Metabolic and Hormonal Changes After Laparoscopic
Roux-en-Y Gastric Bypass and Sleeve Gastrectomy:
a Randomized, Prospective Trial
Ralph Peterli & Robert E. Steinert &
Bettina Woelnerhanssen & Thomas Peters &
Caroline Christoffel-Courtin & Markus Gass &
Beatrice Kern & Markus von Fluee & Christoph Beglinger
Published online: 22 February 2012
#The Author(s) 2012. This article is published with open access at Springerlink.com
Background The mechanisms of amelioration of glycemic
control early after laparoscopic Roux-en-Y gastric bypass
(LRYGB) or laparoscopic sleeve gastrectomy (LSG) are not
Methods In this prospective, randomized 1-year trial, out-
comes of LRYGB and LSG patients were compared, focusing
on possibly responsible mechanisms. Twelve patients were
randomized to LRYGB and 11 to LSG. These non-diabetic
patients were investigated before and 1 week, 3 months, and
overnight fast, and blood samples were collected before, dur-
(CCK), ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY
Results In both groups, body weight and BMI decreased
markedly and comparably leading to an identical improve-
ment of abnormal glycemic control (HOMA index). Post-
surgery, patients had markedly increased postprandial plas-
ma GLP-1 and PYY levels (p<0.05) with ensuing improve-
ment in glucose homeostasis. At 12 months, LRYGB
ghrelin levels approached preoperative values. The post-
prandial, physiologic fluctuation returned, however, while
LSG ghrelin levels were still markedly attenuated. One year
postoperatively, CCK concentrations after test meals increased
lessinthe LRYGBgroupthantheydidintheLSG group,with
the latter showing significantly higher maximal CCK concen-
trations (p<0.012 vs. LRYGB).
Conclusions Bypassing the foregut is not the only mecha-
nism responsible for improved glucose homeostasis. The
balance between foregut (ghrelin, CCK) and hindgut
(GLP-1, PYY) hormones is a key to understanding the
Bariatric surgery is the most successful weight loss therapy
for morbid obesity, achieving markedly improved glycemic
control (including diabetes resolution in most patients) and
Clinical Trial Registration: www.ClinicalTrials.gov. NCT00356213
R. Peterli (*):M. Gass:B. Kern:M. von Fluee
Department of Surgery, St. Claraspital,
4016 Basel, Switzerland
R. E. Steinert
Clinical Research Center, Department of Biomedicine,
4031 Basel, Switzerland
Department of Surgery, University Hospital,
4031 Basel, Switzerland
T. Peters:C. Christoffel-Courtin
Department of Medicine, St. Claraspital,
4016 Basel, Switzerland
Department of Gastroenterology, University Hospital,
4031 Basel, Switzerland
OBES SURG (2012) 22:740–748
satiety hormone balance [1–3]. Roux-en-Y gastric bypass
(RYGB) is effective for treating morbid obesity, inducing a
marked and sustained weight loss, even extending to
>10 years [1, 4–8]. Many surgeons therefore consider
RYGB as the bariatric procedure of choice, and nowadays,
a laparoscopic approach is most often undertaken (LRYGB)
Laparoscopic sleeve gastrectomy (LSG) is a newer
approach, initially applied to superobese patients with se-
vere co-morbidities where initial weight loss is intended to
enable a later, definitive LRYGB or biliopancreatic diver-
sion duodenal switch as part of a staged concept .
Recently published prospective studies compared results
from a sole LSG operation to LRYGB [13–17]. Equal early
weight loss, markedly improved glucose homeostasis, and
increased insulin, glucagon-like peptide 1 (GLP-1), and
peptide YY (PYY) levels after both procedures were
reported, though LSG seemed easier to perform and associ-
ated with fewer complications [15, 17]. The mechanisms of
weight loss following bariatric surgery include restriction,
malabsorption, and humoral changes [3, 17–22]. Bypass pro-
cedures inducehormonalchanges thatameliorateor evenlead
to complete remission of type 2 diabetes mellitus [3, 18–21].
In this present 1-year prospective, randomized trial, we com-
pared LRYGB and LSG outcomes and investigated potential
mechanisms responsible for the observed weight loss and met-
hindgut theory [19, 20].
Materials and Methods
All studies were performed according to the principles of the
Declaration of Helsinki. The Local Research and Ethics
Committee in Basel approved the study. The included
patients are a subgroup of an ongoing “Swiss Multicenter
Bypass or Sleeve Study” (SM-BOSS, NCT00356213), com-
paring LSG and LRYGB with regard to primary endpoints,
effectiveness and safety, to be closed as soon as 100 patients
per group have been operated. In this present special group
analysis, only non-diabetic patients from our center were
consecutively included for logistic reasons. Table 1 provides
baseline demographics of the present study. All patients
were informed of the risks and benefits of each procedure
and provided written, informed consent. Computer-generated
random numbers in a sealed envelope determined the type of
surgery (LRYGB or LSG). All operations were performed
laparoscopically and by the same surgeon. The LRYGB tech-
nique included a small gastric pouch with a 25-mm circular
pouch-jejunostomy to a 150-cm antecolic Roux limb and an
exclusion of 50 cm of biliopancreatic limb. The LSG was
done along a 35-F bougie from the angle of His to approxi-
mately 3–4 cm orally to the pylorus.
In this randomized, prospective, parallel group trial, all
patients underwent complete evaluation before the respec-
tive bariatric operation and during follow-up, including
medications, nutritional behavior, anthropometric and clinical
parameters, and blood sampling for glucose, triglycerides,
cholesterol, and other laboratory tests.
For meal studies, subjects were admitted to the Clinical
Research Center before the operation and 1 week and 3 and
12 months after the operation. After fasting overnight (at
least 10 h), an antecubital vein catheter was inserted for
phlebotomy. After taking the fasting sample, a 424-kcal
(1,775 kJ) liquid test meal containing 15 g carbohydrates,
25 g proteins, and 28 g fat was served to stimulate hormone
release. Blood was drawn at the following times: −15, 0
(corresponding to commencing meal intake), 15, 30, 45, 60,
into EDTA tubes containing aprotinin at a final concentration
of 500 KIU/mL of blood and a DPP-IV inhibitor; samples
were immediately processed and kept on ice to retard peptide
breakdown. After centrifugation at 4°C, plasma samples were
kept frozen at −20°C until analysis.
The following hormones were investigated: cholecystokinin
(CCK), GLP-1, PYY, insulin, and ghrelin. CCK concentra-
tions were measured using a sensitive radioimmunoassay
based on an antiserum that recognizes the sulfated tyrosine
residue of all CCK molecules, but has little cross-reactivity
with sulfated gastrin (<1%) and no cross-reaction with
unrelated gastrointestinal peptides. Plasma samples were
Table 1 Baseline demographics
Fasting insulin (μU/mL)
Fasting glucose (mmol/L)
Data are presented as means ± SD. No significant differences between
the two groups were detected
OBES SURG (2012) 22:740–748741
extracted with ethanol, and125I-CCK-8 was used as a label.
The lowest concentration currently measurable was
0.6 pmol/L plasma, using CCK-8 as a standard (details
previously described ).
The lowest ghrelin level detectable by the commercially
available kit (Linco Research Inc. St. Charles, 63304 MO,
USA) used is 93 pg/mL/100 μL sample. At 1 ng/mL, the
intra- and inter-assay coefficients of variation were 10.0%
and 14.7%, respectively .
kit (Linco Research Inc.); the assay used is highly specific for
measuring active GLP-1 but does not detect other GLP-1
forms (e.g., 1–36 amide, 1–37, 9–36 amide, or 9–37). This
assay sequentially (1) captures active GLP-1 with a monoclo-
nal antibody (binds specifically to the N-terminal region of
active GLP-1 molecules); (2) removes unbound materials; (3)
binds an anti-GLP-1–alkalinephosphatase detection conjugate
to immobilized GLP-1; (4) removes unbound conjugate; and
(5) quantifies bound detection conjugate by adding methyl
umbelliferyl phosphate which, with alkaline phosphatase,
forms fluorescent umbelliferone. Since the degree of fluores-
cence is directly proportional to the active GLP-1 concentra-
tion, the latter is interpolated from a curve using reference
standards of known active GLP-1 concentrations. The intra-
and inter-assay variabilities were below 9% and 13%, respec-
tively. The lowest level of GLP-1 currently detectable is 0.25
pmol/L (100 μL plasma sample) .
PYY was measured with a commercially available kit
(Linco Research Inc.). The guinea pig antibody displays
100% cross-reactivity with human PYY1-36 and human
PYY3-36, but not with human pancreatic polypeptide,
NPY, leptin, or ghrelin). [125I]PYY, purified by HPLC (spe-
cific activity 302 μCi/μg), was used as a label. The lowest
sample). The intra- and inter-assay variabilities were below
9% and 9%, respectively .
The lowest level of insulin currently detectable with the
commercial radioimmunoassay (Cisbio International, 30200
Bagnols, France) used is 4.6 μU/mL (100 μL sample). The
intra- and inter-assay coefficients of variation were 12.2% and
9.0%, respectively . Blood glucose concentrations were
measured using a commercial hexokinase-glucose-6-phos-
phate-dihydrogenase method (Roche,4070Basel,Switzerland).
Data analysis was performed using the statistical software
package, SPSS for Windows V. 15.0 (SPSS Inc., Chicago,
IL 60606-6306, USA). Values are reported as means ± SEM.
Descriptive statistics were used for demographic variables,
such as age, weight, height, and BMI. Hormones were ana-
lyzed by calculating time courses, the area under the plasma
concentration time profiles (AUC), and maximum plasma
concentrations (Cmax). The general linear model procedure
of repeated measuresANOVA using simplecontrastwas used
to test for significant differences in longitudinal changes from
baseline. To test for significant differences between the two
treatment groups, the Student’s independent t test and the
Bonferroni–Holm correction to adjust for multiplicity of test-
ing were used. All tests were two-tailed, with p<0.05 consid-
ered statistically significant.
Twelve patients were randomized to LRYGB and 11 to
LSG. All surgical procedures were successfully concluded
laparoscopically with no conversion to open surgery. Table 1
provides demographics: Both groups had similar preopera-
tive characteristics, including BMI, a clearly disturbed glu-
cose homeostasis, expressed as elevated fasting glucose and
insulin concentrations, and a highly pathological HOMA
index, indicating insulin resistance. Normal values for the
HOMA index were defined from values obtained in a test
series of 60 healthy normal weight persons at our institution.
All patients underwent a complete evaluation at 1 week,
3 months, and 1 year postsurgery.
Weight Loss and Glycemic Control
Both procedures achieved a marked reduction in body weight
and BMI(Table2). LRYGB patientslostslightlymoreweight
at 3 and 12 months, but this was not statistically significant.
Accordingly, excessive BMI loss at 12 months was 77%
(LRYGB) and 65.6% (LSG) (both p<0.001 vs. preoperative
values,nosignificant difference between the groups; Table2).
Fasting glucose and insulin levels dropped, and insulin resis-
tance (HOMA index)returnedtonearnormalvalues at1 year,
Meal-Stimulated Satiety Hormone Secretion
Upper Gastrointestinal Peptides
Ghrelin Physiological ghrelin levels in the non-obese are
characterized by a rise during fasting periods and a rapid
postprandial fall. The postprandial ghrelin inhibition was
missing in all our patients preoperatively. One week post-
operatively, ghrelin levels were lower than preoperatively in
both groups (p<0.05 vs. preop values). Lower ghrelin levels
could be observed for fasting and meal-stimulated ghrelin
levels as well. However, the decrease was more prominent in
the LSG group, both at 1 week and 3 months postoperatively
742OBES SURG (2012) 22:740–748
(lower AUC and lower Cmax, Fig.3a, c; Table3).Despite the
initial fall, fasting ghrelin levels even exceeded preoperative
values in the LRYGB group after 1 year, but the physiological
response with the typical postprandial fall was reestablished.
Contrarily, patients with LSG showed permanently attenuated
ghrelin levels after 1 year (although slightly higher than at
3 months), interestingly without postprandial decline.
CCK Both groups showed a normal CCK response after stim-
ulation with the standardized test meal before operation. Post-
operatively, patients with LSG as well as with LRYGB had
elevated CCK concentrations. The1-week values were mark-
edly increased, but the effect was short-lasting (60 min). The
postprandial test meal response 1 year postoperatively revealed
the LSG group. Differences in maximal CCK concentrations
were statistically significant (p<0.012) (Fig. 3b, d; Table 3).
Lower Gastrointestinal Peptides
GLP-1 Both groups had a defective GLP-1 response to test
meal intake before the operation. LRYGB patients exhibited
an early marked increase in postprandial GLP-1 levels at
1 week after this form of bariatric surgery (p<0.001 vs.
preop; Fig. 4a, c; Table 3). The markedly increased GLP-1
response was unchanged after 3 months and 1 year in the
LRYGB group; a similar but less prominent pattern was
seen in the LSG group, although the AUC was numerically
clearly smaller in the LSG patients.
Peptide YY Before surgery, PYY levels did not significantly
increase in response to food, suggesting a defective PYY
response. Fasting PYY levels decreased after surgery in both
study groups and expressed an exaggerated postprandial PYY
response 1 week after the operation, an effect that was slightly
less prominent but still present 3 months and 1 year later
(Fig. 4b, d; Table 3). The response pattern and secretory
output were comparable, with no significant differences.
Bariatric surgery is the only current treatment option that
leads to sustained weight loss and reduction in mortality for
morbidly obese patients [1–3]. LRYGB is presently the gold
standard, resulting in greater weight loss than purely restric-
tive procedures [1, 2]. LSG is a novel bariatric procedure
that avoids intestinal bypass. In this prospective, random-
ized, controlled study, we show that, at 1 year, weight loss
and sustained improvement in glycemic control manifest
themselves to almost the same extent and at a similar pace
after LRYGB and LSG procedures, which are both safe and
highly effective therapies for morbid obesity. These outcomes
contrast with those following adjustable gastric banding, a
be a reliable alternative to LRYGB and also suggest that
foregut exclusion cannot be the sole explanation for the
marked weight loss and improvement in glucose metabolism
satiety hormones based on their release site (foregut, hindgut).
The general consensus is that many of the improvements in
Table 2 Weight, BMI, and EBMIL (%) after LRYGB or LSG
Parameter TreatmentPreoperative1 week 3 months1 year
Data are presented as means ± SD. No significant differences between the two groups at the same time points were detected
EBMIL excessive BMI loss
*p≤0.01; **p≤0.001 0 significant differences compared to preoperative within each group
Fig. 1 HOMA index in the two groups of patients (LRYGB and LSG)
before, as well as 1 week and 3 and 12 months after the respective
operation. Data are means±SEM
OBES SURG (2012) 22:740–748743
Fig. 2 Fasting and meal-stimulated time courses of glucose and insu-
lin in two groups of patients (LRYGB and LSG) before, as well as
1 week and 3 and 12 months after the respective operation. a Glucose
in the LRYGB group, b insulin in the LRYGB group, c glucose in the
LSG group, d insulin in the LSG group. Data are means ± SEM
Fig. 3 Fasting and meal-stimulated time courses of ghrelin and CCK
in the two groups of patients (LRYGB and LSG) before, as well as
1 week and 3 and 12 months after the respective operation. a Ghrelin in
the LRYGB group, b CCK in the LRYGB group, c ghrelin in the LSG
group, d CCK in the LSG group. Data are means ± SEM. Details on the
statistical analysis are given in Table 3
744 OBES SURG (2012) 22:740–748
glycemic control achieved by bariatric surgery are likely to be
associated with alterations in the secretion of hormones from
the gut. LSG restricts the volume capacity of the stomach; in
contrast, the LRYGB procedure excludes food from the stom-
gut to altered chyme [3, 18, 21]. It is most likely that both
duodenal exclusion (foregut hypothesis) and rapid exposure
of distal small intestine to nutrients (hindgut hypothesis) are
mechanisms that potentially contribute to improved glycemic
control. The two procedures induce slightly different hormon-
al patterns over time, although the improvement in weight
loss, BMI, and glucose homeostasis remains comparable
1 year after surgery. Our observations provide a basis for
explaining the procedures’ possible mechanisms.
Foregut vs. Hindgut Hypotheses It has been proposed that
the anatomical rearrangement alters food passage dynamics,
evoking changes in gut hormone secretion to food [3,
19–21, 23]. A variety of studies focusing on hormonal
changes after LRYGB have demonstrated decreased ghrelin
levels on the one hand and increased levels of GLP-1, PYY3-
36, and adiponectin after weight loss on the other hand. These
changes support the possibility of hormonal weight-
independent effects [3, 18–21, 23, 24]. Very few studies have
investigated hormonal changes after LSG [14, 15]; here, we
document markedly decreased ghrelin levels and increased
concentrations of CCK, GLP-1, and PYY3-36.
Consistent with the hindgut hypothesis, RYGB creates a
shortcut to the distal small intestine; the stomach is restricted,
and chyme is excluded from the foregut. Endogenous GLP-1
and PYY levels were low in both groups before surgery,
suggesting diminished endogenous levels of these hormones
inobeseindividuals[3, 18, 21].Here,postprandialGLP-1and
PYYvalues dramatically and lastingly increased after RYGB,
most likely by direct nutrient contact with distal intestinal L
cells. Surprisingly, as this procedure does not alter small
intestine food passage, a similar increase in GLP-1 and PYY
was seen after LSG. An explanation for this might be that
GLP-1 release is not only triggered via direct nutrient contact
with distal L cells . Another stimulus for GLP-1 secretion
Table 3 Upper (ghrelin and
CCK) and lower (GLP-1 and
PPY) gastrointestinal peptides
after LRYGB or LSG,
preoperative and at 1 week,
3 months, and 1 year postsurgery
Data represent means ± SEM.
p<0.05 0 significant differences
between the two groups at the
same time points
NS not significant, AUC area
under the concentration
time profile, Cmax maximum
***p≤0.001 0 significant
differences compared to the
preoperative within group
ParameterTreatment Preoperative1 week 3 months1 year
AUC (ng min/mL)LRYGB
AUC (pmol min/L) LRYGB
AUC (pmol min/L) LRYGB
AUC (ng min/mL)LRYGB
OBES SURG (2012) 22:740–748745
is derived by proximal nutrient signals, e.g., increased CCK
secretion. CCK blood levels are stimulated by long chain free
fatty acid formation . This could explain the markedly
more pronounced CCK stimulation in the LSG group. As
expected, both operations greatly enhanced postprandial
GLP-1 and PYY surges. The hormonal changes and weight
loss clearly enhanced insulin secretion and sensitivity, as
estimated by the HOMA index. Of note, glucose homeostasis
began improving 1 week after surgery, even before any mean-
ingful weight loss. Although weight loss is associated with
improved glucose control, it has been suggested that post-
RYGB improvement in glucose metabolism is greater than
with equivalent weight loss from other regimens [3, 5–8, 21,
27]. Here, we provide experimental evidence that improve-
ment in glucose control is similar with LSG as well as with
Furthermore, at 1 year follow-up, BMI values were similar
with both procedures, and the changes paralleled improve-
ments in dyslipidemia (lower triglycerides, increased HDL
cholesterol levels) . The LSG results are interesting: In
contrast to adjustable gastric banding, which like LSG is a
gastric restrictive procedure, ameliorated glycemic control
was observed already at 1 week postoperatively, even before
substantial weight loss occurred. These findings concur with
results from Lee et al., who compared matching patients with
moderate obesity (BMI 27–35 kg/m2) but poorly controlled
diabetes undergoing either sleeve gastrectomy or a sleeved
version of RYGB. After 6 months, both procedures achieved
equivalent weight loss and improvement in glycemic control
A potential explanation for PYY and GLP-1 increases
following LSG could be accelerated gastric emptying and
earlier contact of chyme with the L cells of the hindgut.
Scintigraphic studies performed up to 2 years after LSG
showed accelerated gastric emptying for solid and liquid
foods [31, 32]. In contrast, a recent MRI study, focused
on the motility changes postoperatively, could demon-
strate two different functional regions in the remnant
stomach: The antral motility remained unchanged even
very early postoperatively, whereas the sleeved stomach
seemed to be nearly aperistaltic even 6–8 months post-
The clinicalimportanceofincreasedPYYlevelsis unclear:
over-expression of PYY in transgenic mice did not change
weight or food intake, but other studies have proposed that
pharmacologic concentrations of PYY function as anorexic
signals, reducing food intake, body weight, and body fat mass
[34, 35]. In summary, glycemic control improved in both
marked increases in GLP-1 (although slightly more so in the
RYGB group) and PYY secretions and changes in meal-
stimulated CCK release.
Fig. 4 Fasting and meal-stimulated time courses of GLP-1 and PYYin
the two groups of patients (LRYGB and LSG) before, as well as 1 week
and 3 and 12 months after the respective operation. a GLP-1 in the
LRYGB group, b PYY in the LRYGB group, c GLP-1 in the LSG
group, d PYYin the LSG group. Data are means ± SEM. Details on the
statistical analysis are given in Table 3
746 OBES SURG (2012) 22:740–748
Ghrelin Hypothesis The relationship between bariatric sur-
gery and ghrelin levels is controversial. Some years ago,
Cummings and co-workers provided initial evidence for
reduced secretion of the orexigenic, prodiabetic, foregut
hormone, ghrelin, contributing to the anorexic and anti-
diabetic effects of RYGB . Other authors have
failed to confirm these findings . Here, we present
postprandial ghrelin profiles over a 1-year period fol-
lowing both procedures. The first interesting observation
is the lack of postprandial suppression of ghrelin levels
before surgery in both groups, suggesting that the phys-
iological regulation of ghrelin secretion is, at least,
partially lost in morbidly obese subjects. In sleeve gas-
trectomy patients, ghrelin levels were markedly reduced
and remained extremely low for several months after the
operation, but showed a small (but still markedly re-
duced) increase in ghrelin after 1 year. This finding is
not surprising because the stomach produces the major-
ity of ghrelin. In contrast, ghrelin levels were reduced in
post-RYGB patients, but not as pronouncedly so as with
LSG. Over time, ghrelin levels returned to preoperative
levels but with a major difference: Patients had regained
the physiologic postprandial suppression after meal in-
gestion 1 year after surgery.
The changes in ghrelin can contribute to the marked
decrease in weight loss, appetite, and food intake that
follows both surgical procedures, but should be more
prominent after the LSG procedure [7, 36]. Recent
studies in mice deficient for both ghrelin and its recep-
tor indicate that a complete functional absence of ghre-
lin signaling is sufficient to decrease body weight and
fat mass [38–40]. The changes in ghrelin should also
contribute to improved glucose homeostasis, as ghrelin
can stimulate insulin counter-regulatory hormones, sup-
press the insulin-sensitizing adipokine, adiponectin, and
inhibit insulin secretion [28, 38–40]. From these results,
we infer that part of the glycemic improvement after
LSG arises from reduced ghrelin secretion.
Our observations are intriguing and to a certain extent
unexpected as neither the upper (foregut) nor the distal
(hindgut) intestinal hypothesis can fully account for im-
provement in glucose homeostasis. These results suggest
rather that the balance between foregut (ghrelin, CCK)
and hindgut hormones (GLP-1, PYY) is a key for under-
standing the improved glucose homeostasis. Another im-
portant factor for the improvement of glucose homeostasis is
nutrient sensing and metabolism influencing insulin sensitiv-
ity, thus supporting the nutrient-related hormone release and
balance. To completelyunderstandthe effects and interactions
how different bariatric procedures influence nutrient-sensing
regulatory mechanisms, influence gut hormone balance,
and finally affect glucose homeostasis, more research is
for editorial assistance. We are indebted to Luisa Baselgia and the team at
the Clinical Research Center for excellent assistance in performing
the meal studies and Gerdien Gamboni for expert technical assis-
tance in the laboratory. This research was supported by grants from
the Swiss National Science Foundation (grant nos. 320000-118330
and 320000-120020), a grant from the Stiftung zur Förderung der
Forschung in der Gastroenterologie, and by a grant from Ethicon
Endosurgery GmbH, Europe.
for Ethicon Endosurgery GmbH, Europe. CB has received an unre-
stricted grant from Hoffmann-LaRoche, Basel, Switzerland. All other
authors declare that they have no conflict of interest.
RP has received unrestricted grants from and consults
Commons Attribution License which permits any use, distribution, and
reproduction in any medium, provided the original author(s) and the
source are credited.
This article is distributed under the terms of the Creative
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