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Biosci. Biotechnol. Biochem., 66 (3), 689–692, 2002
Luteolin, a Flavone, Does Not Suppress Postprandial Glucose AbsorptionThrough an Inhibition of a-Glucosidase Action
Toshiro MATSUI,† Mio KOBAYASHI, Sachiko HAYASHIDA, and Kiyoshi MATSUMOTO
Department of Bioscience and Biotechnology, Division of Bioresource and Bioenvironmental Sciences,Faculty of Agriculture, Graduate School, Kyushu University, 6-10-1 Hakozaki, Higashi-ku,Fukuoka 812-8581, Japan
Received September 25, 2001; Accepted October 26, 2001
In order to clarify the postprandial glucose suppres-
on the antioxidant,7) antimutagenic,8) and antihyper-
sion via a-glucosidase (AGH) inhibitory action by
tensive eŠects9) of ‰avonoids have been done. In
natural compounds, ‰avonoids were examined in this
addition, their alternative physiological function of
study. Among the ‰avonoids (luteolin, kaempferol,
suppression of glucose absorption at the small intes-
chrysin, and galangin), luteolin showed the potent mal-
tine has been also reported.1,10) Among the ‰avo-
tase inhibitory activity with the IC50 of 2.3 mM, while
noids, tea polyphenols such as catechins have been
less inhibitions were observed against sucrase. In addi-
found to inhibit AGH activity2) and glucose trans-
tion, the eŠects of maltase inhibition by ‰avonoids were
port.4) These ˆndings led us to make a further investi-
observed in the descending order of potency of
gation of ‰avonoids commonly present in plant and
luteolinÀkaempferolÀchrysinÀgalangin. Apparently,
food products for any anti-hyperglycemic eŠect. In
the AGH inhibition power greatly increased with the
this paper, we have examined the in vitro and in vivo
replacement of hydroxyl groups at 3? and 4?-position of
AGH inhibition abilities of naturally occurring ‰avo-
the B-ring. However, the inhibitory power of luteolin
noids, i.e., luteolin and chrysin as ‰avones, kaem-
was poorer than a therapeutic drug (acarbose: IC50;
430 nM). As a result of a single oral administration of
a-Glucosidase (AGH, EC 3.2.1.20, 2.2 U Wmg)
maltose or sucrose (2 g Wkg) in SD rats, no signiˆcant
from rat intestinal acetone powder was purchased
change in blood glucose level with the doses of 100 and
from Sigma Chemical Co. (St. Louis, MO, U.S.A.).
200 mg Wkg of luteolin was observed. These ˆndings
All of the ‰avonoids used in this study were
strongly suggested that luteolin given at less than
purchased from Wako Pure Chemical Institute, Co.
200 mg Wkg did not possess the ability to suppress the
(Osaka, Japan). The AGH inhibitory assay was done
glucose production from carbohydrates through the
according to our proposed immobilized AGH
inhibition of AGH action in the gut.
(i AGH) assay system.11) The immobilization of AGHpartially puriˆed from rat acetone powder on CNBr-
a-glucosidase; ‰avonoids; phenolic acids;
activated Sepharose 4B (Pharmacia Biotech AB,
Upsala, Sweden) were described in detail in our
previous paper.11) In the i AGH assay, the i AGH sup-port (10 mg wet gel, 4.1 mU Wmg wet gel) was taken in
To assess the prophylaxis of noninsulin-dependent
an end-capped ASSIST Mini-column with 45–90 mm
diabetes mellitus (NIDDM) disease by dietary food
of polyethylene ˆlter (CC-07, 5 ml, ASSIST, Tokyo,
intake, many natural resources have been examined
Japan), and the assay was started after adding 100 ml
with respect to the exertion of an a-glucosidase
of inhibitor solution and 900 ml of the model intesti-
(AGH, EC 3.2.1.20) or a-amylase inhibitory activi-
nal ‰uid containing maltose (10 mM) or sucrose
ty.1,2) The retardation of membrane-bound AGH
(45 mM) to it. After incubation with a rotating culti-
reaction3) and Wor inhibition of passive glucose trans-
vator (4 rpm, RT-5, TAITEC, Saitama, Japan) at
port4) would successfully ‰atten the postprandial
C for 30 min (maltase assay) or 60 min (sucrase
blood glucose excursions or reduce hyperglycemia. In
assay), the reaction was stopped by ˆltration of the
our studies on AGH inhibition by food compo-
solution in the column. Maltase activity was meas-
nents,5,6) acylated anthocyanins were found to cause
ured by the liberated glucose from maltose in the
the beneˆt of suppression of glucose production
ˆltrate by Glucose-Test Wako (Wako Pure Chemical
from dietary carbohydrates. To date, many studies
Institute, Co., Osaka, Japan). When sucrose was
† To whom correspondence should be addressed. Tel: 81-92-642-3012; Fax: 81-92-642-3012; E-mail: tmatsui@agr.kyushu-u.ac.jp
Abbreviations : AGH, a-glucosidase; noninsulin-dependent diabetes mellitus, NIDDM; BGL, blood glucose level
used as a substrate, F-kit Glucose (Roche Diagnos-tics, Co., Tokyo, Japan) was used for measuring su-crase activity, since sucrose itself interfered with theglucose measurement by the Glucose-Test Wako. The ‰avonoids assayed in this system were dissolvedin dimethylsulfoxide (DMSO). One unit of maltaseor sucrase activity was deˆned as the amount of en-zyme that hydrolyzed 1 mmol of substrate per min un-der the above assay conditions. The concentration ofAGH inhibitor required for inhibiting 50z of theAGH activity under these assay conditions wasdeˆned as the IC50 value. The animal experiments inSD rat were done as follows. Male 6-week-oldSprague-Dawley rats (SPF WVAF Crj:SD, Charles
River Japan, Kanagawa) were fed a laboratory diet(CE-2, Clea Japan, Tokyo) and given water ad libi-tum. All rats were housed for 1 week at 21±19
AGH Inhibitory Activity of Flavonoids Estimated by the
55±5z humidity under controlled lighting from
One mg of ‰avonoid per 1 ml of DMSO solution was put
8:30 to 20:30. Before the experiment, food was
through the immobilized AGH assay. Maltase (open bars) and
withheld for 16 h. A single oral administration of a
sucrase (closed bars) inhibitory activities were evaluated by us-
‰avonoid sample via a stomach sonde was done in
ing maltose (10 mM) and sucrose (45 mM) as substrates at 379C.
SD rats (n=4, 238.7±4.3 g) with either a dosage of100 or 200 mg Wkg sample. The sample dissolved in
1 ml of DMSO was orally administered. After 5 min,
of 23.2z: the IC50 value for luteolin, 2.3 mM; kaem-
2 g Wkg of substrate (maltose or sucrose) dissolved in
pferol, 17.3 mM. However, the i AGH (maltase) inhi-
1 ml of deionized water was administered to each rat.
bition power of four ‰avonoids was much less than
Control rats were administered with the same volume
those of acarbose (IC50; 430 nM) and voglibose (IC50;
of substrate solution without ‰avonoid. At each sam-
5.5 nM) as a therapeutic AGH inhibitor.11)
ple time to 120 min, about 20 ml of blood sample was
On the basis of the result that luteolin had the
collected from the tail vein, then immediately the
strongest i AGH (maltase) inhibitory activity among
blood glucose level (BGL) was measured by a dispos-
the four ‰avonoids (Fig. 1), changes in the BGL after
able glucose sensor (Glutest Pro, Sanwa Chemical
the administration of luteolin with maltose were exa-
Research, Co., Tokyo, Japan). Each result for the
mined in SD rats. Acarbose with the dose of 3 mg Wkg
administration study is expressed as the mean of
was used in this study as a positive control. As seen in
BGL (mg Wdl)±SEM (z). Statistical diŠerences of
Fig. 2, no dose-dependent and no signiˆcant change
BGL in control (without ‰avonoid) and ‰avonoid
in the BGL with the doses of 100 and 200 mg Wkg of
groups at each administration time were evaluated by
luteolin was observed against control SD rats ad-
the unpaired Student's t-test. P valuesº0.05 were
ministered maltose during the experimental period of
considered to be signiˆcant. The care and treatment
120 min. The BGL of 200 mg-dose of luteolin at 0 h
of the experimental rats conformed to Kyushu
seems to be lower than other groups, but there was
University guidelines for the ethical treatment of
no signiˆcant diŠerence among the groups. On the
other hand, acarbose showed a marked BGL reduc-
Figure 1 shows the i AGH inhibition behavior of
tion of 52.3 mg Wdl 30 min after administration
four ‰avonoids, i.e., luteolin, kaempferol, chrysin,
( Pº0.01 vs. control). Thus, to elicit the postprandial
and galangin at the ˆnal concentration of 0.1 mg Wml-
BGL reduction by luteolin, a dosage of more than
DMSO. For maltase inhibition, the eŠects were
200 mg Wkg (À0.17 molWrat body) would be needed.
observed in the descending order of potency of
This strongly supported the ˆnding that luteolin was
luteolinÀkaempferolÀchrysinÀgalangin.
a poor i AGH inhibitor with the IC50 of 2.3 mM
ently, this suggested that the i AGH inhibition power
against maltase (Fig. 1). Though data are not shown,
was greatly aŠected by the replacement of hydroxyl
the in vivo experiment of sucrose administration in
groups at 3?- and 4?-position of the B-ring, not by the
SD rats also showed no eŠect (BGL30min,control;
diŠerence in the aglycone structure of ‰avone and
152.7±1.5 mg Wdl, BGL30min,luteolin; 154.0±2.0).
‰avonol. Sucrase inhibitions showed the same
It has already been proved that the catechins typi-
descending order as maltase inhibition, but their
cal in tea polyphenols elicited potent sucrase inhibito-
power was lower than maltase inhibition. Thus, the
ry activity, in particular esteriˆed catechins such as
‰avonoids used in this study inhibited maltase in
epigallocatechin gallate.2) Matsumoto et al.12) demon-
preference to sucrase. Among them, luteolin was the
strated the favorable BGL reduction at À10 mg dose
strongest maltase inhibitor with the inhibitory ratio
of catechin Wrat, following a signiˆcant suppression
1 W5400 lower than that of acarbose (Fig. 1).
Although their experimental results might be correctwithin the conventional baker's yeast AGH inhibito-ry assay system, the fact that the BGL in SD ratadministered luteolin was not suppressed (Fig. 2)supported the validity of the in vitro results from ourproposed i AGH assay system (Fig. 1).
In conclusion, it was found that luteolin did not
possess an in vivo suppression eŠect on glucoseproduction from carbohydrates through AGH inhi-bition in the gut.
Part of this work was supported by a Grand-in Aid
for Scientiˆc Research on Priority Areas from the
EŠects of Luteolin on Blood Glucose Levels after Single
Ministry of Education, Science, and Culture of
Oral Administration of 2 g Wkg Maltose in SD Rats.
One ml of 100 (#) and 200 mg Wkg ($) luteolin was given to
male 7-week-old SD rats. Acarbose () with the dose of3 mg Wkg was used as a positive control. After 5 min, 1 ml of
2 g Wkg of maltose solution was administered to each rat. Con-
trol rats () were administered the same volume of substrate so-
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Dottorato in Ingegneria Industriale Elenco Pubblicazioni Dottorandi - anno 2011 • Frau A. , Baratti R., Alvarez J., “Composition estimation of a six-component distillation column with temperature measurements”, in Advanced Control of Chemical Processes, Vol. 7, (Eds. E. Engell and Y. Arkun), (ISBN: 978-3-902661-54-8) (doi: 10.3182/20090712-4-TR-2008.00068), p. 447-452. • S. Car
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