ORIGINAL ARTICLE

Accelerated Intestinal Glucose Absorption in

Morbidly Obese Humans: Relationship to Glucose
Transporters, Incretin Hormones, and Glycemia

Nam Q. Nguyen, Tamara L. Debreceni, Jenna E. Bambrick, Bridgette Chia,

Judith Wishart, Adam M. Deane, Chris K. Rayner, Michael Horowitz,

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and Richard L. Young
Department of Gastroenterology and Hepatology (N.Q.N., T.L.D., J.E.B., C.K.R.), Royal Adelaide Hospital,
Adelaide, South Australia 5000, Australia; Discipline of Medicine (N.Q.N., J.W., A.M.D., C.K.R., M.H.,
R.L.Y.), University of Adelaide, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia; Nerve-
Gut Research Laboratory (B.C., R.L.Y.), Hanson Institute, Adelaide, South Australia, 5000, Australia; and
Intensive Care Unit (A.M.D.), Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia

Context: Intestinal glucose absorption is mediated by sodium-dependent glucose transporter 1

(SGLT-1) and glucose transporter 2 (GLUT2), which are linked to sweet taste receptor (STR) signaling
and incretin responses.

Objective: This study aimed to examine intestinal glucose absorption in morbidly obese humans
and its relationship to the expression of STR and glucose transporters, glycemia, and incretin
responses.

Design/Setting/Participants: Seventeen nondiabetic, morbidly obese subjects (body mass index

[BMI], 48 ⫾ 4kg/m2) and 11 lean controls (BMI, 25 ⫾ 1 kg/m2) underwent endoscopic duodenal
biopsies before and after a 30-minute intraduodenal glucose infusion (30 g glucose and 3 g 3-O-
methylglucose [3-OMG]).

Main Outcome Measures: Blood glucose and plasma concentrations of 3-OMG, glucose-dependent
insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), insulin, and glucagon were mea-
sured over 270 minutes. Expression of duodenal SGLT-1, GLUT2, and STR (T1R2) was quantified
by PCR.

Results: The increase in plasma 3-OMG (P ⬍ .001) and blood glucose (P ⬍ .0001) were greater in
obese than lean subjects. Plasma 3-OMG correlated directly with blood glucose (r ⫽ 0.78, P ⬍ .01).
In response to intraduodenal glucose, plasma GIP (P ⬍ .001), glucagon (P ⬍ .001), and insulin (P ⬍
.001) were higher, but GLP-1 (P ⬍ .001) was less in the obese compared with lean. Expression of
SGLT-1 (P ⫽ .035), but not GLUT2 or T1R2, was higher in the obese, and related to peak plasma
3-OMG (r ⫽ 0.60, P ⫽ .01), GIP (r ⫽ 0.67, P ⫽ .003), and insulin (r ⫽ 0.58, P ⫽ .02).

Conclusions: In morbid obesity, proximal intestine glucose absorption is accelerated and related to
increased SGLT-1 expression, leading to an incretin-glucagon profile promoting hyperinsulinemia
and hyperglycemia. These findings are consistent with the concept that accelerated glucose ab-
sorption in the proximal gut underlies the foregut theory of obesity and type 2 diabetes. (J Clin
Endocrinol Metab 100: 968 –976, 2015)

ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2015 by the Endocrine Society
Received August 7, 2014. Accepted November 18, 2014.
First Published Online November 25, 2014
Abbreviations: 3-OMG, 3-O-methylglucose; AUC, area under the curve; BMI, body mass
index; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1;
GLUT2, glucose transporter 2; GTs, glucose transporters; HbA1c, glycated hemoglobin;
HOMA, homeostasis model assessment; HOMA-IR, insulin resistance score; SGLT-1, sodi-
um-dependent glucose transporter-1; STR, sweet taste receptor.

968 jcem.endojournals.org J Clin Endocrinol Metab, March 2015, 100(3):968 –976 doi: 10.1210/jc.2014-3144
doi: 10.1210/jc.2014-3144
he causes of the obesity crisis over the last 30 years
T remain unclear but are thought to relate primarily to
increased consumption of energy-dense foods and bever-
ages and decreased physical activity. Increased caloric in-
take is the leading culprit for weight gain, with fast-food
meals (1) and sweetened beverages (2). Although it has
been suggested that intestinal absorption of nutrients is
more rapid and efficient in obese than lean humans pre-
disposing to both weight gain and type 2 diabetes (3), this
issue has attracted little attention. Recently, we reported
that the increase in blood glucose after a carbohydrate-
containing drink was greater in obese compared with lean
subjects (4). Although this is likely to partly reflect the
effect of insulin resistance related to obesity, it is also po-
tentially attributable to accelerated intestinal glucose
absorption.
The outcome of animal experiments suggests that in-
testinal glucose absorption is strongly regulated in the
presence of luminal glucose or sweet tastants via activa-
tion of intestinal sweet taste receptors (STRs), which are
heterodimers of G protein– coupled receptors T1R2 and
T1R3 (5, 6). Upon activation, STRs have the capacity to
promote increased availability of intestinal sodium-de-
pendent glucose cotransporter 1 (SGLT-1) (5, 7) and glu-
cose transporter 2 (GLUT2) (8), the critical transporters
for glucose absorption. Activation of STRs and/or glucose
transporters (GTs) has also been reported to trigger the
release of the incretin hormones glucagon-like peptide 1
(GLP-1) and glucose-dependent insulinotropic polypep-
tide (GIP) (5, 7, 9, 10). Genetically modified mice that have
7-fold higher levels of SGLT-1 protein exhibit an increased
rate of intestinal glucose absorption and develop visceral
obesity (11, 12). Although there are no information re-
garding the expression of either STRs or SGLT-1 in obese
humans, increased accumulation of both apical and ba-
solateral membrane GLUT2 during fasting has been re-
ported in morbidly obese subjects with type 2 diabetes
(13). Although noncaloric sweeteners fail to trigger GLP-1
release acutely in humans (14), lactisole (inhibitor of
STRs) (15) or phloridzin (the competitive inhibitor of
SGLT-1) (16) attenuate the GLP-1 response to enteral glu-
cose. Together, these observations support the potential
role of the intestinal STR/GTs system in the regulation of
glucose absorption, glycemia, and body weight.
We hypothesized that morbid obesity is associated with
increased intestinal glucose absorption, resulting from
dysregulation of the intestinal STR system, GTs, or both.
Increased intestinal glucose absorption may in turn lead to
incretin responses that promote the hyperglycemia, hy-
perinsulinemia, insulin resistance, and lipogenesis ob-
served in obesity. The current study examines intestinal
glucose absorption in morbidly obese subjects and its re-
jcem.endojournals.org 969
lationship to glycemia, incretin hormones, and the expres-
sion of intestinal STR (T1R2), SGLT-1, and GLUT2 tran-
scripts in comparison with healthy lean subjects.
Materials and Methods
Subjects
Morbidly obese subjects (BMI ⬎ 35 kg/m2) and healthy
volunteers (BMI ⬍ 28 kg/m2) were recruited for the study
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between January and November 2013 from an advertise-
ment placed at the hospital notice boards and the Obesity
Clinic of the Royal Adelaide Hospital. Subjects were ex-
cluded if they were age less than 18 years, pregnant,
known to have diabetes, had a contraindication to endos-
copy, a history of surgery on the stomach or small intes-
tine, were receiving drugs known to alter platelet aggre-
gation or thrombus formation, had an International
Normalized Ratio ⬎ 1.5, platelet count ⬍ 50 000, or ab-
normal plasma creatinine. Healthy subjects were selected
to match the age of the obese subjects (Table 1). The study
was approved by the Human Research Ethics Committee
of the Royal Adelaide Hospital. Informed written consent
was obtained from all subjects.
Protocol
The study protocol is summarized in Figure 1. Each subject
was studied after an overnight fast and at 0900 h. Female
subjects were studied exclusively during the follicular
phrase of the menstrual cycle to limit the potential con-
founding effects on gut hormone concentrations. An iv
cannula was inserted in each subject for blood sampling.
A small-diameter (5.3 mm) video endoscope (GIF-XP160,
Olympus) was passed via an anesthetized nostril into the
second part of the duodenum from which mucosal biop-
sies were collected using standard biopsy forceps and
placed into RNAlater (QIAGEN). At T ⫽ 0 minutes, an
intraduodenal infusion of 30 g glucose and 3 g of the glu-
cose absorption marker 3 O-methyglucose (3-OMG, Sig-
ma-Aldrich) was commenced via the biopsy channel of the
endoscope. The infusion was maintained at a constant rate
Table 1. Demographics and Clinical Characteristics of
Morbidly Obese And Healthy Subjects
Lean Morbidly
Healthy Subjects Obese Subjects
Characteristic (n ⴝ 11) (n ⴝ 17)
Age, y 44 ⫾ 6 45 ⫾ 3
Male:female ratio 10:1 5:12a
HbA1c, % 5.6 ⫾ 0.4 5.8 ⫾ 0.3
BMI, kg/m2 25 ⫾ 1 48 ⫾ 4a
Data are mean ⫾ SD.
a
P ⬍ .01 vs healthy subjects.
970 Nguyen et al Glucose Absorption in Obesity
Figure 1. Outline of study protocol.
of 4 kcal/min (ie, 1 g glucose/min) for 30 minutes. At T ⫽
30 minutes additional biopsies were collected and the en-
doscope was then removed. Blood samples (20 ml) were
taken at baseline (fasting), then every 30 minutes over 270
minutes for determination of blood glucose and plasma
concentrations of 3-OMG, GLP-1, GIP, insulin, and glu-
cagon. For blood glucose and plasma of 3-OMG and in-
sulin, more frequent blood sampling was performed
within the first 90 minutes (Figure 1). Blood samples for
measurements of glycated hemoglobin (HbA1c), gluca-
gon, GIP, and GLP-1 were collected into chilled 5-mL
ethylene-di-amine-tetraacetic acid tubes. Both serum and
plasma were separated by centrifugation (3200 rpm for 15
mins at 4°C). Samples were then stored at ⫺70°C until
assayed. Absolute expression of SGLT-1, GLUT2, and
T1R2 transcripts was quantified from duodenal mucosal
biopsies by quantitative real-time RT-PCR. In each sub-
ject, the degree of insulin resistance was estimated at base-
line by homeostasis model assessment (HOMA) (17). In-
sulin resistance score (HOMA-IR) was computed using
the formula: fasting plasma glucose (mmol/l) times fasting
serum insulin (mU/l) divided by 22.5. Low HOMA-IR
values are indicative of high insulin sensitivity whereas
high HOMA-IR values suggest low insulin sensitivity (ie,
insulin resistance) (17).
Measurements
Intestinal glucose absorption
Plasma concentrations of 3-OMG were measured using
high-performance exchange chromatography with an as-
say sensitivity of 0.010 mmol/L (18 –20). Peak and time-
to-peak 3-OMG concentrations, as well as the area under
the curve (AUC) at 120 minutes (AUC0 –120min) and 270
minutes (AUC0 –270min), were quantified.
HbA1c and blood glucose
HbA1c was measured using cation exchange high-perfor-
mance liquid chromatography. Blood glucose was mea-
sured at the bedside using a portable glucometer (Medis-
ense Optimum) (19, 20).
J Clin Endocrinol Metab, March 2015, 100(3):968 –976
Plasma insulin, GIP, GLP-1, and
glucagon
Plasma insulin was measured by
ELISA (ELISA, Diagnostic Systems
Laboratories) with assay sensitivity
of 0.26 mU/L and coefficient of vari-
ation was 2.6% within, and 6.2%
between, assays (19, 20). Total
plasma GIP was measured by RIA
where the sensitivity was 2 pmol/L,
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and both coefficients of variation
were 15% (19, 20). Total plasma
GLP-1 was measured by RIA where the sensitivity was 1.5
pmol/L, and coefficient of variation was 17% within, and
18% between, assays (19, 20). Plasma glucagon was mea-
sured by RIA (GL-32K; Millipore) where the sensitivity
was 20 pg/ml and coefficient of variation was 15% within,
and 12% between, assays (19, 20).
Gene expression of intestinal STRs and GTs
RNA was extracted from duodenal mucosal biopsies using
RNeasy Mini or Micro kits (QIAGEN) following manu-
facturer instructions with RNA yield and quality deter-
mined by NanoDrop (NanoDrop Technologies). Quanti-
tative real time RT-PCR was used to determine absolute
levels of T1R2, SGLT-1, and GLUT2 transcript in 25 ng
total human RNA. Because the absolute number of tran-
scripts was to be quantified, comparison with housekeeper
genes was not required. Primers for these targets were used
as validated primer assays (QuantiTect, QIAGEN; Sup-
plemental Table 1) or for absolute PCR standards, de-
signed from target sequences obtained from the National
Center for Biotechnology Information nucleotide data-
base (Supplemental Table 2) (6, 20). RT-PCR was per-
formed on a Chromo4 (MJ Research) real-time instrument
attached to a PTC-200 Peltierthermal cycler (MJ Re-
search) using a QuantiTect SYBR Green one-step RT-PCR
kit (QIAGEN) according to the manufacturer’s specifica-
tions. Cycling conditions were reverse transcription at
50°C for 30 minutes, 95°C for 15 minutes, then 45 cycles
PCR at 94°C for 15 seconds, followed by 55°C for 30
seconds and 72°C for 30 seconds. A melt curve was gen-
erated (60 –95°C) to verify the specificity and identity of
the RT-PCR products; product size was confirmed on an
electrophoresis gel (BioRad Laboratories). Each assay was
performed in triplicate and included internal no-template
and no-RT controls. Minimum detectable levels for
SGLT-1 and T1R2 transcripts were 2 ⫻ 103 copies; when
levels were not detected, this threshold value was substi-
tuted (20).
doi: 10.1210/jc.2014-3144
Data analysis
The sample size of 17 obese and 11 lean subjects was based on
our previous work (6, 21, 22) comparing duodenal RNA levels
in type 2 diabetes, critically ill, and healthy subjects, giving 80%
power to detect a difference in RNA expression between groups
of 20%, accepting an ␣ error of 0.05. The primary endpoints
were differences in plasma 3-OMG concentrations and the num-
ber of STR and GTs transcripts between the groups. Secondary
outcomes included the differences in incretin responses, glyce-
mia, HOMA-IR scores, and relationships between these vari-
ables between the groups.
Differences in blood glucose, plasma 3-OMG, insulin, GIP,
GLP-1, and glucagon concentrations between morbidly obese
and healthy subjects were assessed by two-way repeated mea-
sures ANOVA with treatment and time as factors. In addition,
the differences in the copy numbers of intestinal SGLT-1, T1R2,
and GLUT2 RNA transcript between the groups were compared
using unpaired t tests. Changes in the expression of intestinal
SGLT-1, T1R2, and GLUT2 among the groups were assessed by
paired [ital]t tests. Linear relationships were evaluated using
Spearman’s Rank Test. Difference in sex between the groups was
analyzed by Fisher’s exact test. Analyses were performed using
GraphPad Prism statistical software, version 6 (GraphPad Soft-
ware). Significance was accepted at P ⬍ .05; data are presented
as mean ⫾ SD.
Figure 2. Intestinal glucose absorption, reflected by changes in plasma 3-OMG concentrations, blood glucose, and plasma concentration of
insulin, GLP-1, GIP, and glucagon during fasting and in response to intraduodenal glucose infusion in morbidly obese and healthy subjects.
*, P ⬍ .001 vs healthy subjects.
jcem.endojournals.org 971
Results
Seventeen morbidly obese subjects and 11 lean healthy
subjects were studied. Demographics in the two groups,
including differences between them, are summarized in
Table 1. All subjects were Caucasian, tolerated the pro-
cedure well, and had a normal macroscopic appearance of
the small intestinal mucosa. There were no complications
related to the endoscopy, duodenal mucosal biopsy, in-
traduodenal glucose infusion, or blood sampling.
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Intestinal glucose absorption
Both the rate of plasma 3-OMG increase and peak con-
centrations were higher in morbidly obese than healthy
subjects (Figure 2A). The time taken to reach to peak
plasma 3-OMG after the intraduodenal glucose infusion
was also earlier in morbidly obese subjects than healthy
subjects (54 ⫾ 3 vs 72 ⫾ 8 min, P ⫽ .01). However, neither
integrated plasma 3-OMG concentrations over 120 min-
utes (obese vs healthy AUC0 –120min: 30.9 ⫾ 1.5 vs 27.5 ⫾
2.6 mmol/L/min; P ⫽ .24) nor 270 minutes (AUC0 –270min:
65.4 ⫾ 2.8 vs 66.5 ⫾ 4.6 mmol/L/min, respectively; P ⫽
.68) differed between the groups, although plasma
972 Nguyen et al Glucose Absorption in Obesity
Figure 3. Changes in the mRNA expression of intestinal T1R2 and glucose transporters (SGLT-1 healthy subjects (P ⫽ .04, Figure 3B).
and GLUT-2) in morbidly obese and healthy subjects.
3-OMG had not returned to baseline (or zero) at 270
minutes.
Glycemia and plasma insulin, glucagon, GIP, and
GLP-1
Fasting blood glucose concentrations tended to be
higher in the morbidly obese than the healthy subjects (6.1
⫾ 0.1 vs 5.8 ⫾ 0.2 mmol/L, P ⫽ .14, Figure 2B). Fasting
plasma insulin (P ⬍ .001) and GIP (P ⬍ .001) were higher
in obese subjects (Figure 3, C and E), whereas fasting
plasma GLP-1 and glucagon concentrations were compa-
rable (Figure 3, D and F).
Blood glucose and plasma insulin, GIP, and GLP-1 con-
centrations were increased markedly in morbidly obese
and healthy subjects following intraduodenal glucose in-
fusion (Figure 2). Plasma glucagon concentrations in-
creased in morbidly obese subjects but not healthy sub-
jects. The increases, reflected by peak concentrations, in
blood glucose and plasma concentrations of insulin, glu-
cagon, and GIP after glucose infusion were greater (Figure
2, B–F), whereas the increase in GLP-1 was less in the
morbidly obese than healthy subjects (Figure 2D).
Figure 4. Relationships of blood glucose, plasma GIP, insulin, GLP-1, and intestinal glucose absorption in morbidly obese subjects.
J Clin Endocrinol Metab, March 2015, 100(3):968 –976
Duodenal transcript levels of
sweet taste receptor and
glucose transporters
SGLT-1 was the most abundant
transcript in the duodenal mucosa of
fasted obese and healthy subjects,
with approximately 30% lower lev-
els of GLUT2 (P ⬍ .001), and much
lower levels of T1R2 (P ⬍ .001, Fig-
ure 3). Fasting or baseline transcript
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levels of SGLT-1, but not GLUT2 or
T1R2, were higher in morbidly
obese subjects when compared with
In obese subjects, SGLT-1 transcript
levels decreased after duodenal glu-
cose infusion, an effect that was not
evident in healthy subjects (P ⬍ .001, Figure 3B). Expres-
sions of GLUT-2 and T1R2 were not affected by duodenal
glucose in either group.
Relationships between intestinal glucose
absorption, glycemia, incretin responses, and
HOMA-IR
Peak plasma 3-OMG concentrations correlated closely
with blood glucose concentrations in obese (r ⫽ 0.70, P ⫽
.0006; Figure 4A) and healthy (r ⫽ 0.58, P ⫽ .05) subjects.
In obese subjects, peak plasma 3-OMG concentrations
were related directly to peak plasma concentrations of GIP
(r ⫽ 0.70, P ⫽ .001) and insulin (r ⫽ 0.61, P ⫽ .01) but
inversely to peak plasma GLP-1 (r ⫽ ⫺0.51, P ⫽ .04)
concentrations (Figure 4, B–D). No relationships between
peak plasma 3-OMG and incretin hormone concentra-
tions were observed in healthy subjects.
HOMA-IR scores were higher in obese than healthy
subjects (3.9 ⫾ 0.5 vs 1.4 ⫾ 0.3, P ⬍ .001). In the obese,
but not healthy, subjects, HOMA-IR scores correlated
modestly with peak (r ⫽ 0.59, P ⫽ .02) and integrate
doi: 10.1210/jc.2014-3144 jcem.endojournals.org 973

porter SGLT-1. Moreover, we showed

that these changes in glucose absorp-
tion in the proximal intestine are as-
sociated with augmented release of
both GIP and glucagon, but a reduc-
tion in GLP-1, which are likely to ac-
count for the observed hyperglycemia
and hyperinsulinemia. We also re-
vealed relationships of peak plasma
3-OMG with blood glucose, plasma

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GIP, and insulin concentrations, and
of duodenal SGLT-1 transcript levels
with peak plasma concentrations of
3-OMG, GIP, and insulin. Overall,
these observations suggest that dys-
regulated glucose absorption in the
proximal gut of the morbidly obese is
an important factor in the develop-
ment of obesity and the related type 2
diabetes, and are also consistent with
the foregut theory, which proposes
that exposure of nutrient to the fo-
regut leads to the release of a factor
that promotes hyperglycemia, hy-
Figure 5. Relationships of intestinal glucose absorption, GIP, insulin, and intestinal glucose perinsulinemia, insulin resistance,
transporter SGLT-1 expression in morbidly obese subjects.
and lipogenesis (23, 24). Avoidance
of such exposure, as is the case with
(AUC0 –270min: r ⫽ 0.61, P ⫽ .01) plasma concentrations Roux-en-Y gastric bypass or, more recently, an endolu-
of 3-OMG. minal sleeve, has been proposed as a bypass mechanism
that leads to improvement in glycemia and facilitates
Relationships between intestinal glucose weight loss (25, 26).
absorption, transporters and incretin responses Physiologically, enhanced glucose absorption in the
Expression of duodenal SGLT-1 transcripts during proximal gut would increase blood glucose concentra-
fasting correlated positively with GLUT2 transcript levels tions, and trigger the release of gut hormones involved in
in healthy subjects, (r ⫽ 0.71; P ⫽ .009) but not in the the incretin response (28, 29). Direct infusion of glucose
obese. There were no relationships apparent between tran-
into the duodenum at a constant rate (4 kcal/min) allows
script levels of T1R2 and SGLT-1 or GLUT2 in either
its absorption to be reliably assessed, independent of the
group. In contrast, in fasted obese subjects, SGLT-1 tran-
substantial interindividual variations in gastric emptying,
script levels correlated positively with peak plasma
including the potential effects of obesity (27), and is a
3-OMG (r ⫽ 0.60; P ⫽ .01), GIP (r ⫽ 0.67; P ⫽ .003), and
major strength of the current study. The secretion of GIP
insulin (r ⫽ 0.58; P ⫽ .015) (Figure 5, A–C). Both at
is likely to be a consequence of the absorption of glucose
baseline and after intraduodenal glucose, transcript copy
via intestinal SGLT-1 (7, 30, 31), because elevation in
number for T1R2 or GLUT2 did not correlate with peak
blood glucose does not, per se, increase plasma GIP (29).
plasma concentrations, or AUC0 –270min, of 3-OMG, GIP,
However, the combination of higher GIP but lower GLP-1
GLP-1, or insulin.
concentrations is likely to be responsible for the aug-
mented releases of insulin and glucagon, leading to the
demonstrated insulin resistance and, potentially, in-
Discussion
creased lipogenesis (26, 28, 31–33). Although glucose-
This study has demonstrated for the first time that the rate dependent insulin release is stimulated by both GIP and
of glucose absorption is increased in the proximal intestine GLP-1, GIP has a stimulatory effect and GLP-1 a suppres-
of morbidly obese subjects, and that this is associated with sive effect on glucagon release (29). It should be recognized
increased duodenal expression of the apical glucose trans- that the higher postprandial blood glucose in obese sub-
974 Nguyen et al Glucose Absorption in Obesity
jects will facilitate incretin-mediated insulin release given
that these were above the threshold of approximately 8
mmol/L (29, 34). This imbalanced release of GIP and
GLP-1 potentially leads to a vicious circle of hyperglyce-
mia, hyperinsulinemia, and hyperglucagonemia, resulting
in insulin resistance, visceral obesity, and weight gain.
The observed relationship between the rate of intestinal
glucose absorption and the increase in plasma GIP in mor-
bidly obese subjects during acute hyperglycemia is con-
sistent with our recent data in healthy volunteers (35), and
is consistent with the concept that accelerated glucose ab-
sorption and augmented GIP release are the unknown fac-
tors responsible for the foregut theory of obesity and type
2 diabetes. Evidence of higher basal and nutrient-stimu-
lated GIP levels in obese and glucose-intolerant than lean
subjects are in keeping with this theory (36, 37). The re-
duced plasma GLP-1 response in conjunction with accel-
erated glucose absorption in the proximal intestine in mor-
bidly obese subjects adds support to the “foregut theory.”
It is likely that diminished glucose-stimulated GLP-1 re-
lease in morbidly obese subjects reflects a reduction in
more distal intestinal exposure of glucose as a result of
increased proximal absorption. Given the documented an-
tidiabetic and appetite-suppressing effects of GLP-1 (29),
this attenuated release may contribute to hyperglycemia
and weight gain in obese subjects.
Our findings suggest that intestinal glucose transport-
ers rather than STRs play a more important role in the
regulation of glucose absorption and incretin responses in
morbidly obese humans. First, there were no relationships
evident between STR (T1R2) transcript levels and the ex-
pression of either glucose transporters, the rate of glucose
absorption, or incretin responses. This contrasts with our
recent data in healthy subjects and nonobese patients with
type 2 diabetes where changes in duodenal T1R2 tran-
scripts in response to duodenal glucose infusion were pos-
itively associated with glucose absorption and GIP levels
(22). Second, in morbidly obese subjects, we showed, for
the first time, that duodenal expression of SGLT-1 was
up-regulated at baseline, and rapidly modulated in re-
sponse to luminal glucose. In contrast, luminal glucose-
induced changes in SGLT-1 and GLUT2 were not evident
in healthy subjects in the current study, consistent with our
previous observations (21). Our results contrast with
those of Ait-Omar and colleagues (13), who reported in-
creased GLUT2 protein expression in obese type 2 diabetic
subjects. The lack of change in duodenal GLUT2 tran-
scripts in the current study may reflect to differences in
diabetic status between the cohorts and/or a complex re-
lationship between expression of GLUT2 transcript and
protein. Third, and possibly most importantly, increased
expression of SGLT-1 has been shown to be associated
J Clin Endocrinol Metab, March 2015, 100(3):968 –976
with accelerated glucose absorption and dysregulated in-
cretin responses. The role of intestinal STRs and GTs in the
pathogenesis of human obesity should be explored further
by the use of specific inhibitors such as lactisole (STR
inhibitor) (15) and/or phloridzin (competitive SGLT-1 in-
hibitor) (30).
The outcomes of the current study highlight the poten-
tial for therapeutic intervention in the treatment of obesity
and type 2 diabetes with 1) pharmaceutical agent(s) that
inhibit glucose transporters, especially intestinal SGLT-1,
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and/or 2) endoscopic devices that prevent exposure of the
proximal gut to carbohydrate, such as the endo-luminal
sleeve. These approaches may confer advantages similar to
that of Roux-en-Y gastric bypass surgery but without the
associated morbidity.
There are several limitations in the current study that
should be recognized. First, transcript levels of SGLT-1,
GLUT2, and T1R2 were quantified, rather than protein.
Although it is unknown whether changes in transcript ac-
curately reflect the activity of mucosal STRs and GLUT2
proteins, the positive relationship between glucose ab-
sorption and SGLT-1 transcript levels in obese subjects is
indicative of strong links between transcript and protein
changes for SGLT-1. Second, the lack of change in expres-
sion of T1R2 and GLUT2 may potentially relate to the
relatively short duration of glucose exposure or to changes
that occur subsequent to acute elevations in glycemia, as
we have described for T1R2 (22). The infusion duration of
30 minutes was chosen in part because of concerns that the
prolonged presence of an endoscope may prove uncom-
fortable for subjects and the rate of infusion was at the
upper end of the normal range of gastric emptying of glu-
cose. Given that all subjects tolerated the study well, it
would now be of interest to determine the effects of more
prolonged periods of glucose infusion on the expression of
intestinal STRs and GTs. In addition, because changes in
SGLT1 protein levels after an intraluminal glucose chal-
lenge may take up to 3 hours to manifest (38), extending
assessments of transcriptional activity and protein levels
of intestinal STRs and GTs over a longer period (ie, 4 h)
may reveal differences. Third, given that dietary intakes
were not systematically recorded, there may be potential
for differences in habitual dietary intake to alter expres-
sion of STRs and GTs. However, given that there were no
significant differences in the fasting expression of T1R2
and GLUT2 between the groups, the overall effect of di-
etary intake is likely to be minimal. Fourth, there was a sex
difference between the obese subjects (female predomi-
nant) and healthy controls (male predominant). Although
the effect of sex on the rate of intestinal glucose absorption
has not been formally assessed, data derived from studies
using an oral glucose tolerance test suggest that sex has no
doi: 10.1210/jc.2014-3144
effect on glucose absorption (39, 40), and our earlier stud-
ies also suggest that sex does not influence the expression
of intestinal STRs or GTs (23). Finally, although diabetes
was not formally excluded by a screening oral glucose
tolerance test in all subjects, HbA1c was less than 6.5%,
and fasting blood glucose less than 7 mmol/L, without
differences between the groups.
In conclusion, glucose absorption in the proximal in-
testine is accelerated in morbid obesity, in association with
increased expression of SGLT-1 transcripts and an incre-
tin profile that has the potential to promote both hyper-
glycemia and hyperinsulinemia. Although these findings
support the concept that accelerated glucose absorption in
the proximal gut may underlay the foregut theory of obe-
sity and type 2 diabetes, further investigation, including
the use of specific inhibitors of STR or GTs, is required.
Acknowledgments
Address all correspondence and requests for reprints to: As-
sociate Professor Nam Nguyen, Department of Gastroenter-
ology and Hepatology, Royal Adelaide Hospital, North
Terrace, Adelaide, South Australia, 5000, Australia. Email:
quoc.nguyen@health.sa.gov.au.
This work was supported by Project grant no. 104362 from
the Royal Adelaide Hospital, South Australia.
Disclosure Summary: The authors have nothing to disclose.
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