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Molecular and Cellular Pharmacology

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DOI: 10.4255/mcpharmacol.09.22

Voglibose, an Alpha-glucosidase Inhibitor, to Increase

Active Glucagon-like Peptide-1 Levels
Yusuke Moritoh1, Koji Takeuchi1 and Masatoshi Hazama2
Pharmacology Research Laboratories and 2Strategic Research Planning Department,
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan
1

PharmSight on Moritoh Y, et al. Chronic administration of voglibose, an alpha-glucosidase inhibitor,

increases active glucagon-like peptide-1 levels by increasing its secretion and decreasing dipeptidyl
peptidase-4 activity in ob/ob mice. J Pharamacol Exp Ther 2009;329:669-76.
__________________________________________________________________________________________________________________

Abstract
Voglibose is an alpha-glucosidase inhibitor used
for lowering post-prandial blood glucose levels in
patients with diabetes mellitus. Voglibose is known
for its ability to increase glucagon-like peptide-1
(GLP-1) secretion in humans. Our recent study
demonstrated new mechanisms by which
voglibose increases plasma active GLP-1 levels in
diabetic ob/ob mice. As expected, the stimulatory
effects of voglibose on GLP-1 secretion resulted in
increased active GLP-1 levels in plasma in the 1day dosing study. Unexpectedly, chronic but not 1day treatment with voglibose decreased plasma
dipeptidyl peptidase-4 (DPP-4) activity by reducing
its circulating protein levels. We have also revealed
that chronic dosing of voglibose increased
Neurod1 and Glucagon gene expression, and GLP1 content in the lower gut. Active GLP-1 levels in
plasma achieved by chronic treatment with
voglibose were higher than those achieved by 1day treatment. In the present overview, by using
acarbose, another alpha-glucosidase inhibitor with
different selectivity, as a comparator, we
demonstrated that inhibition of alpha-glucosidase
induces a decrease in plasma DPP-4 activity in
ob/ob mice. Notably, compared to acarbose,
voglibose has demonstrated more favorable
effects on DPP-4 activity, GLP-1 secretion and gut
GLP-1 content, when glucose levels were equally
improved, leading to higher plasma active GLP-1
levels. These findings provide new insights into
_______________________

Received 08/10/09; accepted 09/11/09

Correspondence: Yusuke Moritoh, Pharmacology Research
Laboratories, Pharmaceutical Research Division, Takeda
Pharmaceutical Company Limited, 17-85, Jusohonmachi
2-chome, Yodogawa-ku, Osaka 532-8686, Japan. Tel. 816-63006764,
Fax.
81-6-6300-6306.
e-mail:
moritou_yuusuke@takeda.co.jp

Mol Cell Pharmacol 2009;1(4):188-192.

the mechanism underlying the increases in active

GLP-1 circulation by voglibose.
Keywords: Dipeptidyl peptidase-4; Glucagon-like
peptide-1; Voglibose

Introduction
Alpha-glucosidase
inhibitors
delay
the
breakdown of carbohydrates in the small intestine
and thus diminish the postprandial increase of blood
glucose levels in animals and humans (1-3).
Voglibose, acarbose, and miglitol are commonly used
in clinical practice (1-3). One intriguing aspect of the
alpha-glucosidase inhibitor is its ability to both
increase and prolong glucagon-like peptide-1 (GLP-1)
secretion in normal individuals and patients with
type 2 diabetes (4-10). GLP-1 (7-36) amide and GLP1 (7-37), both of which are active forms of GLP-1 and
have similar activity, are secreted from gut L-cells
(11). GLP-1 is now known to be involved in the
regulation of insulin secretion (12), glucagon
secretion (13), beta-cell turn-over (14), and extrapancreatic tissue functions (15). The active forms of
GLP-1 are rapidly broken down by the enzyme
dipeptidyl peptidase-4 (DPP-4) (16), leading to the
generation of the inactive forms, GLP-1 (9-36) amide
and GLP-1 (9-37) (16).
Preclinical
and
clinical
studies
have
demonstrated that activating GLP-1 signals by
administration of GLP-1 receptor agonists or DPP-4
inhibitors can improve diabetes in animals and
humans (17-20). Alpha-glucosidase inhibitors delay
carbohydrate absorption, which results in an
increase in sugar absorption in the lower gut (21).
Taking into account that sugar absorption plays a
critical role on GLP-1 secretion (22, 23) and that

188

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Voglibose and Glucagon-like Peptide-1 Levels

GLP-1 producing cells are abundant in the lower gut

(24, 25), delayed carbohydrate absorption is
considered to be an acceptable contributing factor
for stimulating GLP-1 secretion by alphaglucosidase inhibition. However the mechanism by
which alpha-glucosidase inhibitors increase GLP-1
secretion is poorly understood. In addition, limited
data is available in regards to the effects of alphaglucosidase inhibition on active forms of GLP-1
levels.

Results and Discussion

We recently found that voglibose has previouslyunreported mechanisms by which it increases active
GLP-1 levels in diabetic ob/ob mice (24). When
administered in the diet to ob/ob mice for 1-day,
voglibose at doses of 0.001% and 0.005% showed no
effect on plasma DPP-4 activity as expected (24).
This is consistent with the fact that voglibose had no
effect on DPP-4 activity in vitro (24). However, 1-day
treatment of voglibose resulted in increase in
plasma active GLP-1 levels (0.001% voglibose,
8.02.0 pM; 0.005% voglibose, 16.67.8 pM; vehicle,
4.93.0 pM) in ob/ob mice (24). Taken together,
these results indicate that a stimulatory effect on
GLP-1 secretion but not a direct inhibition of the
DPP-4 enzyme may contribute to the increase in
active GLP-1 levels by voglibose.
Interestingly when administered chronically (3-4
weeks), voglibose showed an unexpected effect on
plasma DPP-4 profiles. Chronic administration of
voglibose resulted in a 40-51% decrease in plasma
DPP-4 activity (24). The measurement of plasma
DPP-4 protein concentration revealed that voglibose
decreased its plasma concentrations by 31-43% (24).
These results indicated that it was the ability of
voglibose to decrease the circulating DPP-4 protein
that resulted in the corresponding decrease in
plasma DPP-4 activity. The 40-51% decrease in
plasma DPP-4 activity, which was observed in
voglibose-treated ob/ob mice, was likely to be
sufficient to increase plasma active GLP-1 levels. In
fact, around 30% DPP-4 inhibition by the DPP-4
inhibitor alogliptin significantly increased plasma
active GLP-1 levels in ob/ob mice (20). As expected,
the chronic treatment of voglibose produced higher
levels of plasma active GLP-1 (11.43.9 and 24.46.7
pM by 0.001% and 0.005% voglibose, respectively.
6.01.4 pM by vehicle) compared with the 1-day
treatment with voglibose (8.02.0 and 16.67.8 pM
by 0.001% and 0.005% voglibose, respectively.
4.93.0 pM by vehicle) (24). A similar treatment

Mol Cell Pharmacol 2009;1(4):188-192.

with 0.001% and 0.005% voglibose for 3-4 weeks had

no effects on plasma DPP-4 activity in normal
control mice, which showed lower plasma DPP-4
activity compared with ob/ob mice, indicating that
the voglibose-induced decrease in plasma DPP-4
activity may be specific to diabetic ob/ob mice.
Administration of pioglitazone (0.03% in the diet), a
peroxisome proliferator-activated receptor gamma
agonist, resulted in significantly improved glucose
levels that were comparable to the glucose levels
achieved by voglibose (0.005% in the diet) (24).
However, pioglitazone was unable to alter the DPP-4
concentration and activity (24), indicating that
improving glucose control is not the primary means
by which plasma DPP-4 concentration and activity
are altered in ob/ob mice. Thus, the mechanism by
which
voglibose
decreases
plasma
DPP-4
concentration remains to be determined.
Chronic treatment of voglibose also had an
impact on enteroendocrine cells, which may
contribute to the observed increase in plasma active
GLP-1 levels (24). Once again, it was unexpectedly
observed that chronic treatment with voglibose
resulted in an increase in active GLP-1 content in
the lower intestine (1.5- to 1.6-fold increase) and
colon (1.4- to 1.6-fold increase) (24). The increased
active GLP-1 content in the colon was positively
correlated with an increase in gut gene expression
levels of Neurod1 (1.3- to 1.4-fold increase) and
Glucagon (2.6- to 3.1-fold increase) (24). The
increased gene expression of Neurod1, which is
known to be an essential regulator for
enteroendocrine cell differentiation (26), suggests
that voglibose may induce differentiation of
enteroendocrine cells. A recent study has shown that
oligofructose, a dietary nondigestible carbohydrate,
promoted L-cell differentiation as evidenced by the
increased number of L-cells, elevated Glucagon gene
expression, and a doubling of GLP-1 content in the
proximal colon in rats (27). Thus, voglibosegenerated undigested carbohydrates may play a role
in the increase in gene expression of Neurod1 and
Glucagon, and GLP-1 content in the lower gut.
Further analysis into the complete mechanism is
still warranted.
To assess whether our observations are a class
effect by alpha-glucosidase inhibitors, the effects of
acarbose, another alpha-glucosidase inhibitor, were
compared with those of voglibose in ob/ob mice. The
doses for acarbose were 0.05% and 0.5% in the diet,
which exhibited comparable efficacy at lowering
glucose levels to that of 0.001% and 0.005% of
voglibose in ob/ob mice. Although it was weaker

Voglibose and Glucagon-like Peptide-1 Levels

190

Voglibose
HO

OH
OH

HO

N
H

HO

OH

z No direct inhibition
on DPP-4

OH

Short-term (1 day)

Long-term

Plasma DPP-4 activity

Plasma DPP-4 protein

GLP-1 secretion

Gut GLP-1 content*

Gut Neurod1 and Glucagon gene expression

Plasma active GLP-1

Figure 1. Schematic diagram of effects of short-term or long-term treatment with voglibose in ob/ob mice. Short-term (1-day) treatment
with voglibose had no effect on plasma DPP-4 activity. However, 1-day treatment with voglibose increased GLP-1 secretion, leading to increase
in plasma active GLP-1 levels. Chronic administration of voglibose decreased plasma DPP-4 activity by reducing plasma DPP-4 protein levels.
In addition to enhancing GLP-1 secretion, chronic treatment with voglibose increased GLP-1 content in the lower gut, which was positively
correlated with an increase in gut gene expression levels of Neurod1 and Glucagon. These observation leads to higher plasma active GLP-1
levels in ob/ob mice. * One-day effect of voglibose on gut GLP-1 content was not tested.

than the effect of voglibose, chronic treatment with

acarbose also dose dependently decreased plasma
DPP-4 concentration (-27 to -37%) and activity (-27
to -43%) in ob/ob mice. In addition, in vitro DPP-4
assay revealed no direct inhibition of acarbose on
DPP-4 activity. Taken together with the voglibose
results, alpha-glucosidase inhibition may result in
decreased plasma DPP-4 concentration and activity
in ob/ob mice by some common mechanisms.

A notable difference was, however, observed in

the plasma active GLP-1 levels between voglibose
and acarbose after 1-day and chronic treatment.
Acarbose increased plasma active GLP-1 levels after
1-day treatment with 0.05% and 0.5% doses while
this regimen had no effect on plasma DPP-4 activity
as expected. The active GLP-1 levels produced by
acarbose (6.51.3 pM by 0.05% acarbose and 7.81.0
pM by 0.5% acarbose) were unexpectedly lower

Mol Cell Pharmacol 2009;1(4):188-192.

191

Voglibose and Glucagon-like Peptide-1 Levels

compared to voglibose (0.001% voglibose, 8.02.0 pM;

0.005% voglibose, 16.67.8 pM; vehicle, 4.93.0 pM).
When administered chronically, low-dose acarbose
(0.05%) administration produced 9.06.1 pM of
plasma active GLP-1 levels (6.01.4 pM by vehicle).
While high dose administration of acarbose (0.5% in
the diet) resulted in superior glucose control
compared with the lower dose, it still resulted in
only 9.05.4 pM of plasma active GLP-1 levels.
These results indicate that voglibose may have a
more favorable effect on increasing active GLP-1
levels compared with acarbose. When total amide
GLP-1 levels (intact plus N-terminal-degraded
amide GLP-1) were measured, 0.001% and 0.005%
voglibose induced 1.3- and 1.5-fold increases in
plasma amide GLP-1 levels, respectively, compared
with vehicle alone (24). The administration of 0.05%
acarbose increased amide GLP-1 levels by 1.2-fold,
whereas 0.5% acarbose induced only 1.1-fold
increase in amide GLP-1 levels, compared with
vehicle alone. Consistently, in normal control mice,
administration of 0.5% acarbose decreased amide
GLP-1 levels by 46%, compared with vehicle-treated
normal mice. These results indicate that voglibose
may have a stronger effect on GLP-1 secretion
compared with acarbose in ob/ob mice.
We speculate that the differences in enzymatic
specificities of voglibose and acarbose against
several types of glucosidase enzymes (2), leading to
the
different
composition
of
undigested
carbohydrates in the gut, may be a possible reason
for the variability in GLP-1 secretion. When animal
feces were compared, voglibose-treatment produced
black feces, similar to that of vehicle treated mice,
although somewhat smaller. The feces of acarbosetreated ob/ob mice were brown in color and little
larger than vehicle-treated mice. Acarbose inhibits
alpha-amylase thereby inhibiting the degradation of
chow-derived starch, whereas voglibose has a much
weaker effect on alpha-amylase when given in a
pharmacologically effective range (2). Thus
undigested starch is likely to be included in the
brown feces in acarbose-treated mice. In a previous
report, complex carbohydrates, like boiled brown
rice or barley, were unable to stimulate GLP-1
secretion in contrast to a glucose meal, which clearly
enhanced GLP-1 secretion in healthy human
subjects (28). By contrast, sucrose and maltose, both
of which are disaccharides, had stimulatory effects
on GLP-1 secretion in the ileal loops of
anaesthetized dogs (29). Thus, the lack of inhibitory
activity of voglibose on alpha-amylase activity,
which seems to generate more disaccharides in the

Mol Cell Pharmacol 2009;1(4):188-192.

lower gut than acarbose, may contribute to the

increase in GLP-1 secretion in ob/ob mice.
In addition, unlike voglibose, acarbose was
unable to increase active GLP-1 content in the
lower-intestine in our ob/ob mouse study (vehicle,
10628; 0.05% acarbose, 11418; 0.5% acarbose,
11612; 0.001% voglibose, 15821; 0.005% voglibose,
16631 pmol/g gut weight). Furthermore, our study
demonstrated that colon active GLP-1 content in
acarbose-treated mice was lower compared to
voglibose-treated ob/ob mice (vehicle, 19411; 0.05%
acarbose, 24646; 0.5% acarbose, 25638; 0.001%
voglibose, 27945; 0.005% voglibose, 30725 pmol/g
gut weight). This corresponded with the results that
suggested that acarbose had lower efficacy at
increasing Glucagon gene expression in the colon
(1.8- to 2.3-fold increase by acarbose, and 2.6- to 3.1fold increase by voglibose). Taken together, these
results suggest that the ability of voglibose to
increase GLP-1 secretion and gut GLP-1 content
accompanied with decreasing plasma DPP-4 activity
may explain the reason why voglibose exhibits a
more favorable effect on increasing plasma active
GLP-1 levels compared to acarbose in ob/ob mice
(Figure 1).
In conclusion, our studies showed that the acute
and chronic effects of voglibose on DPP-4 differ;
chronic but not 1-day administration of voglibose
decreased plasma DPP-4 activity by reducing its
circulating levels in plasma. In addition, chronic
treatment with voglibose increased GLP-1 secretion
and elevated GLP-1 content in the lower gut.
Collectively, chronic administration of voglibose
resulted in an increase in plasma active GLP-1
levels, which were higher compared with those
achieved by acarbose. These observations suggest
that voglibose may have additional utility in the
management of type 2 diabetes.

Acknowledgements
The authors would like to thank Michelle Kujawski for
writing support and comments on the manuscript.

Conflicts of Interest
No potential conflicts of interest to disclose.

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