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The Journal of Clinical Endocrinology & Metabolism 89(6):2608 –2615
Copyright © 2004 by The Endocrine Society
doi: 10.1210/jc.2004-0433
Gastric Bypass for Obesity: Mechanisms of Weight Loss
and Diabetes Resolution
DAVID E. CUMMINGS, JOOST OVERDUIN,
AND
KAREN E. FOSTER-SCHUBERT
Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Veterans Affairs
Puget Sound Health Care System, Seattle, Washington 98195
Energy homeostasis and medical vs. surgical methods to
overcome it
Obesity is now a global pandemic that continues to accelerate despite the often Herculean efforts by afflicted individuals to lose weight. These efforts are thwarted by a
physiological system that regulates body weight in a manner
analogous to that by which a thermostat controls ambient
temperature. For each individual, there is a highly genetically influenced level of adiposity that is defended by this
adipostatic control system, wherein alterations in body fat
stores trigger compensatory changes in appetite and energy
expenditure that resist weight change (1). It is hypothesized
that these processes evolved to defend against malnutrition
in times of famine, and hence, the adaptive responses to
weight loss appear to be more robust than are those to weight
gain (as any dieter can attest). Because of this body weight
regulation system, known as energy homeostasis, nonsurgical methods are notoriously ineffective at achieving major,
long-term weight reduction. In general, no more than 5–10%
of body weight is lost through dieting, exercise, and the few
available antiobesity medications, and recidivism after dietary weight reduction is nearly universal (2–5). Importantly,
even mild weight loss confers disproportionate health benefits, in terms of ameliorating obesity-related comorbidities
(6). Nevertheless, more substantial and durable weight reduction would improve these ailments even more effectively,
as well as lessen the stigmatization and emotional suffering
often endured by obese individuals.
At present, bariatric surgery is the most effective method
to achieve major, long-term weight loss (7, 8). The best operations reduce body weight by 35– 40%, and most of this
effect is maintained for at least 15 yr (Refs. 7–10; and Pories,
W. J., personal communication). Postsurgical weight loss
improves all obesity-related comorbidities examined to date,
including diabetes, hypertension, dyslipidemias, nonalcoholic steatohepatitis, sleep apnea and obesity-hypoventilation syndrome, cardiac dysfunction, reflux esophagitis,
Abbreviations: AGB, Adjustable gastric banding; BMI, body mass
index; BPD, biliopancreatic diversion; DM, diabetes mellitus; GIP,
glucose-dependent insulinotropic peptide; GJB, gastrojejunal bypass;
GLP-1, glucagon-like peptide-1; JIB, jejunoileal bypass; PYY, peptide
YY3–36; QALY, quality-adjusted life year; RYGB, Roux-en-Y gastric bypass; VBG, vertical banded gastroplasty.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
pseudotumor cerebri, arthritis, infertility, stress incontinence, and venous stasis ulcers (4, 8, 9). The net effect is an
increase in quality of life and decrease in overall mortality
(11, 12). Estimates of the cost of bariatric surgery per qualityadjusted life year (QALY) range from $5,400 to $36,600/
QALY, well under the $50,000/QALY benchmark that is
generally regarded in the United States as being cost effective
(13, 14). Unquestionably, obesity surgery is a drastic approach that is not without risks; but these are usually outweighed by the risks of morbid obesity, especially when
considering the most modern and increasingly safe bariatric
operations. Among these, Roux-en-Y gastric bypass (RYGB)
appears to offer the best balance of effectiveness vs. risk, and
it is the most widely used surgery for morbidly obese people
in the United States (15). Not surprisingly, massive weight
loss after this procedure reduces obesity-related comorbidities and mortality; but the operation may improve glucose
homeostasis through physiological changes not explained by
weight loss alone (16).
The mechanisms underlying the effects of RYGB on body
weight and glucose metabolism are incompletely understood. Elucidating these mechanisms is a high priority, because such knowledge may facilitate the development of
novel antiobesity medications that could achieve at least
some of the weight loss caused by RYGB, without surgical
risks. Here, we examine the known and hypothesized mechanisms mediating the effects of RYGB, hopefully highlighting avenues for future research to help uncover the secrets
of this intriguing operation.
The spectrum of bariatric surgery
Intestinal malabsorption and gastric restriction are the two
most obvious mechanisms to explain weight loss after bariatric
surgery, and the types of operations are traditionally categorized based on which of these changes they induce (Figs. 1 and
2). Malabsorptive procedures reconstruct the small intestine to
reduce the area of mucosa available for nutrient absorption. The
earliest incarnation of this strategy was the jejunoileal bypass
(JIB) (17). Imposing no restriction on the flow of food, this
procedure simply diverted enteral nutrients around most of the
small intestine, via an anastomosis between the proximal jejunum (⬃14 in. from the ligament of Treitz) and the terminal
ileum (⬃4 in. from the cecum; Fig. 1A). Weight loss was impressive, but the operation was plagued with complications
that ultimately led to its abandonment from clinical practice.
These included oxalate nephrolithiasis, protein malnutrition,
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Cummings et al. • Gastric Bypass for Obesity
J Clin Endocrinol Metab, June 2004, 89(6):2608 –2615 2609
FIG. 1. Malabsorptive bariatric operations. A, Jejunoileal bypass; B, biliopancreatic diversion; C, duodenal switch. Drawings rendered by Dr.
Alejandro Heffess and generously provided by Edward C. Mun.
FIG. 2. Restrictive bariatric operations. A, Vertical banded gastroplasty; B, adjustable gastric banding; C, Roux-en-Y gastric bypass. Drawings
were rendered by Dr. Alejandro Heffess and generously provided by Edward C. Mun.
metabolic bone disease, hypocalcemia, arthritis, and deficiencies of vitamins B12 and D (8). The most serious morbidity of JIB
was hepatic cirrhosis, hypothesized to result from bacterial
overgrowth in the blind-loop intestinal segment, leading to
chronic hepatic inflammation from foreign antigens in portal
blood. The procedure was succeeded by the biliopancreatic
diversion (BPD), with or without a duodenal switch (Fig. 1, B
and C). These operations are also malabsorptive but create no
blind intestinal loops. Malabsorption occurs because pancreatic
and biliary secretions are diverted to the distal approximately
50 cm of the ileum. Thus, most of the small intestine contains
either digestive juices without food or food without digestive
juices, and absorption is limited to the terminal ileum where
these two are briefly combined in a common channel. Although
BPD promotes durable weight loss as effectively as any bariatric
procedure (7), it often causes significant complications, including protein malnutrition, hypocalcemia and metabolic bone
disease, foul-smelling diarrhea, and deficiencies of iron, vitamin B12, and fat-soluble vitamins (8). Consequently, most
American surgeons are reluctant to perform this operation, and
it is generally reserved for the superobese [body mass index
(BMI) ⬎ 50 kg/m2].
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Purely restrictive bariatric operations cause weight loss by
limiting the capacity of the stomach to accommodate food
and constricting the flow of ingested nutrients. Gastroplasty,
commonly dubbed “stomach stapling,” is the original exemplar. This procedure initially involved placing a horizontal staple line to partition the stomach into a small, proximal
pouch and large distal remnant, connected to one another via
a narrow stoma (18). The operation often failed due to dilation of the stoma and/or proximal pouch, or dehiscence of
the horizontal gastroplasty. To avoid these problems, Mason
(19) modified the operation into the vertical banded gastroplasty (VBG), in which the partitioning line extends upward
from the angle of His (to exclude the easily dilatable fundus),
and a polypropylene mesh band reinforces the stoma (Fig.
2A). Although VBG effectively limits the amount of food that
can be consumed at one sitting and causes 30 –50% reduction
of excess body weight within the first 1–2 yr, long-term
results are disappointing (8). Patients often accommodate to
gastric restriction by eating frequent, small meals and calorie-dense foods, such as milkshakes (7). A nearly 80% failure
rate has been reported after 10 yr (20), and randomized,
prospective as well as sequential, comparative studies consistently show that RYGB is more effective than VGB at
inducing and maintaining weight loss (21–25). Consequently, VBG has fallen out of favor (7, 10).
Adjustable gastric banding (AGB) is an increasingly popular, purely restrictive bariatric procedure used extensively
worldwide and approved by the U.S. Food and Drug Administration in 2001 for use in the United States (Fig. 2B).
Essentially an adjustable variant of VBG, this approach involves placement of a prosthetic band around the upper
stomach to partition it into a small, proximal pouch and a
large, distal remnant, connected through a narrow constriction (26, 27). Free of anastomoses, this approach eliminates
the possibility of staple-line dehiscence and is readily accomplished laparoscopically. Moreover, the band aperture
can be modified noninvasively as needed. Risks include band
slippage or erosion into the stomach and reflux esophagitis.
Weight loss after gastric banding is usually less than that
expected from RYGB, but short- and long-term complications are also less frequent (7).
The modern RYGB is the result of several improvements
on a gastric bypass operation first developed in 1969 by
Mason (28), who had observed that postgastrectomy patients
with a small residual gastric remnant experienced substantial weight loss. The stomach is divided into a small, proximal pouch and a separate, large, distal remnant. The upper
pouch is joined to the proximal jejunum through a narrow
gastrojejunal anastomosis (Roux-en-Y configuration, Fig.
2C). Thus, storage capacity of the stomach is reduced to
approximately 5% of its normal volume, and ingested food
bypasses approximately 95% of the stomach, the entire duodenum, and a small portion (15–20 cm) of the proximal
jejunum. The results are impressive. Patients typically lose
35– 40% of total body weight, and most of this effect is maintained for at least 15 yr (Refs. 7–10; and Pories, W. J., personal
communication). As expected, such massive weight loss
ameliorates all obesity-related morbidities, most impressively diabetes (vide infra) (9). Perioperative mortality, largely
from pulmonary embolism or sepsis, is typically reported as
Cummings et al. • Gastric Bypass for Obesity
approximately 1% in the literature (4) but may be more in the
hands of less experienced surgeons. Postoperative complications occur in approximately 10% of cases and include
deep venous thrombosis, anastomotic leaks, internal hernias,
gastrointestinal bleeding, ulcers in the bypassed segments,
torsion or volvulus of the roux limb, closed loop obstruction,
stomal stenosis, wound complications, staple-line disruption, and gallstone formation with rapid weight loss (7–9).
Bypassing of the stomach and duodenum impairs absorption
of iron, calcium, thiamine, and vitamin B12; thus, supplements of these micronutrients and periodic monitoring for
deficiencies are required. The increasingly common use of
laparoscopic RYGB should lessen surgical complications
overall. Operative risk is measured against the medical benefits of massive weight loss. In a study with a mean 9-yr
follow-up, overall annual mortality was reduced to 1.0%
among 154 patients who underwent RYGB, compared with
4.5% among 78 morbidly obese people referred for RYGB
who did not undergo the operation for personal reasons (P ⬍
0.001) (16, 29). In 1991, a National Institutes of Health (NIH)
Consensus Development Panel endorsed only VBG, gastric
banding, and RYGB (15), and the last of these has emerged
as the gold standard (30). The panel recommended that surgical treatment be considered for people with a BMI of 40
kg/m2 or greater and for those with a BMI of at least 35
kg/m2 plus serious comorbidities. Based on recommendations from a panel of experts that convened in May 2004, a
new consensus statement is being developed by the American Society for Bariatric Surgery and other organizations
dedicated to the treatment of morbid obesity.
Mechanisms of weight loss after Roux-en-Y gastric bypass
Although the mechanisms causing weight loss after purely
malabsorptive or restrictive bariatric operations are apparent, less obvious physiological changes may also contribute
to the profound impact of RYGB on body weight and glucose
homeostasis. Unquestionably, gastric restriction plays a role.
Because of reduced gastric capacity, post-RYGB patients experience early satiety and, consequently, eat smaller meals
(31, 32). If this were the only mechanism at work, however,
the energy homeostasis system would drive patients to compensate with increased meal frequency and to favor caloriedense foods in response to massive weight loss. Instead,
people who have undergone gastric bypass typically eat
fewer meals and snacks per day (32, 33). They also voluntarily restrict consumption of calorie-dense foods, such as
fats, concentrated carbohydrates, ice cream, and sweetened
beverages (32, 33). Presumably because of these changes in
eating behavior, RYGB is more effective than VBG, although
the degree of gastric restriction (i.e. proximal pouch volume
and stomal aperture) is at least as great after VBG as after
RYGB (34). In several randomized, prospective trials, RYGB
has caused 50 – 80% loss of excess body weight, as opposed
to only 30 –50% after the equally restrictive VBG (21–25).
Moreover, weight loss after RYGB is considerably more durable than that after VBG.
The two mechanisms cited most often to explain the
greater efficacy of RYGB over VBG are malabsorption and
dumping syndrome. However, clinically significant malab-
Cummings et al. • Gastric Bypass for Obesity
sorption, measured by indices such as albumin, prealbumin,
and fecal fat, is not observed after the standard proximal
RYGB (7, 35–37). Moreover, randomized, prospective trials
show that weight loss after RYGB is comparable to that after
the radical, malabsorptive JIB (Fig. 1A) (38, 39), although only
approximately 3 ft of small intestine is bypassed with RYGB,
compared with 12–18 ft with JIB (34). Dumping symptoms
(nausea, bloating, colic, diarrhea, lightheadedness, diaphoresis, and palpitations) occur in some patients, typically after
high-carbohydrate meals. Although these can promote a negative conditioning response to sweets that may contribute to
weight loss in selected individuals, the severity of dumping
correlates poorly with the efficacy of RYGB, and it is unlikely
that dumping plays a major role in weight loss overall.
In our opinion, RYGB is more effective than VBG primarily
because of the profound loss of appetite that typically results
from RYGB but is less consistent after VBG (7). This decrease
in hunger is not explained by early satiety from gastric restriction alone, because it extends well beyond the immediate
postprandial period. Moreover, it occurs despite a lack of
change in the perception of sweets as being delicious or in the
overall enjoyment of food (11, 32, 40). Levels of the two most
well-established adiposity hormones, leptin and insulin (1),
decrease appropriately after RYGB (41, 42), as expected with
weight loss. Thus, these hormones do not account for the
reduction in hunger and the regulation of body weight at a
new, reduced level. Alterations in gut hormones have long
been hypothesized to mediate these effects, but those initially
examined, cholecystokinin, serotonin, and vasoactive intestinal peptide, are unaffected by gastric bypass (43, 44).
In 2002, we published a report suggesting that impairment
of ghrelin secretion might account, in part, for the loss of
hunger that accompanies RYGB, potentially contributing to
weight loss (45). Ghrelin is an enteric peptide hormone that
is the only known circulating orexigen (appetite stimulant)
(46 – 49). Endogenous levels increase before meals and decrease after food intake in humans and other species, both
among individuals fed on a fixed schedule and in those
initiating meals voluntarily in the absence of cues related to
time or food (25, 50, 51). These and other findings support the
hypothesis that ghrelin stimulates mealtime hunger and contributes to meal initiation. Other data also implicate ghrelin
in long-term body weight regulation, a potential orexigenic
counterpart to leptin (25). Among the evidence supporting
this role is the observation that ghrelin levels increase with
weight loss resulting from numerous causes, including caloric restriction, cancer anorexia, exercise, eating disorders,
and chronic failure of the heart, liver, or kidneys (25, 45). The
implication is that an increase in ghrelin levels may constitute
one of the adaptive responses to weight loss that characterizes long-term energy homeostasis.
Ghrelin is produced principally by the stomach and, to a
lesser extent, the duodenum, the areas affected by RYGB
(52). Because ingested nutrients are dominant regulators of
ghrelin production and because the majority of ghrelinproducing tissue is permanently excluded from contact with
ingested nutrients after RYGB, we hypothesized that RYGB
disrupts ghrelin regulation. In a study examining 24-h
ghrelin profiles, we found that among people who had undergone RYGB 1.4 ⫾ 0.4 yr earlier, integrated area-under-
J Clin Endocrinol Metab, June 2004, 89(6):2608 –2615 2611
the-curve ghrelin values were 77% lower than those of lean
controls and 72% lower than those of matched-obese controls
(45). These low ghrelin levels were especially remarkable in
view of the 36% weight loss that had been experienced by the
RYGB group, a change that would stimulate ghrelin if
achieved by other means. Moreover, the 24-h profiles of
post-RYGB individuals were completely flat, displaying neither the prandial oscillations nor diurnal rhythm characteristic of normal ghrelin profiles.
Following this publication, numerous other groups examined the effect on ghrelin of RYGB, as performed at their centers,
and we are aware of 11 reports on this topic. Three prospective
studies found that ghrelin levels decreased after RYGB, despite
massive weight loss (53–55). Three others, including our own,
reported abnormally low levels of ghrelin in post-RYGB patients, compared with matched-obese controls (45, 56, 57). Four
additional prospective studies found no change in ghrelin levels after RYGB despite massive weight loss, an observation
interpreted as reflecting an impairment of the normal response
of ghrelin to weight loss (42, 58 – 60). Finally, one group reported
that ghrelin levels increased after RYGB, as expected with other
modes of weight loss (61). Although the last study is an outlier,
in many ways it is the best investigation of this topic to date,
with the largest number of subjects and a prospective design.
The implication of this heterogeneity is that there may be subtle
differences in surgical technique that lead to suppression or at
least constraint of ghrelin levels after RYGB, in many but not all
surgeons’ hands. If it is ultimately proven that impairment of
the ghrelin response to weight loss contributes to the longlasting efficacy of RYGB, it will be important to elucidate the
mechanisms by which this occurs, so that the effect can be
sought expressly.
Our initial hypothesis was that RYGB suppresses ghrelin
secretion through a process known as “override inhibition”
(45). This is a phenomenon in which hormones that are normally secreted in response to an episodic stimulus are paradoxically inhibited when that stimulus occurs continuously. By
this mechanism, gonadotropins and GH are paradoxically suppressed by continuous delivery of their normally pulsatile
secretagogues, GnRH and GHRH, respectively (62, 63). In the
case of ghrelin, the normal stimulus would be an empty stomach and duodenum, a condition that is rendered permanent by
RYGB. The possibility that ghrelin-producing cells in the gut are
subject to override inhibition is suggested by several lines of
evidence that we have summarized elsewhere (25). The override inhibition hypothesis predicts that bariatric procedures
that do not exclude the majority of ghrelin-producing tissue (i.e.
the gastric fundus) from contact with enteral nutrients would
not impair ghrelin secretion. Consistent with this prediction,
weight loss achieved by AGB or BPD is associated with either
unchanged or increased ghrelin levels in longitudinal studies
(Cummings, D. E., and K. Clément, unpublished observations;
and Refs. 42, 54, 64, 65).
The override inhibition hypothesis, if valid, has clinical
implications for surgical design (66). According to this
model, the position of the staple line partitioning the stomach
in RYGB could be a critical determinant of weight loss. Placing this partition even slightly too far to the left would
include part of the fundus—the richest source of ghrelin—in
the upper gastric pouch, thus failing to exclude it from con-
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J Clin Endocrinol Metab, June 2004, 89(6):2608 –2615
tact with food and undermining override inhibition. It is
conceivable that this physiology contributes to the lesser
efficacy of horizontal- than vertical-banded gastric bypasses
(8). Similarly, a short biliopancreatic limb (between the distal
gastric remnant and the jejunojejunal anastomosis) could
allow reflux of ingested nutrients from the Roux anastomosis
into the ghrelin-rich stomach and duodenum. Interestingly,
in the one published study that did not find an impaired
ghrelin response to weight loss (61), patients had among the
shortest biliopancreatic limbs and the widest upper gastric
pouches of RYGB patients examined in ghrelin investigations
to date (66). That study also reported less weight loss (29.7%)
than is typically seen after RYGB (35– 40%) and less than was
reported in most other studies of RYGB and ghrelin (66).
Doubt is cast on the override inhibition hypothesis, however,
by our recent rat experiments designed to locate the putative
sensor that detects ingested nutrients and suppresses ghrelin
levels in response to them. Unexpectedly, we and our colleagues in the laboratory of Drs. Harvey Grill and Joel Kaplan
found that nutrients infused into the stomach and constrained
there with a reversible pyloric cuff did not affect ghrelin levels,
which were significantly suppressed when the cuff was opened
(67). Moreover, nutrients infused into the proximal jejunum
suppressed ghrelin as well as did those infused into either the
stomach or proximal duodenum (68). In other words, prandial
ghrelin regulation does not require the presence of nutrients in
either the stomach or duodenum, the principal sites of ghrelin
production. Thus, it seems less likely that exclusion of ingested
nutrients from these areas after RYGB would disrupt ghrelin
regulation. An alternate hypothesis is that ghrelin regulation is
perturbed after RYGB because of denervation of autonomic
input to ghrelin-producing tissue in the foregut. We found in
rats that vagotomy eliminated the normal response of ghrelin
to weight loss, as is often observed after RYGB (69). Severing of
vagal input to the foregut is accomplished variably by different
surgeons performing RYGB, so this hypothesis could explain
some of the heterogeneity in data pertaining to the effect of this
operation on ghrelin levels (66). A neural mechanism might also
explain the very rapid decline in ghrelin levels that was recently
observed within 24 h of the operation, before suppression via
override inhibition from an empty stomach and duodenum
would be predicted to occur (54).
Antidiabetic effects of gastric bypass
The obesity-related comorbidity most dramatically ameliorated by RYGB is type 2 diabetes mellitus (DM). In five published studies examining a total of 3568 people undergoing
RYGB, diabetic patients enjoyed complete remission of their
disease at rates ranging from 82–98%, with most studies showing resolution in approximately 83% of cases (9, 70 –73). The
reversal of impaired glucose tolerance without DM was nearly
universal. Patients whose DM remitted were able to discontinue all diabetic medications and manifest normal fasting glucose and glycosylated hemoglobin levels. In a longitudinal
study of obese people with impaired glucose tolerance followed
for approximately 5.5 yr, bariatric surgery lowered the rate of
progression to DM by more than 30-fold (74). Thus, RYGB is a
highly effective method to reverse DM, which is traditionally
regarded as a progressive, unrelenting disease. The most ob-
Cummings et al. • Gastric Bypass for Obesity
vious mechanism to explain this effect is the beneficial impact
of weight loss on insulin sensitivity. Indeed, patients who have
lost substantial weight after RYGB display increased levels of
adiponectin (which increases insulin sensitivity) and muscle
insulin-receptor concentration, as well as reductions in intramuscular lipids and fatty acyl-coenzyme A molecules (moieties
that cause insulin resistance) (75–77). As predicted, insulin sensitivity, measured by minimal modeling, is increased approximately 4- to 5-fold after RYGB-induced weight loss (75, 77). The
beneficial effects of RYGB on DM, however, cannot be accounted for by weight loss alone. Perhaps the most impressive
observation is that previously diabetic patients typically discontinue all of their DM medications at the time of discharge
from the hospital after RYGB (⬃1 wk), long before major weight
loss has occurred (16, 70).
What mechanisms could explain this dramatic, rapid reversal of DM? The most pedestrian (although quite possibly valid)
is that patients consume no food in the immediate postoperative period, so their pancreatic ␤-cells are not challenged. Starvation-induced alleviation of DM is well known. A few days
later, patients gradually escalate their oral intake; but by the
time they begin to eat reasonably normally at home, they are
losing weight and in a state of negative energy balance, a condition that improves glucose tolerance. Eventually, amelioration of DM can be accounted for by the well-known effect of
weight loss to increase insulin sensitivity, thereby decreasing
glucotoxicity and lipotoxicity and improving ␤-cell function.
A more interesting possibility, which may act in concert
with the above mechanism, is that favorable alterations in gut
hormone release after RYGB improve insulin secretion
and/or action. Ghrelin, which may decrease after this operation, exerts several diabetogenic effects. Exogenous injections in humans increase levels of GH, cortisol, and epinephrine, three of the four classical counterregulatory hormones
(25). Ghrelin administration also suppresses insulin levels in
humans, even in the face of ghrelin-induced hyperglycemia
(78). Finally, ghrelin directly antagonizes insulin-mediated
intracellular signaling events pertaining to glucose metabolism in cultured hepatocytes (79). Thus, at least at pharmacological doses, ghrelin hinders insulin secretion and action,
and chronic administration of ghrelin receptor agonists impairs glucose tolerance in humans (80). If these effects are
physiological and ghrelin acts as an anti-incretin to limit
peripheral glucose utilization in the fasted and preprandial
state, then suppression of ghrelin levels after RYGB could
enhance glucose disposal.
An even more attractive candidate mediator of the antidiabetic effects of RYGB is glucagon-like peptide-1 (GLP-1).
This hormone and glucose-dependent insulinotropic peptide
(GIP) are the classical incretins that stimulate insulin secretion in response to enteral nutrients. Furthermore, GLP-1
exerts proliferative and antiapoptotic effects on pancreatic
␤-cells (81). It may also improve insulin sensitivity, at least
indirectly (82). Accordingly, methods to enhance GLP-1 signaling show great promise for the treatment of type 2 DM
(83). Moreover, GLP-1 inhibits gastric emptying and can
decrease food intake (83). GLP-1 is secreted primarily by the
hindgut after food ingestion, and part of this response results
from direct contact between enteral nutrients and the intestinal L cells that produce GLP-1. After RYGB, ingested nu-
Cummings et al. • Gastric Bypass for Obesity
trients reach the hindgut more readily, bypassing part of the
foregut and unimpeded by the pylorus. The larger postprandial bolus of nutrients in the hindgut should increase GLP-1
levels after RYGB. Although reports of the effect of this
operation on GLP-1 are not published, several studies of JIB,
which also expedites nutrient delivery to the hindgut, show
increased GLP-1 levels after surgery, both within the first
year and as late as 20 yr postoperatively (84 – 86). Biliopancreatic diversion creates a similar shortcut to the ileum; this
operation also increases hormone secretion from L cells and
is at least as effective as RYGB at ameliorating DM (87).
Secretion of other hindgut hormones, if similarly enhanced
after RYGB, could also contribute to the effects of this procedure on glucose homeostasis and energy balance. Recently,
peptide YY3–36 (PYY) was shown to decrease food intake in
humans and body weight in rodents (88, 89). Because this,
too, is primarily a hindgut hormone, its levels, especially
postprandial, should increase after RYGB, an effect that
might contribute to weight loss. Fasting and postprandial
PYY levels do increase after other surgeries that expedite
nutrient delivery to the hindgut, including extensive smallbowel resection (90) and JIB (9 months and 20 yr postoperatively) (84, 86). As predicted, unpublished studies indicate
that postprandial PYY levels are also markedly elevated after
RYGB (Bloom, S. R., personal communication).
Roles of the foregut and hindgut in the effects of
gastric bypass
Although all bariatric operations promote weight loss and
improve glucose homeostasis, gastric bypass and BPD are the
fastest and most effective procedures for both endpoints (70, 91,
92). Both operations cause durable remissions of DM in more
than 80% of cases, typically within a few days after surgery (9,
41, 92, 93). Because these two procedures exclude the intestinal
foregut from digestive continuity, whereas other bariatric operations do not, it has been hypothesized that bypass of this
hormonally active region is an important determinant of the
effects of bariatric surgery (41, 91). As articulated above, suppression or constraint of ghrelin secretion from the bypassed
foregut is one candidate mechanism to explain some of the
effects of RYGB on weight loss and glucose homeostasis. To
integrate extant ghrelin data into the foregut hypothesis, one
would predict that standard BPD, which leaves the ghrelin-rich
gastric fundus in digestive continuity, would not significantly
impair ghrelin secretion, whereas the duodenal switch, in
which most ghrelin-producing tissue is either resected or bypassed, would suppress ghrelin levels (Fig. 1).
A very recent, elegant study by Rubino and Marescaux (94)
provides additional data supporting the foregut hypothesis.
Using Goto-Kakizaki rats, a spontaneous, nonobese model of
type 2 DM, these investigators isolated the effects of RYGB
that are related to exclusion of the duodenum and proximal
jejunum from those related to gastric restriction and bypass.
The stomach was left unperturbed, but food was diverted
from the pyloric area to the proximal jejunum with a gastrojejunal anastomosis. This gastrojejunal bypass (GJB) represents a stomach-sparing bypass of approximately the same
amount of intestinal foregut as is excluded in RYGB. (The
entire duodenum was bypassed. Of the jejunum, 12 cm was
J Clin Endocrinol Metab, June 2004, 89(6):2608 –2615 2613
included in the Roux limb and 8 cm in the biliopancreatic
limb. Thus, 20 cm of jejunum was incapable of absorbing
nutrients, i.e. approximately 20% of the approximately 100cm-long rat jejunum.) Experimental animals displayed similar food intake and body weight as did sham-operated controls, indicating that foregut bypass alone is not sufficient to
cause weight loss. This is not surprising, because the GJB
creates no gastric restriction, leaves most ghrelin-producing
tissue in digestive continuity, and does not involve a vagotomy. The results support assertions made above that malabsorption after foregut bypass (as in RYGB) is unlikely to be
a major contributor to weight loss. The most interesting finding in this study was that GJB rats showed significant improvement in glucose tolerance compared with sham-operated controls, despite equivalent body weights in the two
groups. Compared with controls, bypassed animals had
lower fasting glucose levels at all postoperative time points
for 9 months; a lower glucose nadir after insulin injection;
and lower area-under-the-curve glucose values in response
to an oral glucose load at 1, 2, and 32 wk after surgery. The
GJB resulted in better glycemic control than did either rosiglitazone therapy or substantial weight loss from food restriction. The implication of these findings is that bypass of
the intestinal foregut (e.g. as accomplished by RYGB and
BPD) can ameliorate type 2 DM independently of weight
loss, through mechanisms that remain unclear. The authors
hypothesize alterations in gut hormones, but candidate molecules are not obvious. The incretin hormone, GIP, produced
primarily by the foregut, is stimulated by ingested nutrients
and promotes insulin secretion. Bypass of the foregut should,
theoretically, decrease GIP levels, and there is little consensus on the actual effect of intestinal bypass operations on this
hormone; various reports claim decreased, unchanged, or
increased postoperative levels.
An alternate possibility, which we will dub the “hindgut
hypothesis,” is that bariatric operations that expedite delivery of ingested nutrients to the hindgut promote weight loss
by accentuating the ileal brake. In this phenomenon, the
presence of nutrients in the ileum suppresses gastrointestinal
motility, gastric emptying, small intestinal transit, and thus,
food intake. Neural mechanisms are implicated in this response, as well as hormones, including PYY, GLP-1, neurotensin, and enteroglucagon—all of which are increased in
response to meals and/or at baseline after JIB (43, 84 – 87, 95).
Enteroglucagon, a marker of secretion from the intestinal L
cells that produce GLP-1, is also increased after RYGB and
BPD (87, 96). As detailed above, enhanced GLP-1 secretion
from facilitated delivery of nutrients to the hindgut could
plausibly account for some of the antidiabetic effects of
RYGB, JIB, and BPD. In support of the hindgut hypothesis are
intriguing rodent experiments in which a portion of the ileum was resected and inserted into the midduodenum (97).
Without creating any restrictive or malabsorptive physiology, such ileal interpositions caused major weight loss, possibly by placing the hormone-rich ileum in close contact with
ingested nutrients and enhancing the ileal brake. Consistent
with this mechanism, ileal interposition increases levels of
PYY, GLP-1, and enteroglucagon, and it delays gastric motility and emptying (97–99).
In summary, the mechanisms mediating weight loss and
2614
J Clin Endocrinol Metab, June 2004, 89(6):2608 –2615
improved glucose tolerance after RYGB may include the
following: 1) gastric restriction, leading to early satiety, small
meal size, and negative conditioning; 2) bypass of the foregut, impairing ghrelin secretion via still-cryptic mechanisms, and causing mild malabsorption in the case of longlimb variations only; and 3) expedited delivery of nutrients
to the hindgut, enhancing the ileal brake, and stimulating the
release of PYY and GLP-1, which may decrease food intake
and increase glucose tolerance. Dumping symptoms accompanying ingestion of concentrated carbohydrates may contribute in some people. These hypotheses and the others
articulated herein are but a few of many possible explanations for the weight-reducing and antidiabetic effects of bariatric surgery, because numerous gut hormones have yet to
be examined in this context. Clearly, this is an arena rich with
opportunities for research that should ultimately elucidate
all of the mechanisms underlying the dramatic effects of
bariatric operations. The NIH has recently sponsored a sixcenter program, the Longitudinal Assessment of Bariatric
Surgery (LABS), to address some of these questions over the
next 5 yr or more. Hopefully, insights from this and other
studies will facilitate the development of new medications
that can achieve at least some of the beneficial effects of
bariatric surgery, without the surgery.
Acknowledgments
Received March 3, 2004. Accepted March 18, 2004.
Address all correspondence and requests for reprints to: David E.
Cummings, M.D., Associate Professor of Medicine, University of Washington, Veterans Affairs Puget Sound Health Care System, 1660 South
Columbian Way, S-111 Endo, Seattle, Washington 98108. E-mail:
[email protected].
This work was supported by National Institutes of Health Grant R01
DK61516.
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