/08, weight. We thus decided to give GP in a slightly higher total
N72/08). daily dose of 1600 mg/kg, administered as 800 mg/kg two
times daily. The two-times-daily dosage was based on our
Plant material previous experience from a randomized placebo-controlled
The whole plants of Gynostemma pentaphyllum Maki- clinical trial in type 2 diabetic patients (11).
no-Cucurbitaceae were collected from Hoa Binh province,
in the north of Vietnam, and identified by Professor Pham Plasma glucose (PG) measurement
Thanh Ky, Department of Material Medica, Hanoi College Blood samples for determination of glucose (about 20
of Pharmacy. A voucher specimen (HN-0152) was depos- µl/sample) were taken after a small tail incision. Plasma
ited in the herbarium at Department of Material Medica, glucose levels were monitored by the glucose dehydroge-
Hanoi College of Pharmacy. nase method (Accu-Check Aviva) every 2 days before the
morning oral administration of either GP or placebo.
Method of extraction
The production of GP extract was processed as speci- Intraperitoneal Glucose Tolerance Test (IPGTT) and
fied. Briefly, the process included extraction of the authen- Intraperitoneal Pyruvate Tolerance Test (IPPTT)
ticated GP plants for 2h in boiling water, and with a fol- IPGTT and IPPTT were carried out in overnight fasted
lowing precipitation of impurities by adding concentrated GK rats. PG concentrations were obtained at 0, 15, 30,
70% ethanol. The 70% ethanol was then removed by dis- 60, and 120 minutes after an intraperitoneal (i.p.) injec-
tillation at low pressure, and impurities were removed by tion of glucose (2 mg/g body weight; Glukos APL 500 mg/
filtration. Thereafter, the extract was inspected as a semi- ml) or pyruvate (2 mg/g body weight; Sodium pyruvate,
finished brown powder with typical odour of GP extract. SIGMA), respectively.

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 GP extract decreases HGP in diabetic rats

Subcutaneous (s.c) insulin tolerance test (SCITT) cogen. The active form of GS (that is the form of GS which
For the SCITT, insulin was injected at a dose of 0.5 U/kg is activated by insulin) was measured at a low concentra-
and plasma glucose levels were measured in fasted GK rats tion of glucose-6-phosphate (0.3 mm) and the total GS at a
before the injection of insulin (0 min) and every 15 minutes high concentration (6.0 mm) (21).
for 2 hours and then every 30 minutes for another 2 hours.
Statistical analysis
Isolation and perfusion of GK rat liver for determination Statistical analyses were carried out with Sigmaplot
of hepatic glucose output (HGO) (2001). The results have been calculated as mean ± SEM
Liver perfusions were started between 10 am and noon. and comparisons of the means have been done by unpaired
The rats were anesthetized with an i.p. injection of ket- Student´s t-test and ANOVA was used after treatment with
amine (60-70 µg/g body weight; Pfizer AB, Täby, Swe- Bonferroni´s correction for multiple testing when appro-
den). Livers were perfused in situ without recirculation in priate. Difference was considered significant if the p-value
a 37°C cabinet via the portal vein using Krebs-Henseleit was below 0.05.
bicarbonate buffer (KRB), pH7.4, which was equilibrated
with 95% O2 and 5% CO2. The perfusion pressure was RESULTS
kept constant with a flow rate of 3.0-4.0 ml/min/g liver.
Adrenaline (Merck AB NM, Stockholm, Sweden) Effect of GP extract on PG in GK rats
was diluted into the perfusion medium (KRB) to the fi- The three-day treatment of GK rats with 800 mg/kg
nal concentration of 50 nmol/L. Livers were perfused for GP extract, or placebo extract, given orally twice a day
8-18 minutes. In rats treated for three days, livers were had no significant effect on PG levels (from 9.9 ± 1.2 to
perfused with KRB during eight minutes. In rats treated 8.9 ± 0.6 mmol/L in GP treated, and from 8.5 ± 0.4 to
for three weeks, the first eight minute with KRB only was 8.6 ± 0.3 mmol/L in placebo treated rats). In the three-
followed by adding adrenalin (50 nmol/L) in KRB for 10 week treatment, the PG concentrations were reduced sig-
minutes. Samples of the perfusate were taken at 2-minute nificantly in GP treated rats from 9.8 ± 0.6 to 6.8 ± 0.4
intervals from the inferior caval vein during perfusion, mmol/L (p=0.027), while in the placebo rats, PG levels
and their glucose levels were measured by the glucose were slightly but not significantly decreased from 8.8 ± 0.8
oxidase method using a glucose analyzer (Yellow Springs to 7.5 ± 0.3 mmol/L.
Instruments). Hepatic glucose output was calculated us-
ing the mean glucose concentration in relation to flow rate Effect of GP extract on IPGTT, SCITT and IPPTT in
and hepatic dry weight. These livers were not used for any GK rats
other measurements. In the IPGTT, the baseline glucose tolerance test (day
0) was similar in both groups, the areas under the glucose
Hepatic glycogen content curves (AUCs) during 120 min (0-120 min) being 1995.1
Liver homogenates were extracted in 80% ethanol ± 102.2 vs. 2029.5 ± 135.1 mmol/L, (p=0.843). However,
to remove glucose. An aliquot of each homogenate was after three-week treatment with GP extract, the glucose
mixed with amyloglucosidase (Roche Applied Science) tolerance was significantly improved as compared to that
and incubated at 60°C for 15 minutes to degrade glycogen in the placebo group with AUCs 1149.6 ± 200.0 vs. 1727.9
into glucose residuals. The samples were diluted and incu- ± 95.5 mmol/L, respectively (p<0.05; Fig.1). After three-
bated with 1 ml of Glucose Assay Reagent (o-Dianisidine week treatment, the PG concentrations in rats admin-
Reagent + Glucose Oxidase/Peroxidase Reagent, Sigma- istered with s.c insulin (0.5U/kg, SCITT) were reduced
Aldrich) at 37°C for 30 minutes, followed by the addition similarly in both groups, AUCs (0-240 min) (-149.7 ± 71.8
of 1 ml 12N H2SO4 to stop the reaction. The absorbance of vs. -110.4 ± 65.1 mmol/L, p=0.696; Fig. 2). In the IPPTT,
glucose was read at 540 nm. In parallel, different concen- there were no significant differences in the total glucose
trations of rabbit liver glycogen type III (Sigma-Aldrich) responses between the two groups, AUCs (0-120 min)
were treated as the samples and used as standard curve. (1137.7±67.8 vs. 1240.1 ± 103.6 mmol/L; p=0.432; Fig. 3).
However, when analysing the glucose response from min-
Hepatic glycogen synthase (GS) activity ute 15 to minute 120, the AUC (15-120 min) was signifi-
GS was determined by a method based on incorpora- cantly lower in the GP group (415.5 ± 68.0 vs. 641.5 ± 41.8
tion of 14C-labelled uridine diphosphate-glucose into gly- mmol/L; p<0.05).

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 GP extract decreases HGP in diabetic rats

Effect of GP extract on HGO levels in GK rats Effect of GP extract on hepatic glycogen content and
After the three-day treatment with the GP extract, GS activity in liver of GK rats
basal HGO was 20% lower in comparison with that in the The three-week treatment with GP extract significantly
placebo group (28.8 ± 6.5 vs. 36.1 ± 11.6 µmol/min). After reduced the hepatic glycogen content as compared to pla-
three weeks, the basal HGO in GP treated rats was 27% cebo group (18.3 ± 4.6 vs. 35.6 ± 2.9 mg/g liver, respec-
lower (25.7 ± 5.9 vs. 35.1 ± 5.8 µmol/min in treated and pla- tively, p<0.007). The hepatic glycogen synthase activity
cebo groups, respectively), but these differences were not did not differ in the group treated with the GP extract (40.5
statistically significant. However, in the three-week treat- ± 6.3 percent) compared to that in placebo group (35.9 ±
ed GK rats, AUCs for HGO during 18 minutes (0-18 min) 6.2 percent).
was significantly decreased as compared with the placebo
rats (302.8 ± 36.5 vs. 423.5 ± 44.7 µmol/min, p=0.05; Fig. DISCUSSION
4). In addition, infusion of 50 nmol/L adrenaline begin-
ning after 8 min of perfusion (8-18 min adjusted to the 8 Based on our previous results in type 2 diabetic pa-
min of perfusion) did increase the HGO in all rats but the tients, suggesting that GP treatment exerted a potent
response to adrenaline tended to be lower in the treated anti-hyperglycemic effect by improving hepatic insulin
rats compared to the placebo rats (27.5 ± 8.9 vs. 61.0 ± 17.5
µmol/min, p=0.114).
Gynostemma pentaphyllum (6 rats)
Placebo (6 rats)

Gynostemma pentaphyllum (6 rats) 30

Placebo (6 rats)
Plasma glucose (mmol/L) 25
30
Plasma glucose (mmol/L)

25 20

15
20
10
15
5
10
0
5 0 20 40 60 80 100 120 140
0 Time (min)
0 20 40 60 80 100 120 140
Figure 3. Mean of plasma glucose levels in intraperitoneal
Time (min) pyruvate tolerance test after three-week treatment.
Figure 1. Mean of plasma glucose levels in the intraperitoneal
glucose tolerance test after three-week treatment.
Gynostemma pentaphyllum (10 rats)
Placebo (11 rats)

50
HGO (mmol/min /liver)

Gynostemma pentaphyllum (5 rats)

Placebo (5 rats)
7 40
Plasma glucose (mmol/L)

6
30
5
4 20
3
10
2
1 0
0 2 4 6 8 10 12 14 16 18 20
0
0 50 100 150 200 250 300 Time (min)
Time (min)
Figure 4. Mean of hepatic glucose output (HGO) after three-
Figure 2. Mean of plasma glucose levels in the subcutaneous week treatment, (basal perfusion 0-8 min, and addition of 50
insulin tolerance test after three-week treatment. nM adrenaline 8-18 min).

134 June 2011 Vol. 7 No. 2 Int J Biomed Sci w w w.ijbs.org

 GP extract decreases HGP in diabetic rats

sensitivity (11), we decided to explore whether GP extract ducing plasma glucose levels and suppressing HGO levels
modulates hepatic glucose production in GK rats. significantly. The mechanism behind the improved hepatic
Oral administration of GP extract for three days did not insulin sensitivity may relate to suppression of gluconeo-
change the PG levels, whereas the long-term three-week genesis and inhibition of PTP1B.
treatment revealed significant decrease in PG. In addition,
the three-week treatment with GP extract significantly im- ACKNOWLEDGMENTS
proved glucose tolerance and reduced HGO compared to
the placebo rats. Since the results of an insulin tolerance We gratefully appreciate Ms Yvonne Stromberg and
test reflecting the insulin sensitivity mainly in muscle and Elisabeth Noren-Krog for expert assistance with hormone
other extra-hepatic tissues did not differ between the two assays. This study was supported by grants from SIDA/
groups, it seems unlikely that the primary effect of GP ex- SAREC, Osher Centre for Integrative Medicine, the
tract is exerted on the extra-hepatic tissues. Thus, these Swedish Research Council, and the Swedish Diabetes As-
findings suggest that GP-induced improvement in glucose sociation.
tolerance in GK rats is accounted for, at least partly, by
decreased HGO. Moreover, although addition of adrena- CONFLICT OF INTEREST
line did increase the HGO in all rats, the adrenaline effect
tended to be suppressed in the GP extract treated rats. The authors declare that no conflicting interests exist.
HGO plays a prominent role in glucose homeostasis.
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