Content uploaded by Federica del Genio
Author content
All content in this area was uploaded by Federica del Genio
Content may be subject to copyright.
Metabolic surgery: the role of the gastrointestinal tract in
diabetes mellitus
Francesco Rubino, Sarah L. R’bibo, Federica del Genio, Madhu Mazumdar, and Timothy E.
McGraw
Section of Gastrointestinal Metabolic Surgery, Department of Surgery (F. Rubino, F. del Genio),
Department of Public Health (S. L. R’bibo, M. Mazumdar), Department of Biochemistry (T. E.
McGraw), Weill Cornell Medical College/New York Presbyterian Hospital, 525 East 68th Street,
P-714, New York, NY 10065, USA
Abstract
Several conventional methods of bariatric surgery and some novel gastrointestinal surgical
procedures induce long-term remission of type 2 diabetes mellitus (T2DM). In addition, these
procedures dramatically improve other metabolic conditions, including hyperlipidemia and
hypertension, in patients with and without obesity. Several studies have provided evidence that
these metabolic effects are not simply the results of drastic weight loss and decreased caloric
intake but might be attributable in part to endocrine changes that result from surgical manipulation
of the gastrointestinal tract. In this Review, we provide an overview of the clinical evidence that
demonstrate the effects of such interventions—termed metabolic surgery—on T2DM and discuss
the implications for future research. In light of the evidence presented here, we speculate that the
gastrointestinal tract might have a role in the pathophysiology of T2DM and obesity.
INTRODUCTION
Several conventional and novel methods of bariatric surgery—termed metabolic surgeries
— induce long-term remission of type 2 diabetes mellitus (T2DM) and dramatically
improve other metabolic abnormalities, such as hyperlipidemia and hypertension,
independent of the patients’ weight.1–4 Some previous studies demonstrated that these
metabolic effects are not only attributable to drastic weight loss and diminished caloric
intake,1,5,6 but also to endocrine changes that result from surgical manipulation of the
gastrointestinal tract. Here, we evaluate the clinical evidence that demonstrate the effects of
metabolic surgery on T2DM and discuss the implications for future research.
BARIATRIC SURGERY
Surgical techniques
Bariatric surgical procedures have traditionally been divided into three categories:
restrictive, malabsorbitive, or mixed surgery. This classification is made on the assumption
that bariatric surgery controls only food intake and/or nutrient absorption. According to this
conventional view, restrictive surgical procedures, such as laparoscopic adjustable gastric
banding (LAGB) or vertical banded gastroplasty (VBG), induce early satiety during meals
by decreasing the volume of the stomach (Figures 1a and 1b). Malabsorbitive procedures
(Figures 1c and 1d), such as bilio–pancreatic diversion (BPD), divert bile into the terminal
segment of the ileum so that bile and food are only mixed in the final 50–100 cm of the
Correspondence to: F. Rubino frr2007@med.cornell.edu.
NIH Public Access
Author Manuscript
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
Published in final edited form as:
Nat Rev Endocrinol
. 2010 February ; 6(2): 102–109. doi:10.1038/nrendo.2009.268.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
small bowel, thereby drastically reducing nutrient absorption. Mixed procedures, such as
Roux-en-Y gastric bypass (RYGB), involves restriction of the stomach and bypass of the
small bowel, which is, however, shortened much less than it is in BPD (Figure 1e). Other
novel procedures, such as duodenal–jejunal bypass (DJB), ileal interposition and sleeve
gastrectomy are becoming increasingly popular owing to their ability to cause dramatic
weight loss and/or substantial improvement of glycemic regulation among both obese and
nonobese patients (Figure 2). Nevertheless, RYGB, LGB and BPD remain the most widely
used treatments for morbid obesity.1
Clinical outcomes of conventional procedures
Traditional methods of bariatric surgery are associated with high rates of remission of
T2DM, as demonstrated by a meta-analysis of 136 studies that included a total of 22,094
patients who underwent bariatric surgery as a treatment for morbid obesity.1 Although most
of the studies were retrospective and lacked long-term follow-up (duration of follow-up was
1–3 years), the results were still ]impressive: the mean ratios of patients with resolution of
T2DM after LAGB, VBG, RYGB and BPD were 48%, 68%, 84%, and 98%, respectively
(Table 1).
The multicenter, prospective, controlled Swedish Obese Subjects (SOS) study compared the
effects of bariatric surgery (LAGB: n = 156; VBG: n = 451; RYGB: n = 34) with those of
nonsurgical weight-loss treatment patients with obesity. Bariatric surgery resulted in a
16.1% mean weight loss at 10 years after surgery (RYGB: 25.0 kg; LAGB: 13.2 kg; VBG:
16.5 kg), compared with a small weight gain observed in the control group. Fasting
glycemia tended to increase during the study in the control group (18.7% at 10 years),
whereas a substantial decrease in fasting glycemia was detected in surgically treated patients
at 2 years (13.6%) and 10 years (2.5% overall decrease, ranging from 0.8% for gastric
banding and 10% for gastric bypass). Furthermore, at 10 years, the relative risk of incident
T2DM was three times lower, and the rates of recovery from T2DM were three times
greater, for patients who underwent surgery than for individuals in the control group.
Some studies evaluated the procedure-specific effects on T2DM, including a randomized,
controlled trial in which 60 patients with BMI values of 30–40 kg/m2 received either
standard therapy (medical and/or behavioral) or LAGB plus standard therapy.7 2 years after
surgery, remission of T2DM (defined as having a fasting glucose level below 7 mmol/l and
HbA1C <6.2% without the use of pharmacotherapy) was seen in 73% of patients who
underwent surgery and standard therapy versus 13% of patients who received standard
therapy alone. Two large case-series studies8,9 that included patients with T2DM or
impaired glucose tolerance documented normalization of HbA1C levels after RYGB without
antidiabetic medication in 89% and 82% of patients, respectively. A retrospective study on
the effect of BPD in 243 patients with T2DM showed normalization of glycemia in 97% of
patients at 10 years after surgery.10 SG has also been shown to dramatically improve
symptoms of T2DM, at least in the short term, as reported in a 12-month, prospective study
in which 84.6% of patients achieved complete remission of T2DM.11 However, a gradient of
efficacy seems to exist among the various surgical procedures in the rates of normalization
of glycemia achieved without pharmacological intervention, as demonstrated by a study of
72 patients with T2DM who underwent one of three bariatric surgeries over a 30-month
period in a single institution.12 After a mean duration of follow-up of 13 months, patients
who underwent LAGB experienced a mean of 17% decrease of glycemic levels, whereas
those who underwent SG or RYGB experienced decreases of 33% and 69%, respectively.
Improvement of T2DM after gastrointestinal surgery has also been reported in patients with
relatively mild forms of obesity and in nonobese individuals. In a randomized, controlled
trial, 80 patients with a BMI of 30–35 kg/m2 were treated with either a strict medical
Rubino et al. Page 2
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
regimen that included a very low calorie diet, lifestyle modification, and pharmacotherapy,
or LAGB.4 At baseline, 38% of patients in each group had been diagnosed with the
metabolic syndrome; 2 years after surgery, metabolic syndrome was prevalent in 24% of
nonsurgically treated patients but in only 3% of those treated with surgery. Another research
group reported remarkable reduction of fasting plasma glucose levels in a prospective series
of 37 patients with BMI <35 kg/m2 who underwent laparoscopic RYGB.2
A prospective study evaluated the effects of gastric bypass surgery in 44 patients with
T2DM and BMI <35 kg/m2 as compared with 157 patients with BMI >35 kg/m2.3 After 4
years of postoperative follow-up, 90% of patients with BMI <35 kg/m2 and 98% of patients
with BMI >35 kg/m2 experienced normalization of glycemia. The investigators concluded
that 77% of those with a BMI <35 kg/m2 achieved the targets determined by the American
Diabetes Association, namely HbA1C level <7.0%, LDL-cholesterol level <2.59 mmol/l and
triglyceride level <1.695 mmol/l. In this study, 2.2% of patients experienced major
complications (one fatality), and 6.2% of patients experienced minor complications. A
prospective pilot study that used BPD as a primary treatment for T2DM in five patients with
T2DM and nonmorbid obesity (BMI 27–33 kg/m2) documented dramatic reductions of
hyperglycemia and improvements in insulin sensitivity as early as 1 month after surgery.13
Remission of T2DM after BPD in patients with nonmorbid obesity was reported in two
other studies.14,15
Cohen and colleagues16 reported the first two patients who underwent duodenal–jejunal
bypass (DJB) for T2DM; these patients had BMIs of 29 kg/m2 and 30 kg/m2, respectively.
After surgery, the patients’ HbA1C levels normalized within 3 months, and stabilized after 9
months at 5–6% (from 8–9% preoperatively). Importantly, neither patient lost weight, which
suggests that surgery evoked weight-independent antidiabetic mechanisms. In another study,
marked reductions were observed in fasting glycemic levels and HbA1C levels after
laparoscopic DJB, and 18 out of 20 patients with BMI <30 kg/m2 discontinued antidiabetic
medications.17 Another study found a decrease in antidiabetic medication requirements after
DJB but only modest improvements of HbA1C levels (from 9.4 to 8.5%) and blood glucose
levels (from 11.60 mmol/l to 8.55 mmol/l).18 Ileal interposition alone or in combination with
SG among 60 patients with T2DM and BMI 24–34 kg/m2 resulted in adequate glycemic
control in 87% of patients at a mean follow-up of 7.4 months.19,20
Endoluminal duodenal–jejunal sleeve (ELS) is a flexible plastic sleeve that excludes the
proximal intestine from alimentary flow, analogous to the surgical bypass in a standard
RYGB or DJB. The device can be implanted endoscopically without disrupting bowel
continuity or creating surgical anastomoses and has been reported to improve glucose
homeostasis in both animal and human studies.21,22
Nonglycemic metabolic effects
In addition to substantially improving hyperglycemia, bariatric surgery might ameliorate
several other metabolic symptoms, including hyperlipidemia and hypertension. Results of a
meta-analysis1 showed marked decreases in levels of total cholesterol, LDL-cholesterol and
triglycerides after bariatric procedures. Approximately 70% of patients experienced an
improvement in hyperlipidemia, whereas 79% of patients experienced improvement or
resolution of hypertension.1 Surgical improvement of hyperlipidemia and hypertension has
also been reported in patients with BMI <35 kg/m2.2,3,15 These findings indicate that
bariatric or metabolic surgery offers health benefits other than just weight loss and glycemic
control. Several clinical investigations have demonstrated that bariatric operations improve
long-term survival in patients with severe obesity, both with and without T2DM, when
compared with matched control individual who do not undergo surgery: bariatric surgery is
associated with decreases in mortality ranging from 33% to 89%.23–28 In a large case–
Rubino et al. Page 3
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
control study, 7,925 patients underwent RYGB whereas 7,925 matched controls did not
undergo surgery of any kind. 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%.29 In the Swedish Obese Subjects study, patients in the surgical
group experienced a 24% nonadjusted decrease in overall mortality compared with matched
controls; the most prominent decreases were observed in cancer-related and cardiovascular
mortality (38.0% and 20.5%, respectively).30
Safety
The frequent misconception that bariatric surgery is associated with markedly elevated rates
of complications and mortality is not supported by the available data. A meta-analysis of
361 studies that included a total of 85,048 patients showed an overall mortality of 0.28%
within 30 days after surgery, and a mortality of 0.35% between 30 days and 2 years after
surgery.31 Several other studies reported surgical mortality of 0.25%–0.50%.32–35 The
Longitudinal Assessment of Bariatric Surgery consortium conducted a multicenter,
prospective observationalstudy of 30-day outcomes in patients who underwentbariatric
surgery at 10 clinical sites in the US between 2005 and 2007.36 The30-day death rate among
patients who underwent RYGB or LAGB was0.3%, and in total 4.1% of patients
experienced at least one major adverseevent.36 Of note, mortality rates associated with
bariatric surgery are equivalent with those of several common abdominal surgeries, such as
laparoscopic cholecystectomy, which has a mortality rate of 0.3–0.6% in the US.37
Another study, which analyzed the data of more than 9,500 patients who underwent bariatric
surgery at 652 hospitals in the US, showed an impressive 21% decline in 6-month, risk-
adjusted complication rates.38 The study also found that inpatient complication rates fell
from 24% to 15%, despite inclusion of a high percentage of elderly and ailing operative
patients. These data demonstrate that over the past several years, morbidity and mortality
associated with bariatric surgery have steadily declined. Such improvements have been
largely attributed to the widespread use of minimally invasive laparoscopic techniques, in
addition to other factors,39,40 such as implementation of centers of excellence and greater
experience with the procedures.
CONTROL OF T2DM BY METABOLIC SURGERY
Effects on glucose and insulin homeostasis
Several studies suggest that RYGB and BPD might improve T2DM by enhancing insulin
sensitivity41 and/or by improving β-cell function. The beneficial effect of gastric bypass
surgery on β-cell function is supported by two observations. One is represented by the
increasing rate of reported hyperinsulinemic hypoglycemia in patients who have undergone
RYGB,42 which suggests that the postoperative milieu after RYGB, at least in some cases,
can overstimulate the function and possibly the growth of β cells. Further support derives
from the observation that gastric bypass surgery can also restore acute β-cell response to
glucose, which suggests that the defect in glucose-induced insulin secretion, which is typical
of T2DM, is a reversible abnormality.43
Gastric bypass surgery also consistently improves oral glucose tolerance, both in animals
and humans. A study where oral glucose tolerance tests were performed in nine obese
women with T2DM before and 1 month after RYGB and in 10 matched women after a diet-
induced, equivalent weight loss (10 kg) showed a dramatic improvement of oral glucose
tolerance and an increase in the levels of glucagon-like peptide-1 (GLP-1) and in the overall
incretin-related effect after RYGB, but not in the control group.44
Rubino et al. Page 4
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Weight-independent antidiabetic effects
Increasing evidence suggests that certain types of surgical manipulations of the
gastrointestinal tract ameliorate T2DM by mechanisms other than weight loss and
diminished caloric intake. A direct role of surgical manipulation of the gastrointestinal tract
on diabetes mellitus was suggested by an experiment in nonobese diabetic rats (Goto-
Kakizaki strain) that underwent DJB surgery.45 These rats experienced substantially greater
improvement of glucose homeostasis than matched control rats that had undergone sham
operation, diet restriction or therapy with insulin-sensitizing drugs.45 Similar findings have
been reported in other studies that used in the same animal model46–48 as well as in rodent
models of diet-induced insulin resistance,49,50 and numerous cases of glycemic
improvement have been reported in humans following experimental gastrointestinal
procedures that cause little to no weight loss.16,17 Additional evidence of weight-
independent mechanisms of T2DM control derives from observations that bypass surgical
procedures induce higher rates of T2DMD remission than restrictive forms of bariatric
surgery or nonsurgical interventions, despite equivalent weight loss, consistent with the
study discussed above that compared the results of RYGB and dieting.44
In a randomized, controlled trial that compared SG and gastric bypass, greater rates of
T2DM remission were found among patients treated with gastric bypass than among those
treated with SG, despite equivalent weight loss in both groups. Similar results were found in
studies that compared LAGB and RYGB.51,52 These observations suggest that manipulation
of the gastrointestinal anatomy by bypass surgery directly influences metabolic pathways,
which ultimately results in the improvement of glucose homeostasis and body-weight
regulation. Consequently, weight loss and T2DM control might be considered two separate
outcomes of gastrointestinal surgery, which means that improvement of glycemia is not
necessarily secondary to weight loss.
Possible neuroendocrine mechanisms
Gastrointestinal bypass procedures connect two otherwise separated segments of the
gastrointestinal tract, thereby allowing nutrients to reach the distal portion of the small
intestine more rapidly than usual and bypassing the contact of nutrients with much of the
stomach, the entire duodenum and part of the jejunum. Two major hypotheses exist for
improvement of glycemia following gastrointestinal surgery. According to the ‘lower
intestinal hypothesis’53 (also known as ‘distal’ or ‘foregut’ hypothesis54), the rapid delivery
of nutrients to the lower intestine increases stimulation of L-cells, which results in increased
secretion of hormones that enhance insulin release and/or insulin action (for example,
GLP-1), and a subsequent decrease in blood glucose levels. According to the ‘upper
intestinal hypothesis’53 (also defined as ‘proximal’ of ‘hindgut’ hypothesis54),
gastrointestinal bypass reduces the secretion of upper gastrointestinal factors that decrease
insulin secretion and/or promote insulin resistance. Reduction of the amount of these
putative anti-insulin factors (or anti-incretins) would increase insulin action, and so improve
symptoms of T2DM. Although the proximal and distal hypotheses are often conceptualized
in terms of the release of hormones, they are also compatible with the theory that altered
nutrient flow triggers neural signaling rather than hormone release.
The distal and proximal hypotheses are often presented as mutually exclusive. Although
such presentation might be convenient for didactic purposes, no reported data precludes the
possibility that the distal and proximal mechanisms both contribute to the efficacy of gastric
bypass procedures. For example, the exclusion of the proximal bowel per se might cause
changes in levels of distal gut hormones as proximal signals are involved in the regulation of
L-cells secretory functions.55
Rubino et al. Page 5
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
A number of gastrointestinal hormonal changes have been reported to occur following
gastric surgery, consistent with the hypotheses that alterations in gastrointestinal anatomy
affect endocrine functioning of the gut. For example, RYGB induces substantial hormonal
changes, even before weight loss takes places.56 Increased levels of peptide YY and
GLP-144,57–60 have been consistently reported in several animal and human studies. RYGB
also seems to alter secretion of ghrelin61 and GIP.56,62 These hormones are all involved in
the regulation of energy homeostasis via their effects on peripheral organs, as well as the
brain. Although the exact molecular mechanisms that underlie the improvements in
metabolism following gastric bypass surgery are not known, these findings establish that
changes in gastrointestinal anatomy have profound effects on the gastrointestinal tract’s
control of metabolism. Furthermore, as a number of gastrointestinal hormones and neural
signals are produced at various sites of the gastrointestinal tract, different surgical methods
might activate distinct mechanisms of action.
RATIONALE FOR A PARADIGM SHIFT
The evidence provided here supports the need for a conceptual shift in the way
gastrointestinal surgery should be regarded. Currently, the term ‘bariatric’ (which originates
from the Greek word for ‘weight’ [baros]) reflects the perceived notion that gastrointestinal
surgery is used to primarily induce weight loss. However, strong evidence shows that
bariatric surgery not only induces dramatic weight loss but also improves symptoms of
T2DM, hypertension and hyperlipidemia, and, as noted above, the metabolic improvements
often precede substantial weight loss. On the basis of this evidence, the term ‘metabolic’
surgery seems more appropriate as it refers to the effects of gastrointestinal surgery on the
metabolic syndrome as a whole, while also capturing the metabolic nature of its mechanisms
of action.
Need for revision of BMI-based criteria
A patient’s BMI is used as the primary eligibility criterion for surgical treatment of severe
obesity. According to the guidelines of the National Institutes of Health (NIH),63 only
patients with a BMI >40 kg/m2 or with a BMI >35 kg/m2 accompanied by comorbidities,
such as T2DM, are eligible for gastrointestinal surgery. Although this approach is
convenient, BMI does not accurately predict the diabetes-related risk of morbidity and
mortality. Moreover, no evidence suggests that specific BMI cut-off values can serve as
predictors of successful metabolic control after gastrointestinal surgery. As described above,
several studies have successfully demonstrated that gastrointestinal surgery can be a life-
saving procedure for individuals with severe obesity. Such surgery also seems to
dramatically improve hyperlipidemia, hypertension and hyperglycemia in nonobese
individuals, thereby providing a plausible therapeutic alternative to reducing cardiovascular
risk in selected patients. Therefore, we consider it inappropriate that BMI continues to be
used by clinicians and insurance companies as the sole criterion to determine patients’
eligibility for surgical treatment of T2DM and the metabolic syndrome.
Intestinal factors that contribute to T2DM
The gastrointestinal tract is not commonly considered in discussions of the etiology of
insulin resistance and T2DM. Attention is usually focused on the liver, muscle, adipose
tissue and the pancreatic β cells, which are the major peripheral organs and tissues involved
in the control of whole-body energy homeostasis. In the following discussion, we provide a
number of reasons why the gastrointestinal tract should be included in these considerations.
The gastrointestinal tract is the first organ to receive information about the nutrient load of a
meal and, as an endocrine organ, it transmits this information via hormonal secretion and
Rubino et al. Page 6
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
direct neural signaling to peripheral tissues, as well as the brain, thereby modulating the
control of metabolism. As a consequence, the gastrointestinal tract has a major role in the
integration of nutrients with metabolic responses and changes in its anatomy can,
predictably, have profound effects in the control of metabolism. In fact, the effects of
surgical manipulation of the intestine on T2DM, independent of weight-loss, are consistent
with the hypothesis that the gastrointestinal tract has a physiological role in glucose
homeostasis and might also have a role in abnormalities of glucose homeostasis, such as
insulin resistance and T2DM. Dysfunction of the gastrointestinal tract could provide a
potential explanation for the link between excess nutrition and the development of insulin
resistance and T2DM. The passage of excess nutrients in general or an increase in the
passage of specific nutrients through the gastrointestinal tract could trigger intestinal
neuroendocrine dysfunction, possibly owing to an overstimulation (see the discussion below
on anti-incretin theory). Consistent with the role of excessive nutrient stimulation, all forms
of restriction of nutrient passage throughout the intestine invariably result in improvement of
T2DM, and the data suggest a positive correlation between the decrease of nutrient
stimulation (‘intestinal rest’) and the degree of improvement of T2DM (that is, diet,
restrictive surgery and gastric bypass surgery are associated with relatively small, medium
and relatively great improvement, respectively) (Figure 3).
The epidemic growth of the incidence of T2DM suggests that environmental or infectious
agents contribute to the development of this disease. Although considering the rising
incidences of obesity and T2DM from the perspective of an infectious epidemic is highly
speculative, this approach is supported by some studies.64 We would like to point out that
the gastrointestinal tract is the organ that is first exposed to food-borne toxins or 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, and, therefore, changes in the microbiota might contribute to the epidemic of
obesity and T2DM.65 Future studies are required to unravel the potential role and
contributions of infectious agents, environmental toxins and changes in the gut microbiota
on the rise of these abnormalites.
The anti-incretin hypothesis
As discussed above, a variety of arguments suggest that the gastrointestinal tract is involved
in the development of T2DM and is a potential target for the treatment of this disease.
Nevertheless, we do not understand the role of the gastrointestinal tract at a mechanistic
level. Although a number of possible mechanisms are known, here we discuss only the ‘anti-
incretin’ hypothesis, which could explain both the effects of gastrointestinal surgery on
T2DM and the role of the gastrointestinal tract in the physiology and pathophysiology of
glucose homeostasis. Incretins include gut hormones, such as GLP-1 and gastrointestinal
peptide, whose secretion is triggered by the passage of nutrients through the small bowel.
These hormones increase glucose-stimulated insulin secretion by pancreatic β cells and also
affect gastric emptying, nitrite influx and β-cell prolifereation (via anti-apoptotic effects).66
The ‘anti-incretin’ theory posits the existence of nutritionally-stimulated, gastrointestinal,
neuroendocrine signals that antagonize the effects of incretins.67 A normal, physiologic
balance between incretins and ‘anti-incretins’ would ensure normal excursions of blood
glucose and proper β-cell function. The anti-incretin theory suggests that 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 that are
involved in the regulation of metabolism (such as β cells, adipose tissue and the brain). This
theory predicts that in patients with T2DM, gastrointestinal bypass surgery might prevent
the release of excess of anti-incretins, which restores the proper incretin–anti-incretin
balance, and eventually results in the improvement of T2DM. A corollary of this hypothesis
Rubino et al. Page 7
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
is that in some patients gastrointestinal bypass surgery results in an underproduction of ‘anti-
incretins’, which might cause a shift toward an exaggerated incretin effect, thereby
increasing the risk of postprandial hyperinsulinemia and hypoglycemia. We must
emphasize, however, that this hypothesis has not been confirmed and putative anti-incretins
produced by the gastrointestinal tract have not been identified to date.
An alternative hypothesis regarding the effect of bariatric surgery on insulin sensitivity is
that exclusion of portions of the gut reduces the flux of nutrients, and this reduced flux is
directly responsible for the beneficial effects associated with surgery. Severe caloric
restriction acutely improves insulin resistance, although the underlying mechanism for this
effect is not known. This effect could be directly related to the change in the flux of
nutrients (that is, independent of any effects on the secretion of known and hypothesized gut
hormones). Alternatively, the change in nutrient flux could affect the balance of gut
hormones (including hypothetical anti-incretins) and the change in hormone milieu might be
responsible for changes in insulin sensitivity. Regardless of the explanation for the effects of
altering nutrient flux through the gut, a better understanding of the role of the gut in the
control of insulin sensitivity will certainly support the future development of treatments for
insulin resistance and T2DM.
CONCLUSIONS
Considering the escalating pandemic of T2DM, clinicians must recognize the need for
improved therapeutic options. When behavioral and pharmacological interventions fail to
manage T2DM, metabolic surgery offers an effective alternative, with the potential of
complete remission of the disease. As the data presented in this article indicate, traditional
bariatric or metabolic surgeries are highly safe and effective in patients with severe obesity
and T2DM. Furthermore, gastrointestinal bypass techniques improve glucose homeostasis
through mechanisms beyond reduced caloric intake and weight loss. Continued research to
better understand the weight-independent antidiabetic mechanisms of gastrointestinal
surgery and the role of the gastrointestinal tract in the physiology and pathophysiology of
glucose homeostasis might lead to important discoveries that can ultimately help identify
targets for novel drug development, as well as facilitate the design of interventions that are
less invasive than current methods for the treatment of obesity and T2DM.
Key points
•Conventional and novel bariatric surgeries induce long-term remission of type 2
diabetes mellitus (T2DM) and dramatically improve other metabolic conditions,
including hyperlipidemia and hypertension
•Animal studies and clinical investigations show that the effects of surgery on
T2DM might be partly explained by endocrine changes that result from surgical
manipulation of the gastrointestinal tract
•Current BMI-based criteria for patient selection are not sufficiently inclusive to
define indications for surgical treatment and evaluation of the risk profile of
patients with T2DM
•Randomized, controlled trials that compare surgery with medical treatment
should aim to define the role of surgery in the management of T2DM and
identify new criteria for selection
Rubino et al. Page 8
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
•Research into the mechanisms of action of metabolic surgery represents an
extraordinary opportunity to improve our understanding of the pathophysiology
of T2DM and ultimately improve its treatment
Acknowledgments
This work was supported in part by NIH Grants DK52852 (TEM) and DK069982 (TEM).
References
1. Buchwald H, et al. Bariatric Surgery: A Systematic review and meta-analysis. JAMA
2004;292:1724–1737. [PubMed: 15479938]
2. Cohen R, Pinheiro JS, Correa JL, Schiavon CA. Laparoscopic Roux-en-Y gastric bypass for BMI <
35 kg/m(2): a tailored approach. Surg Obes Relat Dis 2006;2:401–4. [PubMed: 16925363]
3. Lee WJ, et al. Effect of laparoscopic mini-gastric bypass for type 2 diabetes mellitus: comparison of
BMI>35 and <35 kg/m2. J Gastrointest Surg 2008;12:945–52. [PubMed: 17940829]
4. O’Brien PE, et al. Treatment of mild to moderate obesity with laparoscopic adjustable gastric
banding or an intensive medical program: a randomized trial. Ann Intern Med 2006;144:625–33.
[PubMed: 16670131]
5. Suter M, Calmes JM, Romy A, Giusti V. Results of Roux-en-Y gastric bypass in morbidly obese vs.
super obese patients: similar body weight loss, correction of comorbidities, and improvement of
quality of life. Arch Surg 2009;144:312–18. [PubMed: 19380643]
6. Thaler JP, Cummings DE. Hormonal and metabolic mechanisms of diabetes remission after
gastrointestinal surgery. Endocrinology 2009;150:2518–25. [PubMed: 19372197]
7. Dixon JB, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a
randomized controlled trial. JAMA 2008;299:316–23. [PubMed: 18212316]
8. Pories WJ, et al. Who would have thought it? An operation proves to be the most effective therapy
for adult-onset diabetes mellitus. Ann Surg 1995;222:339–50. [PubMed: 7677463]
9. Schauer PR, et al. Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann
Surg 2003;238:467–84. [PubMed: 14530719]
10. Scopinaro N. Biliopancreatic diversion: mechanisms of action and long-term results. Obes Surg
2006;16:683–9. [PubMed: 16756725]
11. Vidal J, Ibarzabal A, Romero F, et al. Type 2 diabetes mellitus and the metabolic syndrome
following sleeve gastrectomy in severely obese subjects. Obes Surg 2008;18:1077–82. [PubMed:
18521701]
12. Gan SS, Talbot ML, Jorgensen JO. Efficacy of surgery in the management of obesity-related type 2
diabetes mellitus. ANZ J Surg 2007;77:958–62. [PubMed: 17931257]
13. Chiellini C, Rubino F, Castagneto M, Nanni G, Mingrone G. The effect of bilio-pancreatic
diversion on type 2 diabetes in patients with BMI <35 kg/m2. Diabetologia 2009;52:1027–30.
[PubMed: 19308351]
14. Noya G, et al. Biliopancreatic diversion preserving the stomach and pylorus in the treatment of
hypercholesterolemia and diabetes type II: results in the first 10 cases. Obes Surg 1998;8:67–72.
[PubMed: 9562490]
15. Scopinaro N, Marinari GM, Camerini GB, Papadia FS, Adami GF. Specific effects of
biliopancreatic diversion on the major components of metabolic syndrome: a long-term follow-up
study. Diabetes Care 2005;28:2406–11. [PubMed: 16186271]
16. Cohen R, Schiavon C, Pinheiro J, Correa J, Rubino F. Duodenal-jejunal bypass for the treatment of
type 2 diabetes in patients with body mass index of 22–34 kg/m2. Surg Obes Relat Dis
2007;3:195–7. [PubMed: 17386401]
17. Ramos AC, et al. Laparoscopic duodenal-jejunal exclusion in the treatment of type 2 diabetes
mellitus in patients with BMI < 30 kg/m2 (LBMI). Obes Surg 2009;19:307–312. [PubMed:
18987919]
Rubino et al. Page 9
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
18. Ferzli GS, Dominique E, Ciaglia M, Bluth MH, Gonzalez A, Fingerhut A. Clinical improvement
after duodenojejunal bypass for non obese type 2 diabetes despite minimal improvement in
glycemic homeostasis. World J Surg 2009;33:972–9. [PubMed: 19288284]
19. DePaula AL, et al. Laparoscopic treatment of type 2 diabetes mellitus for patients with a body
mass index less than 35. Surg Endosc 2008;22:706–16. [PubMed: 17704886]
20. DePaula AL, Macedo AL, Mota BR, Schraibman V. Laparoscopic ileal interposition associated to
a diverted sleeve gastrectomy is an effective operation for the treatment of type 2 diabetes mellitus
patients with BMI 21–29. Surg Endosc 2009;23:1313–20. [PubMed: 18830750]
21. Aguirre V, et al. An endoluminal sleeve induces substantial weight loss an d normalizes glucose
homeostasis in rats with diet-induced obesity. Obesity 2008;16:2585–92. [PubMed: 19279655]
22. Rodriguez-Grunert L, et al. First human experience with endoscopically delivered and retrive
duodenal-jejunal bypass sleeve. Surg Obes Relat Dis 2008;4:55–9. [PubMed: 18201671]
23. MacDonald KG, et al. The gastric bypass operation reduces the progression and mortality of non-
insulin-dependent diabetes mellitus. J Gastrointest Surg 1997;1:213–20. [PubMed: 9834350]
24. Flum DR, Dellinger EP. Impact of gastric bypass operation on survival: a population-based
analysis. J Am Coll Surg 2004;199:543–51. [PubMed: 15454136]
25. Christou NV, et al. Surgery decreases long-term mortality, morbidity, and health care use in
morbidly obese patients. Ann Surg 2004;240:416–23. [PubMed: 15319713]
26. Sowemimo OA, et al. Natural history of morbid obesity without surgical intervention. Surg Obes
Relat Dis 2007;3:73–7. [PubMed: 17196439]
27. Peeters A, et al. Substantial intentional weight loss and mortality in the severely obese. Ann Surg
2007;246:1028–33. [PubMed: 18043106]
28. Perry CD, Hutter MM, Smith DB, Newhouse JP, McNeil BJ. Survival and changes in
comorbidities after bariatric surgery. Ann Surg 2008;247:21–7. [PubMed: 18156918]
29. Adams TD, et al. Long-term mortality after gastric bypass surgery. N Engl J Med 2007;357:753–
61. [PubMed: 17715409]
30. Sjostrom L, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med
2007;357:741–52. [PubMed: 17715408]
31. Buchwald H, Estok R, Fahrbach K, Bane D, Sledge I. Trends in Mortality in Bariatric Surgery: A
systematic review and meta-analysis. Surgery 2007;142:621–32. [PubMed: 17950357]
32. Wittgrove AC, Clark GW. Laparoscopic gastric bypass, Roux-en-Y- 500 patients: technique and
results, with 3–60 month follow-up. Obes Surg 2000;10:233–9. [PubMed: 10929154]
33. Morinigo R, et al. GLP-1 and changes in glucose tolerance following gastric bypass surgery in
morbidly obese subjects. Obes Surg 2006;16:1594–601. [PubMed: 17217635]
34. Wickremesekera K, Miller G, Naotunne TD, Knowles G, Stubbs RS. Loss of insulin resistance
after Roux-en-Y gastric bypass surgery: a time course study. Obes Surg 2005;15:474–81.
[PubMed: 15946424]
35. Pontiroli AE, et al. Laparoscopic gastric banding prevents type 2 diabetes and arterial hypertension
and induces their remission in morbid obesity: a 4-year case-controlled study. Diabetes Care
2005;28:2703–9. [PubMed: 16249543]
36. LABS Consortium. Perioperative Safety in the Longitudinal Assessment of Bariatric Surgery.
NEJM 2009;361:520–1. [PubMed: 19641209]
37. Khuri SF, et al. Comparison of surgical outcomes between teaching and non-teaching hospitals in
the Department of Veterans Affairs. Ann Surg 2001;234:370–82. [PubMed: 11524590]
38. Encinosa WE, Bernard DM, Du D, Steiner CA. Recent Improvements in Bariatric Surgery
Outcomes. Medical Care 2009;47(5):531–5. [PubMed: 19318997]
39. Nguyen NT, Hinojosa M, Fayad C, Varela E, Wilson SE. Use and outcomes of laparoscopic versus
open gastric bypass at academic and medical centers. J Am Coll Surg 2007;205:248–55. [PubMed:
17660071]
40. Han SH, et al. Improved outcomes using a systematic and evidence based approach to the
laparoscopic Roux-en-Y gastric bypass in a single academic institution. Am Surg 2007;73:955–8.
[PubMed: 17983055]
Rubino et al. Page 10
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
41. Mari A, et al. Restoration of normal glucose tolerance in severely obese patients after bilio-
pancreatic diversion: role of insulin sensitivity and beta cell function. Diabetologia 2006;49:2136–
43. [PubMed: 16819611]
42. Patti ME, et al. Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy:
evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia
2005;48:2236–40. [PubMed: 16195867]
43. Polyzogopoulou EV, Kalfarentzos F, Vagenakis AG, Alexandrides TK. Restoration of euglycemia
and normal acute insulin response to glucose in obese subjects with type 2 diabetes following
bariatric surgery. Diabetes 2003;52:1098–103. [PubMed: 12716738]
44. LaFerrere B, et al. Effect of weight loss by gastric bypass surgery versus hypocaloric diet on
glucose and incretin levels in patients with type 2 diabetes. J Clin Endocrinol Metab
2008;93:2479–85. [PubMed: 18430778]
45. Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese animal model of type
2 diabetes: a new perspective for an old disease. Ann Surg 2004;239:1–11. [PubMed: 14685093]
46. Kindel TL, Yoder SM, Seeley RJ, D’Alessio DA, Tso P. Duodenal-Jejunal Exclusion Improves
Glucose Tolerance in the Diabetic, Goto-Kakizaki Rat by a GLP-1 Receptor-Mediated
Mechanism. J Gastrointest Surg. May 12;2009
47. Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose
metabolism in Goto-Kakizaki rats. Am J Surg 2007;194(2):221– 4. [PubMed: 17618808]
48. Wang TT, et al. Ileal transposition controls diabetes as well as modified duodenal jejunal bypass
with better lipid lowering in a nonobese rat model of type II diabetes by increasing GLP-1. Ann
Surg 2008;247(6):968–75. [PubMed: 18520224]
49. Troy S, et al. Intestinal gluconeogenesis is a key factor for early metabolic changes after gastric
bypass but not after gastric lap-band in mice. Cell Metab 2008;8(3):201–11. [PubMed: 18762021]
50. Strader AD, Clausen TR, Goodin SZ, Wendt D. Ileal interposition improves glucose tolerance in
low dose streptozotocin-treated diabetic and euglycemic rats. Obes Surg 2009;19(1):96–104.
[PubMed: 18989728]
51. Pattou F, et al. Restoration of beta cell function after bariatric surgery in type 2 diabetes patients: A
prospective controlled study comparing gastric banding and gastric bypass. Obes Surg
2007;17:1041–3.
52. Pattou F, et al. Catering of insulin secretion after a gastric bypass in type 2 diabetes is independent
from weight loss and correlated to the increase of GLP. Diabetes Metab 2008;34:A23.
53. Cummings DE, Overduin J, Foster-Schubert KE, Carlson MJ. Role of the bypassed proximal
intestine in the anti-diabetic effects of bariatric surgery. Surg Obes Relat Dis 2007:109–15.
[PubMed: 17386391]
54. Moo TA, Rubino F. Gastrointestinal surgery as treatment for type 2 diabetes. Current Opinion in
Endocrinology Diabetes & Obesity 2008;15:153–158.
55. Damholt AB, Buchan AM, Kofod H. Glucagon-like-peptide-1 secretion from canine L-cells is
increased by glucose-dependent-insulinotropic peptide but unaffected by glucose. Endocrinology
1998;139:2085–91. [PubMed: 9528997]
56. Rubino F, et al. The early effect of the Roux-en-Y gastric bypass on hormones involved in body
weight regulation and glucose metabolism. Ann Surg 2004;2:236–42. [PubMed: 15273546]
57. Le Roux CW, Aylwin SJ, Batterham RL, et al. Gut hormone profiles following bariatric surgery
favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg
2006;243:108–114. [PubMed: 16371744]
58. Le Roux CW, et al. Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric
bypass. Ann Surg 2007;246:780–785. [PubMed: 17968169]
59. Korner J, et al. Differential effects of gastric bypass and banding on circulating gut hormone and
leptin levels. Obesity 2006;14:1553–1561. [PubMed: 17030966]
60. Korner J, et al. Effects of Roux-en-Y-gastric bypass surgery on fasting and postprandial
concentrations of plasma ghrelin, peptide YY, and insulin. J Clin Endocrinol Metab 2005;90:359–
365. [PubMed: 15483088]
61. Cummings DE, et al. Plasma ghrelin levels after diet induced weight loss or gastric bypass surgery.
NEJM 2002;346:1623–1630. [PubMed: 12023994]
Rubino et al. Page 11
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
62. Laferrère B, et al. Incretin levels and effect are markedly enhanced 1 month after Roux-en-Y
gastric bypass surgery in obese patients with type 2 diabetes. Diabetes Care 2007;30(7):1709–16.
[PubMed: 17416796]
63. NIH Conference–Consensus Development Conference Panel. Gastrointestinal surgery for severe
obesity. Ann Intern Med 1991;115:956–961. [PubMed: 1952493]
64. Pasarica M, Dhurandhar NV. Infectobesity: obesity of infectious origin. Advances in food and
nutrition research 2007;52:61–102. [PubMed: 17425944]
65. Burcelin R, Luche E, Serino M, Amar J. The gut microbiotica ecology: a new opportunity for the
treatment of metabolic diseases? Front Biosci 2009;14:5107–5117. [PubMed: 19482607]
66. Lovshin JA, Drucker DJ. Incretin based therapies for type 2 diabetes mellitus. Nat Rev Endocrinol
2009;5:262–269. [PubMed: 19444259]
67. Rubino F. Is type 2 diabetes an operable intestinal disease? Diabetes Care 2008;3(Supplement
2):S290–296. [PubMed: 18227499]
Rubino et al. Page 12
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Figure 1.
Conventional bariatric operations. a During laparoscopic adjustable gastric banding, the
upper part of the stomach is encircled by a saline-filled tube. The extent of restriction can be
adjusted by injecting/withdrawing saline solution to/from the tube. b During Roux-en-Y
gastric bypass, a surgical stapler is used to create a small, vertical gastric pouch. The upper
pouch, which is completely separated from the gastric remnant, is anastomosed to the
jejunum, whereas the excluded biliary limb is anastomosed to the alimentary limb. After
surgery, ingested food bypasses about 95% of the stomach, the entire duodenum and a
portion of the jejunum, but bile and nutrients mix in the distal jejunum and can be absorbed
through the remaining portion of the small bowel. Biliopancreatic diversion involves a
horizontal resection (c) or a vertical resection (d, also known as ‘sleeve gastrectomy’ or
‘duodenal switch’). The reduced stomach is anastomosed to the distal 250 cm of the small
intestine. The excluded small intestine, which carries the bile and pancreatic secretions, is
connected to the alimentary limb. Bile and nutrients mix in a short segment of small bowel,
Rubino et al. Page 13
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
the only site where fat and starches are absorbed; noncaloric nutrients are absorbed in the
alimentary limb.
Rubino et al. Page 14
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Figure 2.
Novel methods of metabolic surgery. a Duodenal–jejunal bypass consists of a stomach-
preserving bypass of a short segment of proximal small intestine (similar to that bypassed in
a standard Roux-en-Y gastric bypass). Some variants of this procedure preserve the pylorus.
This procedure might be associated with a sleeve resection of the stomach, which reduces
the risk of marginal ulcerations and increases weight loss (b). Long-term data about the
efficacy of this procedure are not yet available. c Sleeve gastrectomy not only reduces the
capacity of the stomach but also eliminates the ghrelin-rich gastric fundus, which might
contribute to the beneficial effects of the procedure. Sleeve gastrectomy has been also
shown to improve type 2 diabetes mellitus in patients with severe obesity. The efficacy of
the procedure in the long-term needs to be further investigated. d During ileal interposition,
a small segment of ileum (with its intact vascular and nervous supplies) is surgically
interposed into the proximal small intestine, which increases its exposure to ingested
nutrients. Ileal interposition can be performed alone or in association with sleeve
Rubino et al. Page 15
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
gastrectomy and duodenal exclusion. The procedure requires three anastomoses (gastric
bypass operations include two). The long-term effects of this procedure are unknown.
Rubino et al. Page 16
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Figure 3.
Intestinal factors that contribute to the pathophysiology of T2DM. A dysfunctional intestinal
signal is posited to be involved in the pathophysiology of T2DM. According to this
hypothesis, overstimulation of the gastrointestinal tract (by overeating and/or the presence of
chemical or biological stimuli in modern diets) could lead to insulin resistance, obesity and
T2DM, whereas all forms of restriction of nutrients’ transit could improve these conditions.
Indeed, diet might improve T2DM not just because of a restriction of caloric intake, but
owing to the reduced stimulation of abnormal intestinal mechanisms. Likewise, restrictive
surgery could improve T2DM by reducing the nutrient load even further. Bypass operations,
which completely and indefinitely inactivate a large part of the intestine, reduce nutrient-
related stimuli more than any other approach and are the most effective ways of improving
T2DM, obesity and insulin resistance syndrome. Abbreviation: T2DM, type 2 diabetes
mellitus.
Rubino et al. Page 17
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Rubino et al. Page 18
Table 1
Effects of various types of bariatric surgery on comorbidities.
Improvement
Rates of improvement (%) after surgery
LAGB RYGB BPD
Resolution of T2DM 48 84 98
Resolution of hypertension 43 68 83
Improvement of hyperlipidemia 59 97 99
Excess weight loss 47 62 70
Abbreviations: BPD, biliopancreatic diversion; LAGB, laparoscopic adjustable gastric banding; RYGB, Roux-en-Y gastric bypass; T2DM, type 2
diabetes mellitus. Permission needed from the American Medical Association © Buchwald, H. et al. (2004) JAMA 292, 1724–1737.
Nat Rev Endocrinol. Author manuscript; available in PMC 2010 December 8.
