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gastrointestinal hormone after bariatric surgery .pdf



Nom original: gastrointestinal hormone after bariatric surgery.pdf
Titre: Secretion and Function of Gastrointestinal Hormones after Bariatric Surgery: Their Role in Type 2 Diabetes
Auteur: Alpana Shukla

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GASTROINTESTINAL HORMONES AFTER BARIATRIC SURGERY

REvIEw

Secretion and Function of Gastrointestinal Hormones
after Bariatric Surgery: Their Role in Type 2 Diabetes
Alpana Shukla MD, Francesco Rubino MD
Section of Gastrointestinal Metabolic Surgery, Department of Surgery, Weill Cornell Medical College and New York
Presbyterian Hospital, New York, New York, United States

ABSTRACT
Bariatric surgical procedures were designed primarily to
promote weight loss in morbidly obese individuals. There
is increasing evidence that, apart from producing durable
weight loss, bariatric surgery powerfully ameliorates type 2
diabetes in the majority of morbidly obese individuals. Its
role is also being investigated in less obese patients, with
generally favourable short-term results. While massive
weight loss undoubtedly plays an important role in consolidating the long-term anti-diabetic impact of bariatric
surgery, the role of the altered hormonal gut milieu is now
known to be integral to improved glucose homeostasis.
Changes in levels of glucagon-like peptide 1 (GLP-1), gastric
inhibitory peptide, peptide YY (PYY) and ghrelin have been
described following metabolic surgery. The various surgical
procedures differ in their respective abilities to modulate
gut hormones, depending on whether they involve intestinal diversion or are purely restrictive. The postprandial
GLP-1 response to an oral glucose tolerance test or mixed
test meal is augmented following gastric bypass surgery or
biliopancreatic diversion, while no change is observed after
gastric banding. Increased PYY levels have been reported
following gastric bypass. Levels of ghrelin, an orexigenic
hormone, do not rise following weight loss due to gastric
bypass, although this is not reported consistently in all
studies. In this paper, the authors review the current evidence regarding the use of metabolic surgery to treat type 2
diabetes, focusing on published data from animal and
human studies regarding gut hormone secretion and function following bariatric surgery.

la majorité des personnes qui présentent une obésité morbide.
Son rôle est aussi à l’étude chez les personnes moins obèses et
elle donne des résultats en général favorables à court terme
chez eux. La perte massive de poids joue sans doute un rôle
important dans la consolidation de l’effet antidiabétique à
long terme de la chirurgie bariatrique, mais on sait maintenant que l’altération du milieu hormonal intestinal joue un
rôle intégral dans l’amélioration de l’homéostasie du glucose.
Des modifications des taux de GLP-1 (glucagon-like peptide 1),
de peptide inhibiteur gastrique, de peptide YY (PYY) et de
ghréline ont été décrites après la chirurgie métabolique.
L’importance de la modulation des hormones intestinales que
produisent les diverses interventions chirurgicales varie selon
que la chirurgie est une dérivation intestinale ou purement
restrictive. La réponse postprandiale du GLP-1 à une charge
orale en glucose ou à un repas d’épreuve mixte augmente
après une chirurgie de pontage gastrique ou une dérivation
biliopancréatique, mais la pose d’un anneau gastrique ne la
modifie pas. Une augmentation des taux de PYY a été signalée
après un pontage gastrique. Les taux de ghréline, hormone
orexigène, n’augmentent pas après la perte de poids produite
par un pontage gastrique, bien que toutes les études ne le
signalent pas de façon systématique. Les auteurs de l’article
passent en revue les données actuelles sur le recours à la chirurgie métabolique pour le traitement du diabète de type 2
et mettent l’accent sur les comptes rendus d’études menées
chez l’animal et chez l’humain sur la sécrétion et la fonction
des hormones intestinales après la chirurgie bariatrique.
MOTS CLÉS : chirurgie bariatrique, hormones intestinales,

diabète de type 2
KEywORDS: bariatric surgery, gut hormones, type 2 diabetes

RÉSUMÉ
Les interventions chirurgicales bariatriques visaient au départ
surtout à favoriser la perte de poids dans les cas d’obésité
morbide. Toutefois, il semble de plus en plus probable qu’en
plus de produire une perte de poids durable, la chirurgie bariatrique améliore considérablement le diabète de type 2 chez

INTRODUCTION
Type 2 diabetes is the most common endocrine disorder,
with an estimated 285 million adults worldwide affected by
the disease (1). Diabetes is epidemiologically and pathogenetically linked to obesity through the mechanisms of insulin resistance, inflammation and subsequent lipotoxicity of
beta cells (2). Progressive beta-cell failure and hyperglycemia

Address for correspondence: Francesco Rubino MD, Chief of Gastrointestinal Metabolic Surgery
Weill Cornell Medical College, 1300 York Avenue, New York, New York, 10065 United States. E-mail: frr2007@med.cornell.edu
CANADIAN JOURNAL OF DIABETES. 2011;35(2):115-122.

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CANADIAN JOURNAL OF DIABETES

CONVENTIONAL BARIATRIC/METABOLIC PROCEDURES
Figure 1. Roux-en-y
gastric bypass

Figure 2. Laparoscopic
adjustable gastric banding

Figure 3. Biliopancreatic
diversion

A surgical stapler is used to
create a small gastric pouch;
ingested food bypasses ~95%
of the stomach, the entire
duodenum, and a portion of
the jejunum.

The upper part of the stomach
is encircled with a constrictive
saline-filled tube; the amount
of restriction can be adjusted by
injecting or withdrawing saline
solution.

The stomach and small
intestine are surgically
reduced so that nutrients are
absorbed only in a 50-cm
“common limb.”

are characteristic of type 2 diabetes. Medical management
of diabetes involves a step-wise approach, from lifestyle
intervention (physical activity and nutrition therapy) to
oral antihyperglycemic agents and then insulin. It aims to
address the dual issues of defective insulin secretion and
insulin resistance, and often requires a combination of treatment modalities to achieve and maintain optimal glycemic
control. The recent understanding of the enteroinsular axis
and the role of glucagon-like peptide 1 (GLP-1) in maintaining glucose homeostasis paved the way for the use of GLP-1
analogues and dipeptidyl peptidase-4 inhibitors in clinical
practice. Although these agents have broadened the therapeutic options available for improving glycemic control,
remission of diabetes remains an elusive target.
Several gastrointestinal operations that were initially
designed to promote weight loss have been shown to induce
remission of type 2 diabetes and dramatically improve
other metabolic abnormalities, including hyperlipidemia
and hypertension (3). There is ample data to confirm the
safety and efficacy of conventional bariatric operations—
particularly Roux-en-Y gastric bypass (RYGB) (Figure 1) and
laparoscopic adjustable gastric banding (LAGB) (Figure 2)
—in morbidly obese patients (4,5).
The use of experimental procedures, as well as conventional bariatric operations, is increasingly being explored in
less obese patients who have diabetes, with generally favourable results; however, further assessment of the risk- benefit
ratio is needed. Several studies have demonstrated that the
amelioration of metabolic dysfunction is attributable not only
to weight loss and caloric restriction, but also to endocrine
changes resulting from surgical manipulation of the gut (6,7).

Figure 4. Sleeve
gastrectomy
A longitudinal (sleeve)
resection of the stomach
reduces the functional
capacity of the stomach and
eliminates the ghrelin-rich
gastric fundus.

GLyCEMIC CONTROL AFTER BARIATRIC
SURGERy
Several studies have demonstrated impressive improvements
in type 2 diabetes among patients with morbid obesity following a variety of gastrointestinal surgical procedures. In a metaanalysis of 136 studies involving 22 094 patients with type 2
diabetes resolution defined as persistent normoglycemia
without the need for diabetes medications, Buchwald and
colleagues (3) reported an overall 77% remission of type 2
diabetes after bariatric surgery. The mean procedure-specific
resolution of type 2 diabetes was impressive: 48% for LAGB;
68% for vertical banded gastroplasty (VBG); 84% for RYGB;
and 98% for biliopancreatic diversion (BPD) (Figure 3). It
must be noted, however, that most of these studies were retrospective, with a follow-up duration of only 1 to 3 years.
Two large case-series studies by Pories and colleagues
(330 patients) and Schauer and colleagues (191 patients)
focused principally on diabetes outcomes after RYGB (8,9).
Mean fasting blood glucose (FBG) decreased to near-normal
levels (6.5 and 5.4 mmol/L in the 2 studies, respectively), and
glycated hemoglobin fell to normal levels (6.6% and 5.6%,
respectively) without diabetes medication in 89% and 82%
of patients, respectively. The multicentre Swedish Obese
Subjects (SOS) study (10) compared bariatric surgery (LAGB,
n=156; VBG, n=451; RYGB, n=34) vs. a control group of
well-matched obese patients managed conservatively. Mean
fasting glycemia tended to increase during the study in nonsurgical controls (18.7% at 10 years), whereas a substantial
decrease was seen in surgical patients at 2 years (−13.6%) and
10 years (−2.5%). At 2 years, 72% of subjects with type 2
diabetes in the surgical group achieved disease remission,

GASTROINTESTINAL HORMONES AFTER BARIATRIC SURGERY

INVESTIGATIONAL GASTROINTESTINAL PROCEDURES
Figure 5. Duodenal-jejunal bypass
The operation consists of a
stomach-sparing bypass of a
short portion of proximal inestine,
equivalent to the amount of
intestine bypassed in a standard
gastric bypass (RYGB)–Figure 5A.

A

A variant of this procedure includes
the association of proximal intestinal
bypass with sleeve resection of the
stomach (DJB-SG) to reduce potential
for marginal ulcerations and increase
clinical efficacy–Figure 5B.

Figure 6. Ileal transposition
A small segment of ileum is surgically interposed into the proximal
small intestine, enhancing its exposure to ingested nutrients.

B

compared with 21% in the medically treated arm. At 10 years,
the proportion of subjects in whom remission was sustained
declined to 36% in the surgical group and 13% in the medical group (11). It must be noted, however, that the majority
of patients underwent gastric restrictive procedures rather
than RYGB in this study. Two recent studies have addressed
the issue of recurrence of type 2 diabetes following RYGB.
In a retrospective review of 42 patients, DiGiorgi and
colleagues (12) reported the re-emergence of type 2 diabetes in 26% of patients with initial remission following
RYGB after a mean follow-up of 5 years. Chikunguwo and
colleagues (13) followed 177 obese patients with diabetes
after RYGB and noted that durable remission (>5 years) was
achieved in 56.9% of patients, while the disease recurred in
43% of those with initial resolution of diabetes.
Experimental studies in non-obese animals suggest that
surgery may be beneficial for moderately obese or nonobese patients with type 2 diabetes. Sporadic but consistent
observations of type 2 diabetes remission have been reported
in the literature following gastrointestinal operations with
anatomical similarities to bariatric procedures performed
for gastric cancer or ulcer in non-obese patients (14). More
recently, RYGB, sleeve gastrectomy (SG) (Figure 4) and modified bariatric operations, including duodenal-jejunal bypass
(DJB) (Figure 5A and 5B) and ileal interposition (Figure 6),
have been reported to improve glycemia in patients with
body mass index (BMI) 22.0 to 34 kg/m2 (15-18).

NON-GLyCEMIC METABOLIC EFFECTS OF
BARIATRIC SURGERy
Several studies have demonstrated that the benefits of bariatric

surgery extend beyond amelioration of hyperglycemia, and
include improved lipid profile and blood pressure control.
A meta-analysis of 236 studies and 22 094 patients showed
marked decrease in total cholesterol, low-density lipoprotein
cholesterol and triglycerides after bariatric procedures (3).
Approximately 70% of patients experienced an improvement in hyperlipidemia, whereas hypertension improved or
resolved in 79% of patients. These beneficial effects of metabolic surgery have also been reported in patients with BMI
<35.0 kg/m2 (15,16). Long-term survival in morbidly obese
patients with and without type 2 diabetes is better in surgically treated patients than matched control individuals who
do not undergo surgery. A retrospective cohort study involving 7925 severely obese patients treated surgically with RYGB
and 7925 similarly obese matched controls who did not
undergo surgery examined long-term mortality from various
causes (19). After a mean follow-up of 8.4 years, surgery
reduced overall mortality by 40%, cardiovascular mortality
by 56%, cancer mortality by 60% and diabetes-related mortality by 92%. In the SOS study, patients in the surgical group
(the majority of whom had purely restrictive procedures, i.e.
gastric banding or VBG) had a 24% nonadjusted decrease in
overall mortality, compared with matched controls (10).

MECHANISMS OF DIABETES REMISSION
FOLLOwING GASTROINTESTINAL SURGERy
Effects of weight loss
Improvement in glucose homeostasis is an expected outcome
of weight loss in obese individuals due to either medical or
surgical intervention. Insulin sensitivity increases markedly
after bariatric surgery, accompanied by elevated adiponectin
CANADIAN JOURNAL OF DIABETES. 2011;35(2):115-122.

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CANADIAN JOURNAL OF DIABETES

levels, enhanced markers of insulin signalling in key target
tissues, favourable changes in enzymes mediating glucose
and fatty acid metabolism, and decreased intramuscular and
intrahepatic lipids (6).

Weight-independent antidiabetic effects
There is increasing evidence that certain bariatric procedures exert their antidiabetic effects through mechanisms
that are independent of weight loss and caloric restriction.
Following RYGB and BPD, type 2 diabetes typically resolves
before major weight loss has occurred (6,7). Such rapid
remission of diabetes is not observed following purely
restrictive procedures such as VBG or LAGB. Moreover,
greater improvement has been shown in glucose homeostasis after RYGB than with equivalent weight loss from purely
gastric-restrictive procedures or non-surgical interventions
(20,21). RYGB also restores the normal beta-cell acute insulin response to glucose that is characteristically lost in type 2
diabetes (22). Although the precise mechanisms through
which type 2 diabetes remission occurs following metabolic
surgery remain to be fully elucidated, it is clear that endocrine changes due to rearrangement of the gut anatomy play
an important role.

CHANGES IN INCRETINS
Several studies have examined changes in levels of incretin
hormones following bariatric surgery.

GLP-1
GLP-1 is an incretin peptide that increases glucose tolerance by enhancing glucose-dependent insulin secretion,
suppressing glucagon secretion, inhibiting gastric emptying,
increasing beta-cell mass (at least in experimental animals)
and possibly improving insulin sensitivity (6). GLP-1 is
produced primarily in the ileum and colon by nutrientstimulated L cells.
Early studies reported an increased fasting and postprandial enteroglucagon (previously used as a marker for
GLP-1) after both gastric bypass and jejunoileal bypass (23).
Subsequent changes in both fasting and postprandial GLP-1
levels have been reported in several studies.
The postprandial GLP-1 response is consistently observed
to be augmented during an oral glucose tolerance test or mixed
meal test after gastric bypass or BPD in obese subjects with
and without diabetes (6,24). The rise in GLP-1 occurs as early
as 2 days after surgery and is shown to persist at 6 months and
1 year (23). In contrast to gastric bypass and BPD, purely gastric restrictive procedures (i.e. VBG and gastric banding) are
not associated with any change in GLP-1 levels (25).
Gastric inhibitory peptide
The data regarding gastric inhibitory peptide (GIP) are not

as consistent as those reported for GLP-1. Studies have
found either a reduction of or no change in fasting GIP levels after GBP or BPD. Stimulated GIP levels after a test meal
were reported by Laferrère and colleagues to be increased
1 month after gastric bypass (24); however, other groups
reported a reduction in GIP levels 3 to 12 months after
surgery (23,26).

Incretin effect
Apart from the changes in GLP-1 and GIP levels, it been
demonstrated that the incretin effect on insulin secretion,
which is impaired in type 2 diabetes, is restored to normal
levels 1 month after gastric bypass (22). This effect was
shown to persist at 1 year following surgery in subjects with
type 2 diabetes of <5 years’ duration.
Ghrelin
Ghrelin is an orexigenic hormone produced primarily by the
stomach. Administration of ghrelin or its analogues stimulates food intake. Ghrelin levels have an inverse relationship
with body weight; consequently, obese individuals have
lower ghrelin levels. Weight loss by diet results in increased
ghrelin levels, perhaps contributing to the resistance to lifestyle interventions for obesity. Recent data from human and
animal studies suggest a role for ghrelin in glucose homeostasis beyond its effect on caloric intake. In fact, ghrelin can
stimulate insulin counterregulatory hormones, suppress
the insulin-sensitizing hormone adiponectin, block hepatic
insulin signalling at the level of phosphatidylinositol3-kinase and inhibit insulin secretion (27). Ghrelin deletion
in diabetic ob/ob mice has also been shown to reduce FBG
and insulin levels, and improve glucose tolerance (28).
Several groups have reported decreased ghrelin levels
after RYGB, which may partly account for the improved
glycemia (23,29). Other studies, however, have reported either unchanged or increased ghrelin levels (6,30).
Cummings and colleagues (6) suggested that these heterogeneous findings may be explained by differences in the surgical techniques used, possibly involving variations in the
degree of exclusion of gastric fundus or variable treatment
of the vagus nerve. These variations may account for the disruption of ghrelin secretion in most, but not all, cohorts.
Data from rodent and human studies expectedly indicate
that ghrelin levels are suppressed following resection of the
ghrelin-rich gastric fundus, as occurs with SG (Figure 4)
(31). In contrast, ghrelin levels show the normal physiological rise with weight loss after gastric banding or VBG
(Figure 2) (32).

CHANGES IN GUT HORMONES
Peptide YY
Peptide YY (PYY) is an anorexigenic hormone co-secreted

GASTROINTESTINAL HORMONES AFTER BARIATRIC SURGERY

with GLP-1 from intestinal L cells in response to food
intake. PYY3-36 has been shown to decrease food intake
in humans when injected. Experimental studies in rodents
suggest that PYY may directly ameliorate insulin resistance (33). Several studies have reported elevated PYY
levels after gastric bypass. In a recent prospective, nonrandomized controlled study comparing the effects of
medical and surgical treatment on PYY levels after similar weight loss, it was observed that the PYY area under
the curve increased following gastric bypass and SG,
but remained unchanged in medically treated patients
(34). In another prospective, randomized controlled trial
comparing the effects of laparoscopic RYGB with laparoscopic SG, PYY levels increased similarly after either
procedure (35). DePaula and colleagues evaluated hormonal changes following ileal transposition (Figure 6)
associated with SG in subjects with type 2 diabetes
(BMI 20–34 kg/m2) and noted significant increases in PYY
levels (18). Another study compared the impact of RYGB
and LAGB on PYY levels: PYY levels 30 min post-meal stimulation were ~3.5-fold greater than levels before surgery,
and were significantly greater than in LAGB subjects at the
same time points (36). It may be inferred from the proven
effects of PYY on caloric intake and possible impact on
insulin sensitivity that raised PYY levels contribute in some
measure to improved glycemia following RYGB and SG.

PROPOSED THEORIES FOR IMPROvED
GLyCEMIA
Rapid hindgut delivery hypothesis
According to this hypothesis, the expedited delivery of
ingested nutrients to the lower bowel due to an intestinal
bypass stimulates L cells, which in turn results in increased
secretion of incretin hormones and improved glucose
homeostasis (37). Consistent with the hindgut or lower
intestinal hypothesis, the bariatric operations most noted
for rapid type 2 diabetes remission—RYGB and BPD—
create gastrointestinal shortcuts for food to access the distal
bowel. It must be noted, however, that GLP-1 secretion is
stimulated not only by direct nutrient contact with distal
intestinal L cells, but also by proximal nutrient-related signals that are transmitted from the duodenum to the distal
bowel by neural pathways (6). Since RYGB diverts nutrients away from the duodenum, the operation might theoretically be expected to lower postprandial GLP-1 levels.
However, several studies have demonstrated consistently
that meal-stimulated secretion of GLP-1 and other L-cell
peptides, such as PYY, are substantially increased after
RYGB. Further support for the lower intestinal hypothesis
comes from experimental procedures involving ileal interposition, which greatly enhances postprandial GLP-1 and
PYY surges (18).

Upper intestinal hypothesis
According to the upper intestinal hypothesis (also known as
the proximal or foregut hypothesis), exclusion of a short segment of proximal small intestine (primarily the duodenum)
from contact with ingested nutrients decreases secretion of
gastrointestinal factors that reduce insulin secretion and/or
promote insulin resistance (37). Reduction of the amount of
these putative anti-insulin factors (or anti-incretins) would
increase insulin action and/or secretion, thereby improving
glucose homeostasis.
Data in support of this hypothesis are provided from
the experimental DJB procedure, which was developed by
Rubino and colleagues (38). DJB is a gastric sparing variant
of RYGB in which the stomach is left intact (Figure 6).
In Goto-Kakizaki (GK) rats, a non-obese model of polygenic type 2 diabetes, FBG was significantly decreased over
a 32-week period and glucose tolerance was improved
1 week after DJB, compared with sham-operated controls.
These effects were observed despite no differences in food
intake and body weight between the experimental groups.
Insulin sensitivity also improved in DJB rats 20 weeks after
surgery, compared with controls. Similar observations have
subsequently been made with independent investigations of
nonobese diabetic GK rats and obese diabetic Zucker rats
(39). Likewise, several small, ongoing human studies of DJB
show improved glycemic control in obese and nonobese
patients, with little or no weight loss (17). In a recent study
by Speck and colleagues (40), compared with sham-GK rats,
DJB-GK rats had an increased beta-cell area and decreased
islet fibrosis, increased insulin secretion with increased
GLP-1 secretion in response to a mixed meal, and increased
population of cells co-expressing GIP and GLP-1 in the jejunum anastomosed to the stomach.
In a further attempt to unravel the mechanisms of diabetes control following gastrointestinal bypass and distinguish
the effects of foregut exclusion from rapid hindgut exposure,
Rubino and colleagues (41) designed a study whereby GK
rats underwent either DJB or a gastrojejunostomy (GJ) to
allow for rapid ileal exposure without bypassing the foregut.
DJB rats showed improved oral glucose tolerance, compared
with both GJ and sham-operated controls rats 10 days after
surgery. Rats that underwent GJ were then re-operated on
to exclude the proximal intestine; conversely, duodenal passage was restored in rats that had undergone DJB. Exclusion
of duodenal nutrient passage in re-operated GJ rats significantly improved glucose tolerance whereas restoration
of duodenal passage in DJB rats re-established impaired glucose tolerance. There were no differences in body weight or
food intake between the surgical groups. This study presents
cogent evidence in favour of the foregut hypothesis.
Unlike RYGB, DJB does not restrict the stomach; however, it does create a shortcut for nutrients to the distal
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CANADIAN JOURNAL OF DIABETES

small bowel, similar to RYGB. To investigate whether duodenal exclusion alone may have antidiabetic effects, Rubino
and colleagues developed an experimental model using an
endoluminal sleeve (ELS) to prevent contact between nutrients and duodenal mucosa in rats (42). The ELS represents
a functional duodenal bypass without creating rapid delivery
of nutrients to the distal bowel. Rats undergoing ELS showed
dramatic improvement of glucose tolerance, compared with
matched controls in which the ELS had been fenestrated to
allow nutrients to come in contact with duodenal mucosa.
Consistent results regarding the anti-diabetic effects of the
ELS were also reported by Aguirre and colleagues (43) in a
diet-induced rat model of insulin resistance. The first human
experiments with ELS in 4 morbidly obese patients with type 2
diabetes resulted in normal FBG without diabetes medication
during the 12-week follow-up. Subsequently, a prospective
randomized trial comparing ELS to sham endoscopy plus
a low-fat diet and physical activity regimen demonstrated a
dramatic 2.9% decrease in A1C in the ELS group, compared
with the conventional therapy group (44).

Role of bile acids
It is well-recognized that bile acids play an important role
in the absorption of dietary lipids. Recent rodent studies
suggest bile acids can mediate energy homeostasis by activating the G-protein coupled receptor TGR5 and the type 2
thyroid hormone deiodinase (45). Recent human clinical
trials with the bile acid sequestrant colesevelam showed
improved glycemic control in patients with type 2 diabetes (46). Altered gastrointestinal anatomy following GB
could potentially affect enterohepatic recirculation of bile
acids. A recent study by Patti and colleagues (47) sought
to assess whether circulating bile acid concentrations in
patients who had previously undergone GB differed from
matched (to pre and post-operative BMI) non-operated
controls. Total serum bile acid concentrations were higher
in GB patients than controls, and were inversely correlated
with 2-h post-meal BG and fasting triglycerides and positively correlated with adiponectin and peak GLP-1.
Role of microbiota
The epidemic growth in the incidence of type 2 diabetes suggests environmental or infectious agents may contribute to the
development of disease. Although consideration of the rising
incidence of obesity and type 2 diabetes from the perspective
of an infectious epidemic is highly speculative, this approach
is supported by some studies (48). Indeed, the gastrointestinal tract is the organ that is first exposed to food-borne toxins
and infectious agents, and as it is involved in the control of
metabolism, such insults could have profound metabolic
effects. Notably, the microbiota of the gut can affect the control of energy metabolism; therefore, changes in microbiota

might contribute to the epidemic of obesity and type 2 diabetes. Future studies are required to unravel the potential role
that infectious agents, environmental toxins and changes in
the gut microbiota play in the rise of these abnormalities.

Anti-incretin hypothesis
The anti-incretin theory posits the existence of nutritionally stimulated, gastrointestinal, neuroendocrine signals that
antagonize the effects of incretins (49). A normal, physiologic balance between incretins and anti-incretins would
ensure proper beta-cell function and maintain BG excursions within normal range. The anti-incretin theory suggests
an increase or untimely production of the anti-incretin
signal could disrupt the incretin–anti-incretin homeostatic
mechanism and ultimately affect the functions of a number
of organs involved in the regulation of metabolism (i.e.
beta cells, adipose tissue and the brain). According to this
theory, gastrointestinal bypass surgery in patients with type 2
diabetes prevents the release of excess anti-incretins and
restores balance between incretins and anti-incretins, eventually leading to improved glucose homeostasis. Rarely, this
mechanism may overshoot due to marked underproduction
of anti-incretins, causing a shift toward an exaggerated incretin effect manifesting clinically as severe postprandial hypoglycemia. This hypothesis remains to be confirmed and, as
yet, putative anti-incretins produced by the gastrointestinal
tract have not been identified.
An alternative hypothesis proposes that exclusion of
portions of the gut reduces the flux of nutrients, thereby
improving insulin sensitivity. This altered nutrient flux
may affect insulin sensitivity directly or indirectly through
changes in the gut hormonal milieu.

CONCLUSIONS
Type 2 diabetes is an increasingly prevalent chronic disorder that is reaching pandemic proportions. There is a
pressing need to explore new options for patients who are
not adequately managed with currently available medical
interventions. Conventional bariatric operations are safe
and highly effective in treating morbidly obese patients with
type 2 diabetes. Experimental data from animal models
and human studies indicate that the effect of gastrointestinal surgery on diabetes is related not only to weight loss;
moreover, the benefits of glycemic control might extend to
less obese individuals with type 2 diabetes as well. Weightindependent mechanisms for improved glucose homeostasis
may be secondary to the changed hormonal gut milieu but
may also be, at least in part, influenced by changes in bile
acid metabolism and gut microbiota.
The available evidence demonstrates that procedures such
as RYGB, BPD and SG alter the gut hormone profile significantly, whereas laparoscopic gastric banding affects glucose

GASTROINTESTINAL HORMONES AFTER BARIATRIC SURGERY

homeostasis only through weight loss and caloric restriction.
Beyond the few hormones for which changes after gastrointestinal surgery have been studied, the gut produces dozens
of known biopeptides and possibly other undiscovered factors. Research to identify the mechanisms and molecules
responsible for the anti-diabetic effect of metabolic surgery
will not only expand our understanding of the pathophysiology of type 2 diabetes, but also pave the way for the development of new medications to tackle this metabolic disorder.

ACKNOwLEDGEMENTS
The authors would like to acknowledge Yuko Tonohira for
the illustrations.

AUTHOR DISCLOSURES
No dualities of interested declared.

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