Antihyperglycemic effect of aporphines and their derivatives in normal and diabetic rats

Article abstract of DOI:10.1055/s-2006-947199

The antihyperglycemic actions of some aporphines and their derivatives in normal Wistar, streptozotocin (STZ)-induced diabetic (IDDM) and nicotinamide-STZ induced diabetic (NIDDM) rats were investigated in this study. These compounds included thaliporphine, glaucine, boldine, N-methyllaurotetanine, and predicentrine and the derivatives, N-[2-(2-methoxyphenoxy)ethyl]-norglaucine and diacetyl-N-allylsecoboldine. Bolus intravenous injection of these compounds decreased the plasma glucose levels in a dose-dependent manner in both normal and diabetic rats. Among them, thaliporphine was found to have the most potent antihyperglycemic effect in both NIDDM and IDDM diabetic rats. It was found that thaliporphine could stimulate the release of insulin in both normal and diabetic rats, and a dose of 1 mg per kg thaliporphine could significantly attenuate the increase of plasma glucose induced by an intravenous glucose challenge test in normal rats. Similar treatment with thaliporphine significantly increased the skeletal muscle glycogen synthesis in both normal and diabetic rats. Hence, the hypoglycemic effect of thaliporphine in diabetic rats could be attributed to the stimulation of insulin release and the increase of glucose utilization. Georg Thieme Verlag KG Stuttgart.

Full text of DOI:10.1055/s-2006-947199

Tzong-Cherng Chi1
Shoei-Sheng Lee2
Ming-Jai Su1
Antihyperglycemic Effect of Aporphines and their
Derivatives in Normal and Diabetic Rats
Abstract
rats. It was found that thaliporphine could stimulate the release
of insulin in both normal and diabetic rats, and a dose of 1 mg per
The antihyperglycemic actions of some aporphines and their de- kg thaliporphine could significantly attenuate the increase of
rivatives in normal Wistar, streptozotocin (STZ)-induced diabetic plasma glucose induced by an intravenous glucose challenge
(
IDDM) and nicotinamide-STZ induced diabetic (NIDDM) rats test in normal rats. Similar treatment with thaliporphine signifi-
were investigated in this study. These compounds included tha- cantly increased the skeletal muscle glycogen synthesis in both
liporphine, glaucine, boldine, N-methyllaurotetanine, and predi- normal and diabetic rats. Hence, the hypoglycemic effect of tha-
centrine and the derivatives, N-[2-(2-methoxyphenoxy)ethyl]- liporphine in diabetic rats could be attributed to the stimulation
norglaucine and diacetyl-N-allylsecoboldine. Bolus intravenous of insulin release and the increase of glucose utilization.
injection of these compounds decreased the plasma glucose lev-
els in a dose-dependent manner in both normal and diabetic Key words
rats. Among them, thaliporphine was found to have the most po- Aporphine ´ Thaliporphine ´ Diabetic rats ´ NIDDM ´ IDDM ´ anti-
tent antihyperglycemic effect in both NIDDM and IDDM diabetic hyperglycemia
1175
Introduction
bit antiarrhythmic activity in ischemia-reperfusion rat hearts in
vivo [6], [7]. The present study was aimed to find out whether
Diabetes, which ranks highly among the top ten causes of mor- they possessed hypoglycemic activities in normal Wistar rats,
tality worldwide, often leads to disability from vascular compli- streptozotocin (STZ)-induced diabetic and nicotinamide-STZ-in-
cations and limb amputation in addition to neurological compli- duced diabetic rats, the latter two representing insulin-depen-
cations and premature death [1]. The incidence of acute myocar- dent DM (IDDM) and non insulin-dependent DM (NIDDM) ani-
dial infarction associated with arrhythmia is high in the popula- mal models, respectively.
tion of diabetes mellitus (DM) disease. Therefore, the aim was to
find a new antidiabetic agent with antiarrhythmic activity. The
aporphines, including thaliporphine, glaucine, boldine, N-me- Materials and Methods
thyllaurotetanine, and predicentrine, and the aporphine deriva-
tives, N-[2-(2-methoxyphenoxy)ethyl]glaucine and diacetyl-N- Chemicals
allylsecoboldine (Fig.1), isolated from Lauraceous plants or by Thaliporphine and N-methyllaurotetanine were obtained from
chemical preparation [2], [3], [4], [5], had been reported to exhi- glaucine which, in turn, was prepared by reacting boldine with
Affiliation
1
Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
2
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
Correspondence
M. J. Su, Ph.D. ´ Institute of Pharmacology ´ College of Medicine ´ National Taiwan University ´ No. K1, Sec. 1,
Jen-Ai Rd ´ Taipei ´ Taiwan ´ Republic of China ´ Phone: +886-2-2312-3456 ext. 8317 ´ Fax: +886-2-2397-1403 ´
E-mail: mjsu@ha.mc.ntu.edu.tw
Received October 28, 2005 ´ Accepted June 2, 2006
Bibliography
Planta Med 2006; 72: 1175±1180 ꢀ Georg Thieme Verlag KG Stuttgart ´ New York
DOI 10.1055/s-2006-947199 ´ Published online August 21, 2006
ISSN 0032-0943

N-trimethylanilinium iodide under alkaline conditions [5], a re- Animals
action that also yielded predicentrine due to incomplete O-me- In this study, we used male Wistar rats, weighing 250±300 g, as
thylation with hydrogen bromide [2]. Diacetyl-N-allylsecobol- our laboratory animals. The rats were supplied by the Medical
dine was prepared by O,O-acetylation of N-allylsecoboldine School Animal Center, National Taiwan University. Insulin-de-
(
Ac O/pyridine), which was synthesized from boldine and allyl pendent diabetes mellitus (IDDM) rats were induced according
2
bromide under reflux [3]. N-[2-(2-Methoxyphenoxy)ethyl]glau- to the previous method [8]. In brief, an intravenous injection of
-
1
cine was prepared from norglaucine [5] and (2-methoxyphen- STZ (Sigma Chemical Co.; St. Louis, MO, USA) at 60 mg kg dis-
oxy)acetaldehyde by reductive N-alkylation (NaCNBH , MeOH). solved in 1% citrate buffer into the femoral vein was performed
3
1
±1
All compounds were essentially pure by TLC and H-NMR.
under pentobarbital anesthesia (30.0 mg kg , i.p.) in adult Wis-
tar rats fasted for 72 hours. Rats with plasma glucose concentra-
tions of 20.0 mmol L±1 or greater in addition to polyuria, hyper-
phagia and decrease of body weight were considered as diabetic.
All studies were carried out 2 weeks after the injection of STZ.
Non-insulin dependent diabetes mellitus (NIDDM) rats were in-
duced according to the previous method [9] by which fasted
Wistar rats were intra-peritoneally administered with 200 mg
nicotinamide (Sigma, St. Louis, MO, USA) per kg of body weight.
Fifteen minutes later, animals under light ether anesthesia were
administered with 60 mg streptozotocin (Sigma Chemical Co.)
per kg of body weight via tail vein injection to induce diabetes.
The plasma glucose concentrations of these NIDDM rats were
±1
within 9.0±11.0 mmol L . All studies were performed 4 weeks
after the injection of STZ.
Determination of plasma glucose
Blood samples (0.2 mL) were collected with a chilled syringe
containing 10 IU heparin (Sigma; St. Louis, MO, USA) from the
tail vein of rats under anesthesia with sodium pentobarbital
Fig. 1 The chemical structures of aporphines and aporphine deriva- (30.0 mg/kg, i.p.). Blood samples were then centrifuged at
tives in the present study.
13000 rpm for 3 min, and an aliquot (10 mL) of plasma was added
1
176
Fig. 2 The relationship of the dose and hy-
poglycemic activity of aporphine derivatives
in normal rats. Data are mean  SEM
(n = 8). Asterisks indicate significant differ-
ence as compared with the basal plasma
glucose before drug-treatment (* P < 0.05,
** P < 0.01 by one-way ANOVA with Dun-
nett's post-hoc test). Glibenclamide used
as positive control. Glibenclamide (1.0 mg
±
1
kg ) lowered the plasma glucose from
±
1
±1
1
19.3  5.8mg dL to 82.6 6 2 mg dL in
normal rats (n = 8, P < 0.01).
Chi T-C et al. Antihyperglycemic Effect of¼ Planta Med 2006; 72: 1175±1180

to 1.0 mL of Glucose Kit Reagent (Biosystems S.A.; Barcelona, Measurement of serum insulin concentrations
Spain) and incubated at 37 8C in a water bath (Yamato-BT-25; To- Determination of the serum insulin concentration was per-
kyo, Japan) for 5 min. The concentration of plasma glucose was formed by using an adopted ELISA (Rat Insulin ELISA; Mercodia
then estimated via an analyzer (Biosystems 330; Barcelona, AB; Uppsala, Sweden) [10].
Spain) with samples run in duplicate.
Intravenous glucose tolerance test (IVGTT)
An intravenous glucose tolerance test (IVGTT) was performed ac-
cording to the method described previously [3]. Briefly, the basal
plasma glucose concentration was obtained from samples taken
Fig. 3 The relationship between dose and
hypoglycemic activity of aporphine deriva-
tives in NA-STZ-diabetic rats. Data are
mean  SEM (n = 8). Asterisks indicate sig-
nificant difference as compared with the ba-
sal plasma glucose before drug-treatment
(* P < 0.05, ** P < 0.01 by one-way ANOVA
with Dunnett's post-hoc test). Glibencla-
mide used as positive control. Glibencla-
±
1
mide (1.0 mg kg ) lowered the plasma glu-
±
1
cose from 157.0  4.4 mg dL to 111.0 
±
1
6
.4 mg dL in NA-STZ-diabetic rats (n = 8,
P < 0.05).
1177
Fig. 4 The relationship between dose and
hypoglycemic activity of aporphine deriva-
tives in STZ-diabetic rats. Data are mean 
SEM (n = 8). Asterisks indicate significant
difference as compared with the basal plas-
ma glucose before drug-treatment (* P <
0.05, ** P < 0.01 by one-way ANOVA with
Dunnett's post-hoc test). Insulin (0.5 IU/kg,
i.p.) lowered the plasma glucose from 467.8
±
1
±1

5.8mg dL to 388.0  6.2 mg dL (n = 8,
P < 0.05) used as positive control.
Chi T-C et al. Antihyperglycemic Effect of¼ Planta Med 2006; 72: 1175±1180

from the femoral vein of Wistar rats under anesthesia with so- dium acetate, pH 4.8) containing amyloglucosidase (Sigma).
dium pentobarbital (30.0 mg/kg, i.p.) before the IVGTT. A solu- Samples were then analyzed by measuring glucosyl units using
tion of thaliporphine at 1.0 mg/kg or the same volume of saline the Trinder reaction. The reaction mixture was neutralized with
was injected into the femoral vein of rats. After 30 min, blood 1 N NaOH [13].
samples (0.2 mL) from the femoral vein were drawn and indicat-
ed as 0 min. Then, a glucose dose of 1.0 g/kg was injected through Statistical analysis
the femoral vein of rats. Rats receiving a similar injection of Results of plasma glucose lowering activity were calculated as
saline at the same volume were taken as control. Blood samples percentage decrease of the initial value according to formula:
(
1
0.2 mL) from the tail vein were drawn at 10, 20, 30, 60, 90, and (Gi±Gt)/Gi”100%, where Gi was the initial glucose concentra-
20 min following the glucose injection for the measurement of tion and Gt was the plasma glucose concentration after treat-
the plasma glucose concentrations. Rats were maintained under ment with test agents. Data are represented as the mean  sem
anesthesia by pentobarbital throughout the procedure.
for the number (n) of animals in the group as indicated in the fig-
ures. The results from the experiments are shown as mean 
SEM. Statistical analysis was performed by one-way analysis of
Glycogen assay
About 50 mg of muscle sample was dissolved in 1 N KOH at 70 8C variance (ANOVA) with Dunnett's post-hoc test. P < 0.05 was re-
for 30 min. The dissolved homogenate was neutralized by glacial garded as statistically significant.
acetic acid and incubated overnight in acetate buffer (0.3 M so-
1
178
Fig. 5 Comparison of the plasma glucose lowering activity of thalipor-
phine derivatives at doses of 0.3 mg/kg (i.v.) in (A) normal rats, (B) NA-
STZ-diabetic rats, and (C) STZ-diabetic rats. Values of mean  S.E.M. were
obtained from eight animals in each group. Asterisks indicate significant
difference in plasma glucose lowering activity between vehicle and drug-
treatment groups (n = 8, p < 0.05, by one-way ANOVA with Dunnettºs
post-hoc test). Insulin (0.5 IU/kg, i.v.) was used as positive control and
lowered the plasma glucose by 24.1  0.5% (n = 8) in normal rats, by
2
0.5  3.4% (n = 8) in NA-STZ-diabetic rats, and by 16.9  0.9% (n = 8)
±
1
in STZ-diabetic rats. Glibenclamide (0.3 mg kg , i.v.) was used as positive
control and lowered the plasma glucose by 24.1  4.6% (n = 8) in normal
rats, by 19.1  1.8% (n = 8) in NA-STZ-diabetic rats, and by 1.2  1.4%
(n = 8) in STZ-diabetic rats.
Chi T-C et al. Antihyperglycemic Effect of¼ Planta Med 2006; 72: 1175±1180

Results and Discussions
Table 2 Stimulation of insulin release in NA-STZ-diabetic rats by thali-
We found that intravenous injection of aporphines and apor-
phine derivatives (Fig.1) could lower the plasma glucose concen-
tration in the normal and diabetic rats with different activities.
Thaliporphine significantly decreased the blood glucose at doses
ranging from 0.1 to 1.0 mg/kg in normal rats (Fig. 2), NA-STZ-dia-
betic rats (Fig. 3), and STZ-diabetic rats (Fig. 4). However, higher
doses were required to lower the plasma glucose in normal and
NA-STZ-diabetic rat by N-[2-(2-methoxyphenoxy)ethyl]norglau-
cine [more than 5.0 mg/kg (Figs. 2 and 3)] and by diacetyl-N-al-
lylsecoboldine [more than 3.0 mg/kg (Figs. 2 and 3)]. In STZ-dia-
betic rats, the plasma glucose lowering activities of N-[2-(2-
methoxyphenoxy)ethyl]norglaucine and diacetyl-N-allylseco-
boldine were found at doses higher than 7.0 mg/kg and 5.0 mg/
kg, respectively. Thaliporphine had a more potent plasma glu-
cose lowering activity than N-[2-(2-methoxyphenoxy)ethyl]nor-
glaucine and diacetyl-N-allylsecoboldine in either normal or dia-
betic rats. The plasma glucose lowering activities of thalipor-
phine and other aporphines, including boldine, and glaucine, N-
methyllaurotetanine and predicentrine, were compared with the
effect of insulin (0.5 IU/kg, i.p.) in normal, NA-STZ-diabetic, and
STZ-diabetic rats as shown in Fig. 5. Insulin (0.5 IU/kg, i.p.) de-
creased the plasma glucose by 24.1  0.5% in normal rats, 20.5 
porphine derivatives
Groups
Plasma insulin (mIU mL±1
)
Pre-treatment
post-treatment
NA-STZ rats (NIDDM)
Vehicle
6.8 2.3
6.4  2.3
6.4  0.5
7.2  2.4
6.6  2.3
6.2  2.6
6.7  2.0
7.2  2.5
Thaliporphine (1.0 mg kg±1
)
15.2  3.3*
15.1  2.0*
9.5  1.6
Boldine (1.0 mg kg±1
N-Methyllaurotetanine (1.0 mg kg±1
Predicentrine (1.0 mg kg±1
)
)
)
10.4  1.8
14.6  2.3*
17.8 2.7*
Glaucine (1.0 mg kg±1
)
Glibenclamide (1.0 mg kg±1
)
Values expressed as mean  S.E.mean from eight animals in each group.
P < 0.05 vs. animal treated with vehicle only.
*
Table 3 Stimulation of insulin release in NA-STZ-diabetic rats by apor-
phine derivatives
Plasma insulin (mIU mL±1
Groups
)
Pre-treatment
Post-treatment
3
.4% in NA-STZ-diabetic rats, and 16.9  0.9% in STZ-diabetic
NA-STZ rats (NIDDM)
rats. At the loading dose of 0.3 mg/kg, the order of the averaged
plasma glucose lowering activities were thaliporphine (normal
Vehicle
Thaliporphine (1.0 mg kg±1
6.8 2.3
6.4  2.3
7.1  2.2
7.2  2.5
)
15.2  3.3*
15.8 2.2*
1
9.1  2.2%, NIDDM 19.1  3.5%), glaucine (normal 16.5  2.5%,
NIDDM 17.2  3.1%), boldine (normal 14.6  2.6%, NIDDM 11.6 
.6%), predicentrine (normal 14.0  2.3%, NIDDM 8.7  3.2%) and
N-[2-(2-Methoxyphenoxy)ethyl]
norglucine (7.0 mg kg
±
1
)
Diacetyl-N-allylsecoboldine
6.3  1.816.3  2.5*
6.3  2.0
3
±
1
(
5.0 mg kg
)
N-methyllaurotetanine (normal 5.5  2.2%, NIDDM 3.9  1.5%) in
normal rats and NA-STZ-diabetic rats. However, in STZ-diabetic
rats, the order of the averaged plasma glucose lowering activities
was found to be N-methyllaurotetanine (14.1  2.5% decrease),
predicentrine (11.1  2.8% decrease), thaliporphine (11.7  2.5%
decrease), glaucine (4.7  2.5% decrease) and boldine (3.6  2.1%
decrease). Blood insulin levels in normal and NIDDM rats were
significantly increased by thaliporphine from 7.7  2.2 to 14.9 
Glibenclamide (1.0 mg kg±1
)
18.9  2.7*
Values expressed as mean  S.E. mean from eight animals in each group.
P < 0.05 vs. animal treated with vehicle only.
1179
*
Table 4 Effect of thaliporphine on glycogen synthesis in skeletal mus-
cle from normal and diabetic rats
Group
Glycogen synthesis (mmol/g wet weight )
Table 1 Stimulation of insulin release in normal and diabetic rats by
Normal
thaliporphine
Vehicle
49.3  2.9
59.6  3.2*
71.0  3.2*
Thaliporphine
Insulin
Groups
Plasma insulin (mIU mL±1
)
Pre-treatment
Post-treatment
NA-STZ rats (NIDDM)
Vehicle
45.2  3.5
60.5  3.6*
77.9  1.9*
Normal rats
Thaliporphine
Insulin
Vehicle
Thaliporphine (1.0 mg kg±1
Glibenclamide (1.0 mg kg±1
NA-STZ rats (NIDDM)
Vehicle
Thaliporphine (1.0 mg kg±1
Glibenclamide (1.0 mg kg±1
7.6  1.3
7.7  2.2
8.4  2.5
8.2  1.5
14.9  2.3*
20.2  2.0*
)
STZ-diabetic rats
Vehicle
)
)
)
30.1  2.3
65.6  3.3*
72.7  5.5*
Thaliporphine
Insulin
6.8 2.3
6.4  2.3
6.7  2.0
7.2  2.5
)
15.2  3.3*
19.2  2.7*
Values expressed as mean  S.E.mean from six animals in each group.
*
P < 0.05 vs. control animal treated with vehicle only.
STZ rats (IDDM)
Vehicle
Thaliporphine (1.0 mg kg±1
Glibenclamide (1.0 mg kg±1
3.2  0.3
2.9  1.4
3.7  0.3
3.1  0.5
3.3  0.6
4.2  1.2
)
.3 mIU mL±1 and 6.4  2.3 to 15.2  3.3 mIU mL , respectively
n = 8, P < 0.05) (Table 1). The alteration of plasma insulin levels
±1
2
(
associated with the plasma glucose lowering effect of aporphine
derivatives was mainly examined in NA-STZ-diabetic rats and
Values expressed as mean  S.E.mean from eight animals in each group.
P < 0.05 vs. animals treated with vehicle only.
*
Chi T-C et al. Antihyperglycemic Effect of¼ Planta Med 2006; 72: 1175±1180

Fig. 6 Effect of thaliporphine on plasma glucose in Wistar
normal rats receiving an intravenous glucose tolerance test
(
1
IVGTT). IVGTT was performed by injection of glucose at
±
1
g kg into two groups of normal rats 5 min after intrave-
±
1
nous injection with thaliporphine (1 mg kg , open circles)
or vehicle (solid circles) through the femoral vein. The blood
samples were obtained at the indicated time points before
(0 min) and after i.v. glucose. Asterisks indicate the signifi-
cant difference in plasma glucose between vehicle- and tha-
liporphine-treated groups checked at the same time point
(* P < 0.05, n = 8, by one-way ANOVA with Dunnett's post-
hoc test).
compared with glibenclamide (1.0 mg/kg, i.v.), which is known References
as an insulin secretagogue [11], [12]. At 1.0 mg/kg, thaliporphine,
boldine and glaucine increased plasma insulin to a level compar-
able to that induced by glibenclamide (Table 2). N-[2-(2-Methoxy-
phenoxy)ethyl]norglaucine and diacetyl-N-allylsecoboldine,
which have less potent hypoglycemic activities than thalipor-
phine, have to be administered at higher doses (7.0 mg/kg and
1
2
3
Lopez-Candales A. Metabolic syndrome X: a comprehensive review of
the pathophysiology and recommended therapy. J Med 2001; 32:
2
83±300
Rao NSK, Lee SS. Preparation of thaliporphine and liioferine from glau-
cine by treatment with hydrogen bromide. J Clin Chem Soc 2000; 47:
2
27±30
Lee SS, Lin YJ, Chen MZ, Wu YC, Chen CH. A facile semisynthesis of li-
tebamine, a novel phenanthrene alkaloid, from boldine via a biogene-
tical approach. Tetrahedron Lett 1992; 33: 6309±10
5
.0 mg/kg each) to induce a comparable increase of plasma insu-
lin level (Table 3) and a comparable decrease of plasma glucose
level (Fig. 3) in NA-STZ-diabetic rats. In STZ-diabetic rats, thali-
porphine did not alter the insulin level (Table 1) but significantly
decreased the plasma glucose level (Fig. 4). Table 4 shows that
thaliporphine could increase glycogen synthesis of the soleus
skeletal muscle in either normal or diabetic rats. The effect of
thaliporphine on glucose utilization was further verified with
the IVGTT test, which shows that thaliporphine markedly accel-
erated the glucose uptake and utilization into peripheral tissues
4
5
Guinaudeau H, Leboenf LM, Cave A. Aporphine alkaloids. J Nat Prod
1975; 38: 275
Huang WJ, Chen CH, Singh OV, Lee SL, Lee SS. A facile method for the
synthesis of glaucine and norglaucine from boldine. Synth Commun
2
002; 32: 3681±6
6
7
8
Hung LM, Lee SS, Chen JK, Huang SS, Su MJ. Thaliporphine protects is-
chemic and ischemic-reperfused rat hearts via an NO-dependent
mechanism. Drug Dev Res 2001; 52: 446±53
Su MJ, Chang YM, Chi JF, Lee SS. Thaliporphine, a positive inotropic
agent with a negative chronotropic action. Eur J Pharmacol 1994;
254: 141±50
Forman LJ, Estilow S, Mead J, Vasilenko P. Eight weeks of streptozoto-
cin-induced diabetes induces the effects of cold stress on immuno-
reactive beta-endorphin levels in female rats. Horm Metab Res 1988;
1
180
6
0±90 min after i.v. infusion with glucose (Fig. 6). The result in-
dicates that thaliporphine exerts an antihyperglycemic action
through insulin-dependent and insulin-independent mecha-
nisms. Since boldine and glaucine exerted less potent hypoglyce-
mic action in STZ-diabetic rats, both compounds may lower the
plasma glucose mainly through an insulin-dependent mecha-
nism in NA-STZ-diabetic rats. In contrast, N-methyllaurotetanine
and predicentrine produce their antihyperglycemic effect
through an insulin-independent mechanism. Especially, N-me-
thyllaurotetanine markedly decreased the plasma glucose in
STZ-diabetic rats, but did not affect the plasma glucose in normal
and NA-STZ-diabetic rats. The detailed mechanisms for the dif-
ferences in the antihyperglycemic activities among these apor-
phine and thaliporphine derivatives remain to be determined.
2
0: 555±8
9
Masiello P, Broca C, Gross R, Roye M, Manteghetti M, Hillaire-Buye D et
al. Development of a new model in adult rats administered streptozo-
tocin and nicotinamide. Diabetes 1998; 47: 224±9
10
Jansson L, Carlsson PO, Bodin B, Andersson A, Kallskog O. Neuronal ni-
tric oxide synthase and splanchnic blood flow in anaesthetized rats.
Acta Physiol Scand 2005; 183: 257±62
11
+
Pratz J, Mondot S, Montier F, Cavero I. Effect of K channel activators,
RP52891, cromakalim and diazoxide, on the plasma insulin level, plas-
ma rennin activity and blood pressure in rats. J Pharmacol Exp Ther
1991; 21: 216±22
12
Garrel DR, Picq R, Bajard L, Harfouche M, Tourniaire J. Acute effect of
glyburide on insulin sensitivity in type I diabetic patients. J Clin Endo-
crinol Metab 1987; 65: 896±900
Chou CH, Tsai YL, Hou CW, Lee HH, Chang WH, Lin TW et al. Glycogen
overload by postexercise insulin administration abolished the exer-
cise-induced increase in GLUT4 protein. J Biomed Sci 2005; 12: 991±8
Yu BC, Hung CR, Chen WC, Cheng JT. Antihyperglycemic effect of an-
drographolide in streptozotocin-induced diabetic rats. Planta Med
13
Acknowledgements
14
The present study was supported in part by a grant from the
Technology Development Program for Academia (92-EC-17-A-
2
003; 69: 1075±9
2
0-S1±0010 ).
Chi T-C et al. Antihyperglycemic Effect of¼ Planta Med 2006; 72: 1175±1180