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Journal of Functional Foods 18 (2015) 117128

Available online at

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Extracts and flavonoids from onion inhibit the

intestinal sodium-coupled glucose transporter 1
(SGLT1) in vitro but show no anti-hyperglycaemic
effects in vivo in normoglycaemic mice and
human volunteers
Christine Schulze a, Adina Bangert a, Bettina Schwanck b,
Henning Vollert c, Wolfgang Blaschek b, Hannelore Daniel a,*

ZIEL Research Center of Nutrition and Food Sciences, Department of Biochemistry, Technical Universtiy of
Munich, Gregor-Mendel-Str. 2, Freising 85350, Germany
Pharmaceutical Institute, Department of Pharmaceutical Biology, Christian-Albrechts-University of Kiel,
Gutenbergstrasse 76, Kiel 24118, Germany
BioActive Food GmbH (HV), Am Ihlsee 36a, Bad Segeberg 23795, Germany




Article history:

Extracts and flavonoids from onion are described as having anti-diabetic activities. We here

Received 29 November 2014

demonstrate that an onion extract and individual flavonoids thereof diminish glucose uptake

Received in revised form 15 June

mediated by the intestinal glucose transporter SGLT1 when expressed in oocytes and studied


in mouse intestinal segments in vitro. Strongest inhibition of SGLT1 was observed for quercetin-

Accepted 16 June 2015

4-O-glucoside (Q4glc) in oocytes but with only moderate inhibition in jejunal segments of

Available online

mice. An oral glucose tolerance test (OGTT) performed in obese/hyperglycaemic mice revealed that the onion extract to reduce blood glucose increases significantly. However, an


OGTT performed in healthy volunteers after administration of the onion extract failed to


reveal an effect on glucose and insulin levels. Despite its capability to inhibit intestinal glucose


uptake via SGLT1 in vitro and in mice in vivo, the onion extract did not alter blood glucose


levels during an OGTT in human volunteers and this may predominantly be due to a dosing

Type 2 diabetes



2015 Elsevier Ltd. All rights reserved.


* Corresponding author. Molecular Nutrition Unit, Technical University Munich, Gregor-Mendel-Strasse 2, 85350 Freising-Weihenstephan,
Germany. Tel.: +49 8161713401; fax: +49 8161713999.
E-mail address: (H. Daniel).
Abbreviations: ANOVA, analysis of variances; iAUC, incremental area under the curve; GLUT2, glucose transporter 2; IGT, impaired glucose
tolerance; BW, body weight; Q4glc, quercetin-4-O-glucoside; Q3,4diglc, quercetin-3,4-O-diglucoside; HPLCDAD/ESIMS2, high performance liquid chromatographyelectrospray ionization tandem mass spectrometry; OGTT, oral glucose tolerance test; SGLT1, sodiumdependent glucose co-transporter 1; T2DM, type 2 diabetes mellitus
1756-4646/ 2015 Elsevier Ltd. All rights reserved.



Journal of Functional Foods 18 (2015) 117128


Diabetes mellitus type 2 (T2DM) is one of the major world health

problems and has reached epidemic proportions. There is cogent
evidence that postprandial hyperglycaemia plays an important role in the development of T2DM and in associated
cardiovascular diseases (Balkau, Bertrais, Ducimetiere, &
Eschwege, 1999; Bonora, 2002; OKeefe & Bell, 2007; Qiao et al.,
2000; Song et al., 2002) by causing oxidative stress, inflammation and endothelial dysfunction (Blaak et al., 2012; Brownlee,
2005; Green, Brand, & Murphy, 2004). Postprandial hyperglycaemia has thus been suggested as an important process
for the treatment of diabetes and the prevention of diabetesrelated complications. Inhibitors of -glucosidase (e.g. acarbose)
that delay or suppress the intestinal release of glucose from
complex carbohydrates were shown to reduce postprandial
hyperglycaemia and were proven to decrease the risk of cardiovascular events in patients with impaired glucose tolerance
(IGT) and T2DM (Chiasson et al., 2002, 2003). However, these
inhibitors cannot affect blood glucose increases when food and
particularly beverages with high amounts of free glucose are
consumed. Targeting intestinal glucose absorption by inhibition of the transport proteins in epithelial cells is thus a
rationale to reduce hyperglycaemia.
The intestinal uptake of glucose from dietary carbohydrates is almost exclusively mediated by the rheogenic
symporter SGLT1 that mediates uphill transport of glucose and
galactose. Glucose efflux across the basolateral site into circulation occurs mainly via the facilitated glucose transporter
2 (GLUT2) along the established concentration gradient. As
SGLT1 becomes saturated at glucose concentrations far below
the luminal concentrations reached after a sugar-rich meal, it
has been proposed that GLUT2 is recruited from intracellular
vesicles into the apical membrane (Kellett, Brot-Laroche, Mace,
& Leturque, 2008) to further increase glucose uptake by passive
There is a growing interest in dietary compounds that may
help to manage glucose homeostasis and replace conventional diabetes drugs which have unwanted side effects
(Tschope et al., 2013). Epidemiological studies revealed that a
high intake of fruits and vegetables including onions was associated with a lower incidence of cardiovascular diseases
(Knekt, Jarvinen, Reunanen, & Maatela, 1996). Onions are characterized by a high amount of flavonoids with Q4glc, quercetin3,4-diglucoside (Q3,4diglc) and its aglycone quercetin as the
major compounds (Lombard, Geoffriau, & Peffley, 2002; Yoo, Lee,
& Patil, 2010).
Various health-promoting effects of onions have been described based on antioxidant (Albishi, John, Al-Khalifa, &
Shahidi, 2013a, 2013b; Alpsoy et al. 2013; Campos et al., 2003;
Helen, Krishnakumar, Vijayammal, & Augusti, 2000), antiinflammatory (Dorsch, Schneider, Bayer, Breu, & Wagner, 1990;
Wang, Huang, Lu, & Chang, 2013) and anti-obesity activities
(Matsunaga et al., 2014). Several studies have also reported antidiabetic activity of onion when ingested as oils or extracts (Jung,
Lim, Moon, Kim, & Kwon, 2011; Matsunaga et al., 2014; Taj Eldin,
Ahmed, & Elwahab, 2010). One mechanism described in literature is the inhibition of carbohydrate-digestive enzymes by
onion-extracts and flavonoids thereof that is accompanied by

a diminished increase in postprandial blood glucose levels (Kang

et al., 2010; Kim, Jo, Kwon, & Hwang, 2011). In the present study
we assessed whether onion extract and major flavonoids
derived from onion can reduce intestinal glucose absorption
by inhibition of SGLT1 and GLUT2 in the intestine.


Materials and methods


Standards, reagents and plant material

Quercetin and quercetin-4-O-glucoside were purchased from

PhytoLab (Vestenbergsgreuth, Germany), Quercetin-3,4diglucoside from Extrasynthese SAS (Genay, France).
Radiolabelled 2-deoxy-D-glucose (2-DG) and methyl--Dglucopyranoside (-MDG) were purchased from Hartmann
Analytic GmbH (Braunschweig, Germany). All remaining chemicals were obtained from Sigma Aldrich (Hamburg, Germany).
Stock solutions of flavonoids were prepared in dimethyl sulfoxide (DMSO) with a concentration of 100 mM. The onion extract
(Allium cepa L.) was obtained from the Wellness & Health Care
GmbH (wHc-Service GmbH, Neuenbrg, Germany) and dissolved in DMSO or 70% methanol for HPLC-analysis. The final
concentration of DMSO in all solutions used in the in vitro
studies was not higher than 1% (v/v) proven not to affect transport currents or -MDG uptake into oocytes or murine intestinal

Characterization and quantification of onion
polyphenols by HPLCDAD and HPLCESIMS2
One milligram of dried onion extract was dissolved in 1 mL of
methanol (70%) and sonicated for 30 min. The extract was centrifuged (10 min, 20,200 g at 20 C) before separation and
analysis was performed by HPLCDAD (waters e2695 separation module, Alliance; PDA waters 2998). Chromatographic
separation was performed on an analytical Phenonenex RPC18 column (Aqua 5 m, 125 , 250 4.6 mm) with a security
guard cartridge (AQ C18, 4.0 3.0 mm) at 30 C. Solvent A consisted of water/trifluoroacetic acid (TFA) (99.99/0.01, v/v) and
solvent B of acetonitrile (ACN)/TFA (99.99/0.01, v/v); gradient
elution: 010 min 100% A, 1040 min down to 50% A, 40
50 min down to 0% A, 5051 min up to 100% A, 5160 min 100%
A; flow rate 1 mL/min. Identification and quantification were
performed by co-chromatography of external standards. Calibration curves were used in the range of 5300 g/mL. UV
spectra for flavonols and the aglycones were recorded at 330 nm
and 360 nm, respectively.
Flavonoids were characterized by HPLCESIMS2 using a
Bruker Esquire-LC with an ESI interface in a negative ionization modus (Bruker Daltonics, USA). Fragmentation was carried
out in the automatic mode by which the most abundant ions
were fragmented (MS2). HPLC conditions were performed as described earlier, but TFA was replaced by 0.1% acetic acid (Agilent
1100 series HPLC system, Agilent 1100 UV/VIS, Agilent Technologies, Germany). For determination of the molecular weight
of compounds, a scan from m/z 50 to 1600 was used. Nitrogen was used as nebulizing gas at pressure of 40 psi and the
flow rate was adjusted to 1 mL/min. The temperature and the

Journal of Functional Foods 18 (2015) 117128

voltage of the capillary were maintained at 350 C and 3.5 kV,

respectively. Collision-induced fragmentation experiments were
performed in ion trap using helium as collision gas. For obtaining MS average spectra, the number of MS repetitions was
set at 2. The total flavonoid content was determined by acidic
hydrolysis according to Ph. Eur.6.0/1174. Plant extracts were refluxed for 30 min at 100 C in 0.7 M HCl and 100% acetone.
Complexation with AlCl3 was performed after extraction of
aglyca with ethylacetate. Since complexation requires the
ketone groups in position 4 of the C ring and additionally the
hydroxy group in position 3 (flavonols) or position 5 (flavones), only flavonols and flavones have been included in
analysis. Other constituents such as dihydroflavonols
that could contribute to the total amount of flavonoids
could not be quantified by HPLC in the present work. But
dihydroflavonol levels in onions are usually very low. The total
flavonoid content was expressed in milligram as hyperoside


Isolation and preparation of Xenopus laevis oocytes

Guidance on the housing and care of the Xenopus laevis as well

as oocyte isolation and preparation were approved by the state
ethics commission (Reference no. 55.2-1-54-2532.3-64-11) and
were carried out as described previously (Kottra & Daniel, 2007).
Isolated oocytes of stage V/VI were injected with 23 nL of the
human SGLT1 (hSGLT1) cRNA (1 g/L) or with 18 nL of the
human GLUT2 (hGLUT2) cRNA 34 days prior to the uptake

Electrophysiological studies in oocytes
expressing hSGLT1
The experimental procedure was carried out as described previously by Schulze et al. (2014). Apparent kinetic constants Km
and Imax (nA) and IC50 values were determined as described
by Kottra and Daniel (2007). Dixon-type experiments were
carried out at 60 mV.

Uptake experiments in oocytes expressing hGLUT2
with radio-labeled glucose
Since the glucose transporter 2 (GLUT2) is a non-electrogenic
transporter, all studies on hGLUT2 expressed in oocytes were
performed using 3H-labelled 2-desoxy-D-glucose (2-DG), a GLUT2
specific substrate which is not metabolized. Four days after
cRNA injection, 510 oocytes were incubated in 250 L of Barths
solution (pH 7.4) containing 1 mM non-labelled 2-DG and 1.8 M
H-labelled 2-DG [2 Ci/mL] in the presence or absence of the
compound to be tested. After 30 min incubation on a shaking
incubator at RT, incubation medium was removed, oocytes were
washed 3 times in ice-cold Barths solution and lysed individually in scintillation vials by addition of 100 L 10% SDS and
agitation for 1 h at RT. After mixing with 3 mL scintillation cocktail (Rotiscint Eco plus, Roth, Germany) the signals were
detected in a liquid scintillation counter (Perkin Elmer Wallac
GmbH, Freiburg,Germany). Results were expressed as percentage of 2-DG per oocyte per 30 min.




Male C57BL/6N mice were used throughout all experiments.

The animals had free access to food and tap water and were
maintained in a temperature-controlled room (22 C) on a 12 h
light/dark cycle. The diets were purchased from Ssniff GmbH
(E1534 for standard chow, E15741-34 for high fat diet, E1500004 for control diet, Soest, Germany). All experiments were carried
out according to the German guidelines of animal care and approved by the state Animal Ethics Committee (Reference
number: 55.2-1-54-2532-22-11).

Glucose uptake studies employing everted
jejunal rings
Twelve week old male C57BL/6N mice, kept on a standard chow,
were fasted for 6 hours. Afterwards mice were anaesthetized
with isoflurane (Baxter, Unterschleiheim, Germany) and killed
by cervical dislocation. The experimental procedure was carried
out as described previously by Schulze et al. (2014).


Feeding study and oral glucose tolerance test in mice

Eight week old mice were randomized into 6 groups (n = 10)

with similar mean body weight. Three groups were either fed
a high fat diet containing 60% kcal from fat (beef tallow, soy
bean oil), 21% kcal from carbohydrates (corn starch) and 19%
kcal from protein (casein) or a control diet containing 11% kcal
from fat (soy bean oil), 66% kcal from carbohydrates (corn starch,
maltodextrin) and 23% kcal from protein (casein) for a period
of 12 weeks. After 12 weeks of dietary intervention (at the age
of 20 weeks) mice were fasted for 6 h prior to glucose gavage.
Three hundred microlitres of a 20% glucose solution (B.Braun
Melsungen AG, Melsungen, Germany) was orally administered by gavage in the absence or the presence of 2.08 mg Q4glc
(15 mM) or 14 mg onion extract (around 2 mg of Q4glc). The
test compounds were solved in a DMSO/water mixture before
added to the glucose solution with a final DMSO concentration of 3%. To exclude possible effects of DMSO on blood glucose
response the same amount was added to the control OGTT.
Blood samples were collected from the tail tip before and 15,
30, 60, 90 and 120 min after glucose load with subsequent blood
glucose measurements using the glucometer Freestyle Lite
(Abbott GmbH & Co. KG, Germany). After 120 min, mice were
narcotized and killed by cervical dislocation.



In total, 15 healthy male volunteers [mean SD age: 24.1 2.0

y; weight: 77.2 7.3 kg; body mass index (BMI; in kg/m2):
23.2 1.2] were recruited in the study after a medical entry examination including complete clinical chemistry check,
determination of fasting blood glucose concentration and anthropometric measurements. Individuals were excluded if they
had an acute or chronic disease, any metabolic abnormality
or any kind of allergy or food intolerance. Habitual smokers
and subjects that had used any prescribed medication and/
or dietary supplement within 2 weeks of entering the study
were also excluded. To further limit potential confounding
factors, individuals were excluded if they reported daily intense


Journal of Functional Foods 18 (2015) 117128

sports activities (>8 hours/wk) and if there was family history

of type 2 diabetes. Basal values for mean venous blood glucose
and plasma insulin measured after a 12-hour fast in the volunteers were 77.7 2.0 mg/dL and 33.6 4.1 pmol/L, respectively.
The studies were carried out in the Human Study Center
of the Else Krner-Fresenius Center for Nutritional Medicine
(Technische Universitt Mnchen, Freising, Germany). The study
protocol was approved by the ethical committee of the
Technische Universitt Mnchen (#2867/10) and corresponds
with the Declaration of Helsinki. All subjects provided written
informed consent before their inclusion in the study and were
free to withdraw from the study at any time with no obligations.


Study design

The study was performed in a randomized crossover design

with each subject serving as its own control. Volunteers were
requested to refrain from flavonoid-rich foods and beverages, including fruits, vegetables, juices, coffee, tea and chocolate
1 day before the test days. On the study day the volunteers were
required to come to the study center at 8 am in the morning.
After a 12-hour fast, a permanent venous catheter was placed
in the subjects arm vein and after a 15 min adaption period,
the first blood sample was drawn (fasting state) and subjects
were requested to drink 150 mL water. After a period of 30 min
further blood samples were taken before (0 min) and 15, 30,
45, 60, 120 and 180 min after ingestion of 75 g glucose solved
in 250 mL water (OGTT). Volunteers were asked to drink the
full amount of glucose solution within 2 minutes. A second test
was performed as on the first day with the difference that the
subjects had to ingest the capsuled onion extract (3.1 g with
an amount of 600 mg flavonoids, composition see Table 1)
30 min prior to the OGTT. During the test days, participants
additionally collected 24 h urine, fractionated into different collection periods of 03 h, 38 h and 824 h.


Analysis of blood and urine samples

Blood was collected into 4.9 mL EDTA collection tubes

(SARSTEDT) and was immediately centrifuged for 10 min at
3000 g and 20 C except for venous blood glucose determination which was done before centrifugation using the Super GL
easy + system (Hitado Diagnostic Systems GmbH, Mhnesee,
Germany). Blood plasma was stored at 80 C until analysis.
The 24-h-urine collection started after ingestion of the glucose
solution. The first pass of urine, which was collected before
placing the permanent venous catheter, was collected as spontaneous sample. To avoid bacterial degradation of glucose and
polyphenolic compounds, urine collection flasks were filled with
sodium acid (0.1%) and stored in cool bags during the entire
collection period. Urine samples were stored at 80 C until
further analysis. Plasma insulin levels were determined by ELISA
kit (DAKO Insulin, DAKO Ltd., Ely, UK) according to manufacturers instruction.


Statistical analysis

All results were expressed as means SEM. Experiments with

oocytes or mouse intestinal segments were statistically analyzed by one-way-ANOVA with Dunnetts multiple comparisons
post hoc test using Graph Pad Prism version 4.0 for Windows
(GraphPad Software, San Diego, USA). Changes in venous blood
glucose and plasma insulin concentrations from the baseline
concentrations were calculated by subtracting the fasting value
from the highest value and were presented as incremental ()
concentrations. The incremental area under the curve (iAUC)
for venous blood glucose and plasma insulin was calculated
from the incremental concentrations by using the trapezoid
rule. Statistical analysis of the in vivo results was carried out
using the statistic program SAS (Version 9.2; SAS Institute Inc,
Cary, USA). All blood data were analyzed by use of two-way
ANOVA with either repeated measures for two factors (time

Table 1 Flavonoids identified in the onion extract by HPLCESIMS2.



tr (min)

max (nm)








823 [M + Cl], 625 (162)

463 (162)
823 [M + Cl], 625 (162), 463 (324)
823 [M + Cl], 625 (162)
463 (162), 301 (324)
477 (162), 315 (324)
463 (162), 301 (324)

Retention time (tr), detection wavelength ().

927 [2MH]
301 (324)
927 [2MH]

301 (162)
301 (162)

Journal of Functional Foods 18 (2015) 117128

and treatment) (human study) or repeated measures for one

factor (time) (mouse study). iAUCs were analyzed by use of oneway ANOVA with repeated measures (human study) or without
repeated measures (mouse study). All tests were adjusted for
multiple comparisons by means of TukeyKramer post-hoc test.
In all experiments, a probability of p 0.05 (*) was significant,
whereas p 0.01 (**) and p 0.001 (***) were defined as statistically highly significant.



Identification and characterization of onion
polyphenols by HPLCDAD and HPLCESIMS2
Flavonols in the onion extract were analyzed by HPLCDAD and
HPLCESIMS2 as described in Section 2. In total, up to 20 flavonol derivatives could be identified (Table 1, Fig. 1). The total
amount of flavonoids was calculated to be equivalent to
18.8 mg/100 mg onion dry mass. HPLC analysis of individual
components without prior hydrolysis of the extract identified quercetin-derivatives as the most abundant compounds,
with Q4glc (9.5 mg/100 mg dry mass; compound 11), Q3,4diglc
(5.4 mg/100 mg dry mass; compound 5) and the aglycon quercetin (5.4 mg/100 mg dry mass; compound 16) itself as the main
component (Fig. 1, Table 1). Additional quercetin-glucosides were
also found but only in trace amounts. Other flavonols detected were isorhamnetin and kaempferol as well as derivatives
thereof, but those all had 30 to 50-times lower concentrations than the quercetin derivatives (Fig. 1, Table 1).

Inhibition of human SGLT1 expressed Xenopus
laevis oocytes by onion extracts and flavonols from onion
using TEVC
To exclude that the test compounds by themselves are substrates of human SGLT1, extracts were first tested for their ability
to generate a transport current in the absence of any specific


SGLT1 substrate. Addition of 1 mM -MDG (KM = 1.0 0.03 mM)

to oocytes expressing hSGLT1 induced a mean transport current
of 153 nA at a membrane potential of 60 mV. However, 1 mg/
mL onion extract did not induce any significant current (Fig. 1A)
suggesting that all sugars were removed in the extraction process
and no flavonoids that could be transported by hSGLT1 were
contained. To assess the inhibitory activity of the onion extract
on hSGLT1 currents as induced by 1 mM -MDG, measurements were performed in the absence and the presence of
increasing concentrations of the onion extract. As shown in
Fig. 2A, the addition of 0.25 mg/mL onion extract reduced the
-MDG-currents by almost half (48%), whereas 1 mg/mL almost
completely (86%) inhibited transport currents. The calculated
IC50 value for inhibition at a membrane potential of 60 mV
was 326.5 57.9 g/mL (n = 5). Reversibility of inhibition was
studied by wash-out and testing in oocytes with 1 mM -MDG.
The regain of full transport currents is shown in Fig. 2A for the
highest concentration of the onion extract.
We next studied which of the components identified in the
extract were able to inhibit SGLT1-mediated transport. While
Q4glc revealed the strongest inhibition of -MDG-mediated
transport via hSGLT1 with an IC50 value of 0.17 0.002 mM, quercetin showed only a moderate inhibition of transport currents
with an IC50 value of 0.62 0.05 mM (Fig. 2B). Q3,4diglc even
failed to inhibit hSGLT1 at a concentration of 0.1 mM but also
at a higher concentration of 0.25 mM (data not shown). Dixon
plot analysis at concentrations of -MDG of 1, 2 and 4 mM and
increasing concentration of onion extract (Fig. 2C) and Q4glc
(Fig. 2D) revealed apparent Ki values of 231.3 98.4 g/mL for
the onion extract and 0.11 0.04 mM for Q4glc; with a suggested competitive type of inhibition.

Inhibition of human GLUT2 expressed in cRNAinjected Xenopus laevis oocytes by the onion extract and
quercetin derivatives
There is some evidence that at high luminal glucose concentration GLUT2 may translocate from an intracellular pool into

Fig. 1 HPLC chromatogram of the onion extract. Detection at 330 nm. Peak identities are numbered in Table 1.


Journal of Functional Foods 18 (2015) 117128

Fig. 2 Inhibition of the -MDG-induced transport currents (A) in the presence of increasing concentrations of the onion
extract at different membrane potentials, -MDG(1) means the measurement of -MDG-induced transport currents before
the exposition to onion extract; -MDG(2) means the measurement of -MDG-induced transport currents after the
exposition to onion extract; (B) at 60 mV in the presence of flavonoids identified in the onion extract. All compounds were
added in a concentration of 100 M. The IC50 values were calculated at a membrane potential of 60 mV. (C) Dixon plot
analysis for inhibition of -MDG-mediated currents by the onion extract or (D) by Q4glc. The crossing point of regression
lines above the abscissa shows that the inhibition is of competitive type. The Ki value determined from the plot is
231.3 98.4 g/mL for the onion extract and 0.11 0.04 mM for Q4glc. Mean values of 46 oocytes SEM. Statistical
differences were evaluated by one-way ANOVA with Dunnetts posthoc test. *p < 0.05, **p < 0.01, ***p < 0.001.

the apical membrane allowing on top of SGLT1 larger quantities of glucose to be absorbed. We therefore studied whether
the onion extract and its constituents can also inhibit human
GLUT2 when expressed in oocytes. As shown in Fig. 3, the onion

extract at a concentration of 0.25 mg/mL was able to reduce

GLUT2-specific 2-DG uptake (1 mM) by 78%. From the individual compounds studied, Q4glc was found to reduce 2-DG
uptake by 50% at a concentration of 0.1 mM and quercetin led
to an even stronger reduction of hGLUT2-mediated transport
by around 65%.

The onion extract and Q4glc inhibit SGLT1 in
murine jejunal tissues
Uptake experiments in everted jejunal rings were carried out
using 1 mM -MDG supplemented with 0.3 Ci/mL [ 14 C]radiolabelled -MDG either in the absence or in the presence
of increasing concentrations of the onion extract or Q4glc. The
apparent Km for -MDG uptake into the mouse tissue was
6.5 1.1 mM (n = 4) and affinity was thus considerably lower
than in oocytes. The onion extract (Fig. 4A) inhibited -MDG
uptake significantly dose-dependent with a calculated EC50 value
of 2.6 0.9 mg/mL. Q4glc showed only moderate inhibition of
SGLT1 in mouse intestinal rings with a decrease of -MDG
uptake by 25% at a concentration of 1 mM and 35% at 2 mM
but this failed to reach statistical significance (Fig. 4B).
Fig. 3 Inhibition of 2-DG uptake in oocytes expressing
hGLUT2 in the presence of 0.25 mg/mL onion extract (OE)
or 100 M of the major onion flavonols. Mean values of 46
oocytes SEM. Statistical differences were evaluated by
one-way ANOVA with Dunnetts posthoc test. *p < 0.05,
**p < 0.01, ***p < 0.001.

The onion extract but not Q4glc diminish
postprandial glucose response in obese C57BL/6N mice
C57BL/6 mice were fed a high-fat diet for 12 weeks which led
to a weight gain of 12 g (41.3 0.8 g vs. 29.0 0.3 g, p < 0.0001)

Journal of Functional Foods 18 (2015) 117128


Fig. 4 Dose-dependent inhibition of -MDG uptake into murine everted jejunal rings by onion extract (A) or Q4glc (B).
Mean values of 35 mice SEM. Statistical differences were evaluated by one-way ANOVA with Dunnetts posthoc test.*
p < 0.05, **p < 0.01, ***p < 0.001.

associated with hyperglycaemia as judged by mean fasting

blood glucose levels of 136.7 5.3 mg/dL as compared to
101.1 4.0 mg/dL in control mice to (p < 0.0001). Both, obese and
control mice, were subjected to an OGTT. The administration
of the onion extract together with the glucose load showed no
significant effects on the rise of blood glucose concentration
in control mice (Fig. 5A) or the iAUC over the 120 min period
(Fig. 5C). However, in obese mice the onion extract (Fig. 5B) significantly reduced the increase in blood glucose concentration
at 15 min (p < 0.001) and 30 min (p = 0.017) after administration of glucose and a significant decrease in the iAUC over the
entire time period of 0120 min (p = 0.007). Q4glc in comparison to the extract did not cause a significant change in the rise
of blood glucose and iAUCs in both, the high fat and the control
group (Fig. 5A, C).

In healthy young men, administration of the onion
extract did not cause changes in postprandial glucose and
insulin levels nor urinary glucose excretion
Fifteen healthy young men were subjected to an OGTT with
or without prior administration of 3.1 g onion extract. Similar
to the findings in lean mice, the changes () in postprandial
venous blood glucose and insulin response or in iAUC (Table 2)
were not significantly different at any time in the same volunteers with or without the onion extract (Fig. 6A, B). Since
kidney tubular cells express SGLT1 and SGLT2 we also monitored glucose excretion over 24 hours but the onion extract did
not show any significant changes in urinary glucose output
when compared to glucose alone (Fig. 6C).



We here demonstrate that a flavonoid-rich onion extract and

its major constituents can inhibit the intestinal glucose transporters SGLT1 and GLUT2 in vitro and thereby have the potential
to attenuate postprandial blood glucose levels in vivo. The onion
extract and the most abundant flavonol contained, Q4glc, effectively inhibited SGLT1 when expressed in Xenopus leavis
oocytes and also inhibited glucose uptake into mouse intes-

tinal segments in a reversible and competitive manner.

Moreover, when administered in mice with impaired glucose
tolerance, the onion extract diminished postprandial blood
glucose increases in response to an OGTT. However, in
normoglycaemic mice and in healthy young men the extract
failed to influence postprandial blood glucose and plasma
insulin levels following an OGTT. This suggests that other
mechanisms than inhibition of intestinal glucose uptake may
cause the anti-hyperglycaemic effects observed in the diabetic state and this could include systemic effects of onion
constituents for example on hepatic metabolism.


Characterization of onion flavonols

In accordance with other studies (Lombard et al., 2002; Yoo et al.,

2010) Q4glc was identified as the most abundant polyphenol
in the onion extract followed by Q-3,4diglc and quercetin. In
total, 20 flavonol derivatives could be identified in our onion
extract in line with findings by Slimestad, Fossen, and Vagen
(2007). In addition, Lee and Mitchell (2012) analyzed different
onion varieties and found flavonol levels of up to 0.54 mg/
100 mg for Q-3,4diglc, 0.560.54 mg/100 mg for Q4glc and 0.020
1.1 mg for quercetin per 100 mg dry mass. These data reveal
that the flavonols within the onion extract used here are concentrated by a factor of 1020 as compared to onions.

Interaction of the onion extract and contained
polyphenols with the glucose transporters in vitro
Although inhibition of glucose transporters by onion extracts
has never been studied, the interaction of quercetin and Q4glc
with SGLT1 has been demonstrated in several in vitro studies
(Ader, Block, Pietzsch, & Wolffram, 2001; Cermak, Landgraf, &
Wolffram, 2004; Kottra & Daniel, 2007; Kwon et al., 2007). Quercetin only modestly inhibited hSGLT1 in oocytes in line with
previous findings (Kottra & Daniel, 2007) although other studies
failed to show any significant effect of quercetin on glucose
uptake via SGLT1 (Cermak et al., 2004; Kwon et al., 2007; Song
et al., 2002). The strongest inhibition amongst the onion flavonols tested was observed with Q4glc, indicating that a glucose
moiety at this position increases SGLT1 binding affinity. This


Journal of Functional Foods 18 (2015) 117128

finding contrasts data by Kwon et al. (2007) that failed to show

any significant SGLT1 inhibition for Q4glc. This discrepancy may
originate from the different experimental conditions. In the
studies by Kwon et al. (2007) oocytes were studied under openvoltage conditions which results in a major loss of affinity when
SGLT1 transport causes a membrane depolarization whereas
we performed the studies under voltage-clamp conditions. In
intestinal tissues however a strong inhibition of SGLT1mediated uptake by Q4glc in comparison to only moderate
inhibition caused by quercetin and quercetin-3-O-glucoside has
been demonstrated (Ader et al., 2001; Cermak et al., 2004). Interestingly, the onion extract showed an even stronger inhibition
of GLUT2 than of SGLT1 when expressed in oocytes. Transport of 2-DG via GLUT2 revealed quercetin as the strongest
inhibitor, followed by Q4glc in analogy to the findings reported by Kwon et al. (2007) using the same expression system.
The concentration of Q4glc and quercetin within the onion
extract (at 0.25 mg/mL) accounted to approximately 50 M for
each compound suggesting that those could significantly contribute to the GLUT2 inhibitory effect found.


Fig. 5 Effect of a single dose of Q4glc or onion extract coadministered with glucose (60 mg) on rise in blood glucose
concentration in 20 week old male C57BL/6N mice at the
end of the 12-week feeding trial. (A) Control diet, (B) high
fat diet. (C) IAUCs calculated over a period of 120 min. Data
are shown as mean of n = 10 mice SEM. Statistical
difference was evaluated with two-way-ANOVA with
repeated measures for one factor (time) and multiple
comparison posthoc test (TukeyKramer test) for (A) and (B)
or by use of one-way ANOVA without repeated measures
(C) using SAS. *p < 0.05, **p < 0.01.

Effects of the onion extract on glucose homeostasis

In the human study, the onion extract containing 295 mg Q4glc

and 167 mg quercetin failed to affect venous blood glucose
and plasma insulin levels when provided 30 min prior to the
OGTT. This lack of an effect like in normoglycaemic mice
suggests that the total flavonoid content of 600 mg provided
by the onion extract may have been too low to cause significant inhibition of intestinal glucose uptake in vivo. It also seems
important to take into account that that pure Q4glc as the
most abundant onion flavonoid also failed to affect postprandial blood glucose concentration in response to an OGTT in
mice. How can this discrepancy between the in vitro and in
vivo findings be explained? The most obvious difference is the
dose of extract or test compound relative to the substrate concentration provided to the intestine in vitro and in vivo. The
quantity of the extract given to the volunteers is relatively
small (and limited by capsulation and solubility) compared
to the standard glucose dose of 75 g of D-glucose as provided
via an OGTT in humans. Moreover, it has been shown that
lactase phlorizin hydrolase (LPH), an exo-enzyme of the brush
border membrane in the small intestine, can rapidly hydrolyze dietary glucosides such as Q4glc by acting on the
-glucosidic linkage and releasing the aglycone (Day et al.,
2000; Day, Gee, DuPont, Johnson, & Williamson, 2003). Quercetin as the cleavage product of Q4glc however has a much
lower affinity for SGLT1-binding (Cermak et al., 2004; Kottra
& Daniel, 2007; Kwon et al., 2007) and thus a far lower potency
for transport inhibition. In contrast to the mouse studies in
which the extract was administered together with glucose,
in humans the capsules containing the extract were administered 30 min prior to the OGTT. The rationale for that was
that the capsules had to empty from stomach and dissolve
to reach proper concentrations in the upper small intestine
when glucose arrives there. However, it is also conceivable
that by this mode of administration a certain amount of Q4glc
already underwent hydrolysis with release of quercetin which
hardly inhibits SGLT1. We recently reported in a similar study
that the administration of an apple extract 30 min prior to


Journal of Functional Foods 18 (2015) 117128

Table 2 . Postprandial venous blood glucose and plasma insulin incremental area under the curve (iAUC) in healthy
young men after an OGTT with 75 g glucose (reference) or after an OGTT with prior ingestion (30 min) of 3.1 g onion
Glucose iAUC (mg/dL)

Insulin iAUC (pmol/L)

Time (min)


Onion extract



Onion extract



167.3 13.8
567.8 50.6
1224.8 108.9
1854.8 178.5
2678.3 299.6
3075.8 383.9
3354.75 485.1

174.8 16.4
504.8 59.7
1033.5 117.3
1622.3 173.7
2582.3 270.4
3158.3 388.3
3689.25 523.0


63.2 13.8
1167.2 212.3
3959.8 623.3
7406.1 1029.6
12,698.0 1643.0
15,353.8 1893.0
16,880.2 1991.7

144.9 48.1
1110.0 261.6
3306.1 742.6
6210.7 1355.9
11,596.8 2079.1
14,818.8 2282.5
16,636.6 2344.0


All values are means SEM, n = 15. Significant differences in venous blood glucose and plasma insulin iAUCs were evaluated by one-wayANOVA with repeated measures and multiple comparison posthoc test (TukeyKramer test).

an OGTT resulted in a significant reduction in the rise of blood

glucose and plasma insulin concentrations in healthy volunteers (Schulze et al., 2014). This suggests that the lack of an
effect here is specific for the onion extract and not dependent on study design.
Although Q4glc failed to cause any significant change in
plasma glucose levels in obese/hyperglycaemic animals, the
onion extract showed significant effects. This suggests other
minor flavonoids to have an activity or that synergistic or additive effects between the different flavonoids come into play
to alter glucose responses more effectively. Such effects have
been described in vitro for selected plant extracts and mixtures (Farrell, Ellam, Forrelli, & Williamson, 2013; Manzano &
Williamson, 2010). Moreover, an additive inhibitory effect on
glucose absorption into rat intestinal segments was observed
in the presence of phlorizin and an aqueous extract of Bauhinia
megalandra, with kaempferol-3-O-rhamnoside as the main flavonoid (Gonzalez-Mujica, Motta, Marquez, & Capote-Zulueta,
2003; Rodriguez, Gonzalez-Mujica, Bermudez, & Hasegawa,
2010). We also cannot exclude that constituents of the extract
are absorbed more efficiently and cause inhibition of basolateral
GLUT2 and thus reduce glucose efflux into blood leading to
reduced hyperglycaemia. This may also provide a possible explanation for the reduction of glucose absorption in the diabetic
but not healthy state. It has been proposed that GLUT2 is permanently located at the brush border membrane in insulin
resistant individuals (but not lean and healthy humans) allowing higher rates of glucose and fructose absorption (Ait-Omar
et al., 2011; Tobin et al., 2008). A more potent inhibition of
GLUT2 by quercetin and Q4glc than of SGLT1 in insulin resistant states could thus well explain the observed antihyperglycaemic effect in our obese mice. When quercetin was
administered orally in diabetic Zucker fa/fa rats together with
a glucose bolus, a significant reduction of hyperglycaemia was
reported (Song et al., 2002) and here the authors also argued
that quercetin may inhibit glucose influx into enterocytes via
apical GLUT2 but not SGLT1. In human studies the findings
are also inconsistent. In type 2 diabetic volunteers quercetin
(400 mg) given 30 min prior to an OGTT with 100 g glucose
failed to alter blood glucose concentrations (Hussain, Ahmed,
Mahwi, & Aziz, 2012) while onion extracts were shown to have

an effect on the glucose plasma levels in patients with type 2

diabetes (Myint et al., 2009). This suggests more and other
effects of the extract than that of quercetin alone and this
may well include effects on insulin release and/or on insulin
sensitivity by absorbed constituents (Williamson, 2013). Various
herbs and dietary supplements are known to alter -cell insulin
output or peripheral insulin activity (Welihinda, Arvidson, Gylfe,
Hellman, & Karlsson, 1982; Yeh, Eisenberg, Kaptchuk, & Phillips,
2003). For quercetin, glucose-induced insulin release from isolated rat pancreatic islets revealed an increase (Bardy et al.,
2013; Hii & Howell, 1985; Youl et al., 2010). As an example for
effects in target tissues of insulin may be the recent in vitro
study that revealed that extracts from vinification byproducts
of Vitis vinifera with quercetin as the dominant constituent
significantly inhibited glycogen phosphorylase (GP), an enzyme
that catalyzes the first step of intracellular degradation of glycogen to glucose-1-phosphate and the hepatic release of glucose
(Kantsadi et al., 2014). GP inhibitors have been suggested as
new hypoglycaemic agents for treatment of T2DM (Treadway,
Mendys, & Hoover, 2001) similar to inhibitors of hepatic glucose6-phosphatase, an enzyme involved in the glucose release from
glucose-6-phosphate as the final step in gluconeogenesis
and glycogenolysis (Arion et al., 1997; Herling et al., 1998). So,
onion extracts or onion-derived polyphenols have the potential to affect physiological processes beyond intestinal glucose
absorption and their effect will likely depend on dose and
Interestingly, in normal and in streptozotocin-induced diabetic rats oral administration of either sucrose or starch
simultaneously with onion extracts resulted in significant decreases of blood glucose responses (Kang et al., 2010; Kim et al.,
2011; Kim, Jo et al., 2011). This was shown to be caused by the
inhibition of sucrase and -glucosidase; both enzymes are responsible for the release of glucose from oligosaccharides with
quercetin as a particular strong inhibitor of sucrase. These
finding suggests that onion and extracts thereof could preferentially improve blood glucose and glucose homeostasis via
an inhibition of glucose release from oligosaccharides rather
than by inhibition of glucose absorption.
In contrast to intestine, the renal tubule expresses in addition to SGLT1 the SGLT2 transporter with the latter mediating


Journal of Functional Foods 18 (2015) 117128



We here demonstrate that an onion extract containing mainly

quercetin and quercetin glucosides inhibits human SGLT1 expressed in oocytes, reduces sugar absorption in mouse intestine
and diminishes glucose responses after an OGTT in mice with
impaired glucose tolerance. However, in normoglycaemic mice
as well as in healthy young men, the onion extract failed to
affect postprandial blood glucose and plasma insulin levels and
this may depend on a rearrangement of glucose transporters
in the intestine in insulin resistant states.

The authors thank the Bundesministerium fr Bildung und
Forschung (BMBF) (0315371B) for funding these studies.We thank
Barbara Gelhaus, Pia Rder and Ronny Scheundel for excellent technical assistance and the participants of the human
study for their compliance. Furthermore, we would like to thank
Adelmar Stamfort for statistical support.We thank Ulrich Girreser
and Sven Wichmann for excellent support with the LCMS analysis. The authors have declared no conflict of interest.

Appendix: Supplementary material

Supplementary data to this article can be found online at

Fig. 6 The mean (SEM) incremental venous blood glucose

(A) and plasma insulin concentration (B) as well as the
urine glucose concentration (C) of 15 healthy young men
after performance of an OGTT or an OGTT with prior
ingestion (30 min) of 3.1 g onion extract. Statistical
differences were evaluated with two-way-ANOVA with
repeated measures and multiple comparison posthoc test
(TukeyKramer test). *p < 0.05, **p < 0.01.

most of renal glucose reabsorption. Both transporters have

similar affinities for glucose. Since quercetin is bioavailable and
is filtered in kidneys, we tested whether the onion extract given
to the human volunteers affected glucose disposal into urine
after the OGTT. Such an effect was shown previously after ingestion of an apple extract rich in phlorizin (Schulze et al., 2014).
Ingestion of the onion extract resulted however not in any
changes in urinary glucose output assessed over 24 hours after
the OGTT.

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