In Brief

Bariatric surgery induces a mean weight loss of 15–30% of initial body weight (depending on the procedure), as well as a 45–95% rate of diabetes remission. Procedures that induce greater weight loss are associated with higher rates of diabetes remission. Improvements in glucose homeostasis after bariatric surgery are likely mediated by a combination of caloric restriction (followed by weight loss) and the effects of altered gut anatomy on the secretion of glucoregulatory gut hormones.

Obesity, which afflicts 35.9% of U.S. adults, dramatically increases the risk of type 2 diabetes.1,2  More than two-thirds of the 23 million U.S. adults who have type 2 diabetes are obese.3,4  Nutrition therapy, exercise, and medical management remain the cornerstones of both obesity and diabetes treatment, but the long-term success of lifestyle modification has been modest.5 

Bariatric surgery is currently the most effective therapy for producing mean long-term (10-year) weight losses of ≥ 15% of initial body weight, and such weight losses are associated with significant reductions in the incidence of comorbid conditions such as type 2 diabetes.5  In 2009, > 220,000 bariatric surgery procedures were performed in the United States alone.6  Given its dramatic effects on glucose homeostasis, bariatric surgery has garnered increasing interest as a potential treatment for type 2 diabetes.79 

As shown in Figure 1, several bariatric procedures are currently available.9  These procedures were initially classified as restrictive, malabsorptive, or combined (based on their purported mechanism of weight loss), but recent evidence suggests that the mechanisms for each type are less clear than originally thought and likely involve multiple pathways.10  Bariatric surgeries are now more broadly classified as: 1) restrictive procedures, which dramatically reduce the volume of the stomach to limit gastric capacity and promote early satiety but do not alter intestinal anatomy; or 2) gastrointestinal (GI) diversionary procedures, which bypass segments of the small bowel.11 

Figure 1.

Bariatric and metabolic surgical operations. Reproduced from the National Institute of Diabetes and Digestive and Kidney Diseases Web site (ref. 9).

Figure 1.

Bariatric and metabolic surgical operations. Reproduced from the National Institute of Diabetes and Digestive and Kidney Diseases Web site (ref. 9).

Adjustable gastric banding (AGB), in which an inflatable silicone band is placed around the fundus of the stomach, is believed to be the most commonly performed restrictive procedure worldwide.12  In this procedure, the GI anatomy remains intact, and the rate of gastric emptying is not altered.13 

As recently as 20 09, AGB accounted for 40% of bariatric procedures performed in the United States.14  However, AGB is rapidly being supplanted by vertical sleeve gastrectomy (VSG), a newer restrictive procedure that removes 75% of the stomach, including virtually all of the hormonally rich gastric fundus.5  Although VSG is conceptually a restrictive procedure, the removal of endocrine-rich gastric tissue and the accelerated rate of gastric emptying15,16  caused by this procedure is hypothesized to have significant physiological implications and may account for its superior efficacy relative to other restrictive procedures.

Roux-en-Y gastric bypass (RYGB), the most commonly performed GI diversionary procedure, restricts gastric size and bypasses the entire duodenum and the proximal jejunum.17  RYGB accounts for ~ 50% of bariatric surgeries performed worldwide.12  Biliopancreatic diversion (BPD) is a more extensive surgical procedure that includes a partial gastrectomy and bypasses a longer segment of the small bowel to induce significant malabsorption.17  BPD accounts for only 5% of bariatric procedures performed in the United States and is usually reserved for patients who have a BMI > 50 kg/m2.17  Detailed descriptions of these procedures are provided in Table 1.5 

Typically, procedures that induce greater weight loss are associated with higher rates of diabetes remission.18  However, comparison of bariatric data has been difficult because of a lack of standardization in reporting weight loss.7,1922  In the surgical literature, weight loss is typically expressed as a percentage of excess weight lost (EWL), in which excess weight is defined as total preoperative weight minus ideal weight.18  The percentage of EWL is thus defined as weight loss/excess weight × 100. The percentage change in total weight and percentage change in BMI after bariatric surgery have also been reported.1822 

In a meta-analysis, Buchwald et al.22  evaluated the effect of bariatric surgery on weight loss and obesity-related comorbidities in 135,246 patients. An overall EWL of 55.9% was reported for all procedures, whereas individual rates associated with each procedure varied (Table 2). On average, bariatric surgery has been found to result in a BMI reduction of 10–15 kg/m2 and a weight loss of 30–50 kg.18,19 

Table 1.

Description of Bariatric Surgery Procedures Currently in Use5 

Description of Bariatric Surgery Procedures Currently in Use5
Description of Bariatric Surgery Procedures Currently in Use5

Two randomized, controlled trials reported greater weight loss with RYGB than with AGB.23,24  A recent trial that included 250 participants randomly assigned to RYGB or AGB reported a mean percentage of EWL of 68.4 and 45.4%, respectively, 4 years after surgery.24  These results were similar to those of an earlier, smaller, randomized trial that provided 5 years of follow-up, in which the mean EWL was 66.6% in participants who underwent RYGB and 47.5% in those who underwent AGB.23 

Although VSG and AGB are both classified as restrictive procedures, VSG appears to induce superior weight loss compared to AGB. One randomized trial that compared the magnitude of weight loss between the two procedures at 1 and 3 years found that AGB resulted in an EWL of 41.4 and 48%, respectively, versus 57.5 and 66%, respectively, for VSG.25  Two randomized trials reported comparable short-term weight loss between VSG and RYGB at 3 months26  and 12 months.27  In a randomized trial that compared the long-term efficacy of VSG and RYGB on weight outcomes, Kehagias et al.28  also reported comparable weight loss between the two procedures at 3 years (68 vs. 62% of EWL, respectively).

Maximal weight loss is typically achieved 12–18 months after all procedures,21  although evidence suggests that some patients regain a significant amount of weight several years after surgery.29  Ten-year follow-up from the Swedish Obese Subjects (SOS) study, a prospective cohort study that included 4,047 obese participants who underwent a variety of bariatric surgery procedures or nonsurgical conventional management, found that each procedure was associated with significant weight regain.29  Mean weight loss decreased in the RYGB group from 32% at 1 year to 25% at 10 years, in the gastric banding group from 20 to 13%, and in the group treated with vertical banded gastroplasy (a restrictive procedure now rarely performed) from 25 to 18%. For all procedures, substantial weight loss was nonetheless sustained at a greater level than that achieved with nonsurgical weight loss interventions.

There is considerable heterogeneity among definitions of diabetes remission, which hinders comparison of remission rates among various surgical studies. Diabetes remission is often broadly defined as “normal” fasting blood glucose and A1C values without the use of antidiabetic medications.18  However, this definition does not include specific criteria for A1C levels (cut-offs have varied from < 6.0 to 7.0% in the surgical literature), a quantifiable timeframe for which antidiabetic medications must be discontinued, or more rigorous measures of assessment (e.g., oral glucose tolerance testing).

In response to a growing demand for a standardized definition of diabetes remission, a consensus group consisting of experts in pediatric and adult endocrinology, bariatric/metabolic surgery, transplantation, metabolism, and hematology-oncology was convened by the American Diabetes Association (ADA) in 2009.30  “Partial remission” was defined as mild hyperglycemia (fasting glucose levels of 100–125 mg/dl and A1C levels of < 6.5%) for at least 1 year in the absence of active pharmacological therapy or ongoing procedures. “Complete remission” was defined as a return to normal measures of glucose metabolism (fasting glucose levels of < 100 mg/dl and A1C levels < 6.0%) for at least 1 year in the absence of active pharmacological therapy or ongoing surgical procedures such as repeated replacement of endoluminal devices. “Prolonged remission” was defined as complete remission for at least 5 years' duration. The group was unable to reach a consensus on the value of oral glucose tolerance testing in defining remission.

Table 2.

Remission and Improvement in Type 2 Diabetes Associated With Various Bariatric Procedures*22 

Remission and Improvement in Type 2 Diabetes Associated With Various Bariatric Procedures*22
Remission and Improvement in Type 2 Diabetes Associated With Various Bariatric Procedures*22

Observational evidence suggests that bariatric surgery is associated with a 45–95% rate of diabetes remission, depending on the type of procedure.18,22,31  In the largest meta-analysis to date,22  which included 3,188 patients with type 2 diabetes who underwent bariatric surgery, the disease resolved in 78% and resolved or improved in 87%. Weight loss and diabetes remission were greatest for BPD, followed by RYGB, and then AGB (Table 2). VSG was not included in this meta-analysis because it was not a commonly performed bariatric procedure at the time.

Among studies that included exclusively diabetic patients, the rate of clinical and biochemical remission of diabetes in the first 2 years after surgery was 82%. Sixty-two percent remained free of diabetes > 2 years after surgery. However, many of the studies in this meta-analysis had significant methodological limitations. Therefore, cautious interpretation of conclusions about bariatric surgery and diabetes remission is advised. Few of the studies were randomized, controlled trials, and many were uncontrolled case series with significant amounts of missing data. Participants were not always enrolled consecutively, and heterogeneous outcomes were used to define diabetes remission.

Using the more stringent definition recommended by the ADA consensus group, Pournaras et al.32  retrospectively compared rates of diabetes remission in 209 subjects with type 2 diabetes who underwent RYGB, VSG, and AGB at three bariatric centers in the United Kingdom. Mean follow-up was 23 months (range 12–75 months). A total of 72 (34.4%) had complete remission of diabetes according to the new definition. The remission rates were 40.6% after RYGB, 26% after VSG, and 7% after AGB (P < 0.001 between groups). The remission rate for RYGB was significantly lower with the new definition than with the previously used definition (40.6 vs. 57.5%, P = 0.003).

In response to increasing demand for high-quality studies comparing the diabetes remission rates of bariatric surgery and medical management, several randomized, controlled trials have recently been completed.

Dixon et al.33  randomized 60 obese participants with BMIs of 30–40 kg/m2 and a recent diagnosis of type 2 diabetes (< 2 years) to either AGB or conventional medical therapy. The primary endpoint was the rate of diabetes remission at 2 years, defined as a fasting glucose of < 126 mg/dl and an A1C of < 6.2% in the absence of antidiabetic medications. Conventional medical therapy consisted of visits every 6 weeks with at least one member of the medical team, which included a general physician, nurse, diabetes educator, and dietitian, for the duration of the trial. Pharmacological therapy was determined on an individual basis by a diabetologist, and all participants in this group received individual counseling about lifestyle modification. Fifty-five participants (92%) completed follow-up at 2 years. Twenty-two of 30 participants (73%) in the surgical group achieved the primary endpoint compared to 4 of 30 (13%) in the medical therapy group. Surgical and conventional therapy groups lost a mean of 20.7 and 1.7% of initial body weight, respectively.

In the recently completed STAMPEDE (Surgical Therapy and Medications Potentially Eradicate Diabetes Efficiently) trial,Schauer et al. 34  randomly assigned 150 obese participants with poorly controlled type 2 diabetes (A1C > 7.0%) to one of three interventions: 1) intensive medical management alone, 2) RYGB, or 3) VSG, with intensive medical therapy as an adjunct to both surgical procedures. The primary endpoint was defined as the proportion of participants with an A1C ≤ 6.0% at 12 months. All participants received intensive medical therapy per ADA guidelines, including lifestyle counseling, weight management, frequent self-monitoring of blood glucose, and use of newer glycemic therapies such as incretin mimetics.

Of the 150 participants, 140 (93%) completed follow-up at 12 months. Twenty-one of 50 participants (42%) in the RYGB group achieved the primary endpoint, compared to 18 of 49 (37%) in the VSG group, and 5 of 41 (12%) in the medical management group. All participants in the RYGB group achieved the target A1C without antidiabetic medications, whereas 5 of 18 (28%) in the VSG required one or more glucose-lowering drugs. In contrast, the use of antidiabetic medications increased in the medical management group. The mean percentage of weight loss among participants undergoing either RYGB or VSG (25.7 and 24.7%, respectively) was significantly greater than for those undergoing medical therapy (5.2%, P < 0.001 for both comparisons).

Mingrone et al.35  randomly assigned 60 participants with a BMI ≥ 35 kg/m2 and a history of type 2 diabetes for ≥ 5 years to undergo RYGB, BPD, or standard medical therapy. The primary endpoint was the rate of diabetes remission at 2 years (defined as a fasting glucose of < 100 mg/dl and an A1C of < 6.5% without antidiabetic medications). Standard medical therapy consisted of visits (at baseline and months 1, 3, 6, 9, 12, and 24) with a multidisciplinary team that included a diabetologist, dietitian, and nurse. Pharmacological therapy was optimized on an individual basis, and a lifestyle modification program was provided, although the specific nature of this program was not described.

Fifty-six participants (93%) completed the 2-year follow-up. Remission was achieved by 75% in the RYGB group and 95% in the BPD group. No participants in the medical therapy group achieved remission. At 2 years, participants in the two surgical groups had significantly greater percentage reductions in mean body weight than those in the medical therapy group (33.3% for RYGB and 33.8% for BPD, compared to 4.7% for the control group; P < 0.001 for both comparisons).

Importantly, all three of these studies used intensive medical management rather than routine care as the control. The weight loss that was achieved in the medical management groups in these studies was comparable to that reported in three recent randomized trials in which intensive weight loss interventions were delivered within primary care practices.3638  At 2 years, weight loss in the intensive treatment arms in these studies ranged from 1.7 to 5.2%.

If bariatric surgery is to be considered a potential treatment for type 2 diabetes, it is crucial to identify preoperative predictors of remission to help determine which patients will benefit the most from surgery. After adjusting for BMI, sex, and preoperative A1C level, Torquati et al.39  found that preoperative treatment with oral antidiabetic agents (as opposed to insulin) and smaller preoperative waist circumference predicted diabetes remission. Two studies reported that patients with longstanding diabetes (> 10 years), preoperative insulin use, and poor preoperative glycemic control were less likely to achieve diabetes remission.40,41  However, these studies did not control for important confounding factors that may also influence diabetes remission, including age, sex, preoperative BMI, and preoperative A1C level. Eating behaviors and eating habits have been associated with weight loss after bariatric surgery.42  However, it is unknown whether these variables also may be associated with diabetes remission, particularly over long periods of time.

Caloric restriction

All bariatric procedures induce significant reductions in caloric intake in the early postoperative period, and the beneficial effect of caloric restriction on glycemia is well established.43  To determine whether caloric restriction ipso facto accounts for the immediate improvement in glycemic parameters within the first week of RYGB (before weight loss), Isbell et al.44  compared the metabolic response to a mixed-nutrient meal in nine participants before and after RYGB (an average of 4 days postoperatively) and nine matched obese control subjects before and after 4 days of the postoperative diet. Half of the participants in each group had type 2 diabetes.

Participants who underwent caloric restriction comparable to those in the RYGB group displayed similar changes in meal-stimulated glucose and insulin sensitivity after 4 days on an isocaloric diet. The potent insulin secretagogue glucagon-like peptide 1 (GLP-1) increased significantly after RYGB but remained unchanged in the calorie-restricted group.

Because a comparable improvement in glucose tolerance and insulin sensitivity was observed after caloric restriction without alterations in the incretin response, these data suggest that decreased caloric intake alone accounts for the rapid improvement in glycemia after surgery. However, it is important to note that the groups were clinically (although not statistically) different at baseline with respect to weight (153.2 ± 32.2 kg in the RYGB group versus 127.0 ± 36.5 kg in the diet group), and the confounding effects of type 2 diabetes and weight were inadequately adjusted for given the small sample size.45  Furthermore, use of insulin and other antidiabetic medications was not reported, which limits the generalizability of these findings.45 

Weight loss

Weight loss is one of the predominant mechanisms by which bariatric surgery induces diabetes remission, as demonstrated in multiple studies that have shown higher rates of diabetes remission with greater weight loss.17,22,29,33  Studies of AGB provide, perhaps, the strongest evidence for the role of weight loss in diabetes remission because improvements in glucose homeostasis occur independently of changes in the secretion of glucoregulatory gut hormones. In the landmark study by Dixon et al.33  described above, remission of type 2 diabetes was strongly related to weight loss.

Changes in the enteroinsular axis

Significant anatomical differences exist between AGB, VSG, and procedures that bypass segments of the gut (RYGB and BPD), resulting in distinctly different effects on the secretion of the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), the satiety factor peptide YY (PYY), and the orexigenic hormone ghrelin. These neuroendocrine factors are secreted by the gut mucosa in response to ingestion of nutrients, neural signals, and nutrient sensing.46  Many of these peptides influence glycemic control by modulating insulin secretion and possibly insulin sensitivity. The incretin effect is blunted in obese individuals with type 2 diabetes, which may contribute to impaired glucose homeostasis.46 

Because AGB leaves the GI tract intact and does not significantly alter the rate of gastric emptying,13  changes in the secretion of gut hormones occur in response to weight loss only and are less pronounced than changes after malabsorptive or combined procedures.10  RYGB excludes the proximal gut and thus expedites nutrient delivery to the distal ileum, resulting in altered secretion of the enteroendocrine factors described in more detail below.17  Similar changes in the secretion of gut peptides are observed after BPD15  and VSG26,45  because gastric emptying is accelerated after both procedures.15,16 Table 3 offers a summary of the effect of the various bariatric procedures on glucoregulatory gut peptides. Table 4 summarizes the roles these hormones play in influencing appetite and satiety.

GLP-1. This incretin hormone, a potent satiety signal and insulin secretagogue, is secreted by the L cells of the distal ileum in response to nutrients and neural signals arising from the proximal gut.46  GLP-1 acts directly on pancreatic β-cells to enhance glucose-dependent insulin secretion. It also suppresses glucagon secretion, although the mechanism for this has not been clearly elucidated.46  GLP-1 attenuates postprandial glycemia by slowing gastric emptying and exerts additional effects on the central nervous system to induce satiety and decrease food intake.46 

Basal levels and the postprandial response of GLP-1 are reduced in obese individuals with type 2 diabetes.47  Despite the reduced concentration, GLP-1 function remains intact in patients with diabetes when levels are restored.48 

Multiple studies of RYGB and BPD have demonstrated a markedly enhanced GLP-1 response after these two procedures.4954  Such a response appears to be independent of weight loss itself. Laferrère et al.52  demonstrated a sixfold increase in the postprandial GLP-1 response in obese, diabetic participants who had undergone RYGB, whereas the GLP-1 response was unchanged in matched obese, diabetic control subjects who had lost an equivalent amount of weight on a hypocaloric diet. Moreover, GLP-1 levels remain persistently elevated after RYGB, with levels increased at least 1 year after surgery.50 

Because rapid gastric emptying occurs after VSG, the GLP-1 response is also enhanced. One randomized trial that compared the effects of RYGB versus VSG on glucose metabolism reported significant increases in postprandial GLP-1 levels at 1 week and 3 months after both procedures. However, this increased response for GLP-1 was greater with RYGB than with VSG at both time points, as measured by the area under the curve.55  In contrast, GLP-1 levels are not altered by AGB, in part because the rate of gastric emptying is not altered. Korner et al.51  showed that postprandial GLP-1 levels increased threefold after RYGB but remained unchanged after gastric banding.

The physiological activity of GLP-1 has been extensively investigated through blockade of its receptor by exendin 9-39-amide (Ex-9).5660  Ex-9 completely eliminates the effect of endogenous GLP-1 on postprandial insulin release but has no effect on other hormones that enhance insulin secretion.5860  Kindel et al.61  found that diabetic rats that underwent duodenaljejunal exclusion (a procedure that simulates the GI diversion of RYGB but does not induce weight loss) had significant improvement in glucose tolerance compared to sham-operated rats. However, infusion of Ex-9 attenuated the improvement in glucose tolerance, suggesting that GLP-1 directly improves glucose homeostasis in rodents after a gastric bypass–like procedure.

Table 3.

Overview of Altered Secretion of Gut Peptides in Response to Different Bariatric Procedures

Overview of Altered Secretion of Gut Peptides in Response to Different Bariatric Procedures
Overview of Altered Secretion of Gut Peptides in Response to Different Bariatric Procedures
Table 4.

Roles of Hormones Influencing Appetite and Satiety

Roles of Hormones Influencing Appetite and Satiety
Roles of Hormones Influencing Appetite and Satiety

Extending these findings to human subjects, Salehi et al.62  used Ex-9 to determine whether RYGB-associated hyperinsulinism is mediated by enhanced GLP-1 action and whether this accounts for greater β-cell stimulation in subjects with postsurgical hypoglycemia.62  The administration of Ex-9 reduced postprandial insulin secretion rates by 33% in individuals who had undergone RYGB, compared to 16% in BMI-matched control subjects, demonstrating that GLP-1 has a heightened effect on postprandial insulin release after RYGB.

GIP. This incretin hormone is secreted by the K cells of the proximal gut in response to the ingestion of carbohydrates and lipids. Although less potent than GLP-1, GIP also acts on pancreatic β-cells to augment postprandial insulin secretion.63  Unlike GLP-1, GIP does not have any effect on the rate of gastric emptying or satiety. Data from studies examining GIP levels in individuals with type 2 diabetes remain discrepant, with some investigators reporting unchanged64  or even increased levels of this hormone.65  However, multiple studies have consistently demonstrated that the insulinotropic activity of GIP is impaired in type 2 diabetes.6668 

The response of GIP to bariatric surgery has been more variable than that of GLP-1. Several studies52,69  have reported that GIP levels are reduced after RYGB, possibly as a result of reduced stimulation of the K cells in the proximal gut as a consequence of the bypass. In contrast, Laferrère et al.50  reported a transient elevation in GIP levels 1 month after RYGB, but this response was not sustained. Näslund et al.70  reported persistent elevations in GIP levels up to 20 years after jejunoileal bypass. Like RYGB, this procedure causes early delivery of nutrient-rich chyme to the distal small intestine.

Few studies have evaluated the effect of restrictive procedures on GIP concentrations. Two observational studies51,71  reported no change in GIP levels 6, 12, and 24 months after AGB. To date, no studies have examined the effect of VSG on the GIP response.

PYY. This peptide is a satiety signal that is cosecreted with GLP-1 from the L cells of the distal ileum in response to nutrients.72  In addition to decreasing appetite through central mechanisms,73  PYY indirectly affects glucose homeostasis through activation of melanocortin neurons in the hypothalamus that affect insulin sensitivity.74 

Procedures such as RYGB that expedite nutrient delivery to the distal ileum result in an exaggerated PYY response to nutrient ingestion.75,76  Korner et al.75  reported a tenfold increase in postprandial PYY concentrations following RYGB, compared to the response observed in lean and obese nonsurgical control subjects. There have also been reports that PYY levels increase after VSG, but the response appears to be transient. In a randomized trial, Karamanakos et al.55  found that VSG and RYGB resulted in comparable increases in PYY levels for the first 6 months after surgery. However, the secretion of PYY was significantly reduced by 12 months in the VSG group, whereas the response was maintained in the RGYB group. The authors speculated that reduced PYY secretion was the result of physiological adaptation of the gastric remnant over time. Because AGB does not alter the rate of gastric emptying, the PYY response remains unchanged after this procedure.75 

Ghrelin. This orexigenic hormone is primarily secreted by the gastric fundus and proximal small intestine and acts on the hypothalamus to stimulate appetite.10  This hormone and its receptor are also expressed in pancreatic islet cells.10  Ghrelin is known to inhibit insulin secretion, possibly through an autocrine or paracrine mechanism that has yet to be elucidated.77 

The role of ghrelin in diabetes remission after bariatric surgery remains controversial. Ghrelin contributes to the marked loss of appetite and reduction in food intake that mediates weight loss after certain procedures and is known to enhance insulin sensitivity. Because ghrelin inhibits insulin secretion, suppresses the insulin-sensitizing hormone adiponectin, and stimulates the release of counterregulatory hormones,78  a reduction in ghrelin secretion may have beneficial effects on glucose homeostasis.

The effects of gastric bypass on ghrelin levels are inconsistent. Some reports79,80  have demonstrated reduced levels of ghrelin after RYGB, whereas others have shown no change81  or increased levels.82  Sundbom et al.83  reported a transient reduction in ghrelin secretion in the immediate and early postoperative period after RYGB, followed by a gradual increase in ghrelin secretion as weight loss ensued.

Variations in surgical techniques may account for these discrepant findings.10  If a small amount of gastric ghrelin-producing tissue is left intact, the residual cells can compensate to maintain normal ghrelin secretion. Ghrelin secretion is also affected by the vagus nerve, which is sometimes intentionally severed during RYGB. Ghrelin levels are typically higher after procedures such as AGB that maintain vagal integrity.

Because a significant amount of the gastric fundus is removed in VSG, ghrelin levels are significantly reduced after this procedure.26  In a randomized, controlled trial, fasting and postprandial ghrelin levels were found to be lower in participants who underwent VSG than in those who underwent RYGB.26 

Hindgut versus foregut hypotheses

Two possible theories have been proposed to explain the rapid improvement in glucose homeostasis after gastric bypass. The hindgut hypothesis suggests that the expedited delivery of nutrients to the distal ileum (as a result of the shortened length of the small bowel) improves glycemia through the enhanced secretion of gut peptides such as GLP-1, which augments glucose-dependent insulin secretion.84  In contrast, the foregut hypothesis suggests that the exclusion of the proximal bowel (as a consequence of GI rearrangement) prevents the secretion of an unidentified “putative signal” that promotes insulin resistance and type 2 diabetes.84  Existing data from both animal and human studies lend support to both the foregut8588  and hindgut theories,8992  but the predominant mechanism of improved glucose metabolism has yet to be elucidated.

Effects of Bariatric Surgery on Insulin Sensitivity

Bariatric surgery affects both insulin secretion and insulin sensitivity, which are related in a hyperbolic manner such that compensatory increase in one induces a subsequent reduction in the other.93  Although it is well established that insulin sensitivity substantially improves in response to weight loss,42  some of the procedures may also enhance insulin sensitivity independent of weight loss.

The mechanisms underlying improved glucose homeostasis after bariatric surgery have been most intensively studied in participants who have undergone BPD.9496  Mari et al.95  reported a significant increase in insulin sensitivity, as measured by the gold standard hyperinsulinemic-euglycemic clamp methodology, within days of BPD in a group of obese patients with glucose tolerance levels ranging from normal to frank diabetes. Insulin sensitivity did not improve in a matched obese control group with a similar metabolic profile who had undergone abdominal surgery for reasons other than BPD (mainly cholecystectomy and abdominal hernia repair), despite equivalent caloric restriction. This suggests that the improved glucose homeostasis after BPD occurred independent of weight loss and reduced food intake. Other studies have shown normalization of insulin-mediated, whole-body glucose uptake after BPD (often in excess of normal values) when compared to lean individuals, suggesting that this procedure confers supranormal insulin sensitivity.96 

The short-term effects of RYGB on insulin sensitivity are less clear. Several studies9799  that used the hyperinsulinemic-euglycemic clamp methodology found no improvement in insulin sensitivity within the first 4 weeks after RYGB. However, these studies were limited by the fact that participants were either nondiabetic or included a mixture of normoglycemic to frankly diabetic participants. In contrast, Kashyap et al.100  reported enhanced insulin sensitivity as assessed by a hyperglycemic clamp as early as 1 and 4 weeks after RYGB in an exclusively diabetic study population. Insulin sensitivity was unchanged at both time points in participants who underwent gastric restrictive surgery (AGB or VSG), despite weight losses equivalent to those in the RYGB group.

Because diabetic and nondiabetic individuals may respond differently to the various surgeries, further study using rigorous methodology is needed to better elucidate the short-term effects of bariatric surgery on insulin sensitivity.

Use of Bariatric Surgery for Diabetes Remission in Overweight to Mildly Obese Patients

Given the remarkable rate of diabetes remission with bariatric surgery, there is considerable interest in offering this intervention to diabetic patients with a BMI of < 35 kg/m2. Several case series and nonrandomized prospective trials have evaluated the efficacy of various bariatric surgery procedures on diabetes remission in less obese individuals.27,101,102  However, most of these studies have been limited by significant methodological limitations, including small sample size, poor follow-up, and heterogeneous criteria for diabetes remission. In a nonrandomized study that included 20 patients with poorly controlled diabetes and a mean BMI of 31 kg/m2 who underwent VSG, Lee et al.27  reported a 50% diabetes remission rate 52 weeks after surgery. Similar results were reported in a study of AGB performed in diabetic patients with a mean BMI of 33 kg/m2.101  In a case series that included 37 obese, diabetic patients with a mean BMI of 32.5 kg/m2 who underwent RYGB, Cohen et al.102  reported that diabetes was resolved in all participants after a follow-up of 6–48 months. However, participants in this series had mild diabetes (a mean fasting glucose level of 146 mg/dl on oral medications only), and only nine participants returned for follow-up at 48 months.

A 2009 study103  found that, among patients with a BMI of 32–34 kg/m2, only the most severe category of diabetes (A1C level of > 9% on maximal medical therapy) was deemed “appropriate” for bariatric surgery. The expert panel (consisting of 11 bariatric surgeons, two internists, and one endocrinologist) who developed these criteria felt that the current evidence does not support bariatric surgery in individuals with a BMI of < 32 kg/m2.

A recent survey study104  also found guarded enthusiasm among endocrinologists and primary care physicians for the use of bariatric surgery in people with type 2 diabetes and a BMI < 35 kg/m2. Only 20.8% of respondents indicated that they would be likely to refer their patients with type 2 diabetes and a BMI of 30–34.9 kg/m2 to a randomized research trial of bariatric surgery.

Diabetes Relapse Rate

Evidence from the SOS study suggests that improvement in glycemia and cardiovascular benefits persist for years after bariatric surgery.105  However, emerging evidence suggests that diabetes does recur in a significant number of patients.106,107 

One small study106  that included 42 patients who had previously undergone RYGB and had ≥ 3 years of follow-up found that 10 patients (24%) experienced a relapse of diabetes. In that study, diabetes recurrence was defined as an A1C > 6.0% and a fasting glucose level > 125 mg/dl and/or a requirement for glycemic medication in patients who had previously been in remission. Long-term studies suggest an even higher rate of diabetes relapse. In a case series that followed 157 patients who had previously undergone RYGB and had experienced initial remission of diabetes, 68 (43.1%) experienced a recurrence.107  Follow-up ranged from 5 to 16 years, and diabetes status was determined by patient interview and evaluation of antidiabetic medications. Both studies found that less initial weight loss and greater weight regain were associated with a greater likelihood of diabetes relapse.106,107 

The criteria for diabetes relapse have not been clearly defined.108  Postprandial hypoglycemia (typically asymptomatic) is relatively common in patients after RYGB. This may have the cumulative effect of falsely lowering A1C levels and masking the early stages of type 2 diabetes relapse.108  Further long-term studies are needed to assess the durability of diabetes remission and more accurately quantify the rate of relapse.

The issue of diabetes relapse is of particular concern when the use of bariatric surgery is considered for younger adults or adolescents. Consistent with many major academic medical centers in urban areas, the mean age of our patients is 44 years. However, we have recently observed a growing number of individuals in their 30s, many with type 2 diabetes and others with a strong family history of the disease, who are presenting for bariatric surgery with the primary objective of treating or preventing type 2 diabetes. Although surgical interventions may be particularly efficacious in the short term (within the first decade), relapse subsequently may occur and warrant further treatment.

Conclusion

Bariatric surgery induces significant improvements in glucose homeostasis through a number of mechanisms. Diabetes remission rates are highest for procedures that induce the greatest weight loss. Based on meta-analyses, BPD confers the highest rates of remission, followed by RYGB and AGB. Emerging evidence suggests that VSG induces rates of remission that are intermediate between RYGB and AGB.

All bariatric surgery procedures initially induce caloric restriction in the early postoperative period, but the various procedures appear to have differential effects on the secretion of glucoregulatory gut hormones. AGB does not alter the integrity of the GI tract or nutrient transit time and is not associated with changes in the secretion of gut peptides that are known to enhance insulin action. In contrast, VSG, RYGB, and BPD are associated with the enhanced secretion of the incretin hormones, reduced secretion of ghrelin, and greater weight loss. In conjunction, these changes result in reduced hyperinsulinemia and improved insulin sensitivity.

With increasing numbers of diabetic patients undergoing bariatric surgery, long-term randomized clinical trials comparing the effectiveness of surgical and medical therapies for type 2 diabetes are urgently needed. Studies are underway to evaluate the risk-benefit ratio of surgery in individuals with diabetes who meet the present criteria for bariatric surgery, as well as for less obese (BMI 30–35 kg/m2) populations.

This study was supported by grant 1RC1DK086132 from the National Institute of Diabetes and Digestive and Kidney Diseases.

Note of disclosure: Dr. Sarwer has served as a paid consultant for Allergan, BAROnova, EnteroMedics, and Ethicon Endo-Surgery, which are manufacturers of products for bariatric surgery. He is also on the board of directors of the Surgical Review Corporation, which created the International Center of Excellence for Bariatric Surgery program to evaluate bariatric surgeons and hospitals around the world and also manages these bariatric Center of Excellence programs on behalf of several bariatric surgery professional societies.

1.
Flegal
KM
,
Carroll
MD
,
Kit
BK
,
Ogden
CL
:
Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010
.
JAMA
307
:
491
497
,
2012
2.
Geiss
LS
,
Pan
L
,
Cadwell
B
,
Gregg
EW
,
Benjamin
SM
,
Engelgau
MM
:
Changes in incidence of diabetes in U.S. adults, 1997–2003
.
Am J Prev Med
30
:
371
377
,
2006
3.
Kramer
H
,
Cao
G
,
Dugas
L
,
Luke
A
,
Cooper
R
,
Durazo-Arvizu
R
:
Increasing BMI and waist circumference and prevalence of obesity among adults with type 2 diabetes: the National Health and Nutrition Examination Surveys
.
J Diabetes Complications
24
:
368
374
,
2010
4.
Centers for Disease Control and Prevention
:
National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011
.
Atlanta, Ga.
,
U.S. Department of Health and Human Services, Centers for Disease Control and Prevention
,
2011
5.
Colquitt
JL
,
Picot
J
,
Loveman
E
,
Clegg
AJ
:
Surgery for obesity
.
Cochrane Database Syst Rev
2
:
CD003641
,
2009
6.
Taylor
K
:
Metabolic and bariatric surgery fact sheet [article online]
. Available from www.asmbs.org/asmbs-press-kit.
Accessed 3 April 2012
7.
Pories
WJ
,
Swanson
MS
,
MacDonald
KG
,
Long
SB
,
Morris
PG
,
Brown
BM
,
Barakat
HA
,
deRamon
RA
,
Israel
G
,
Dolezal
JM
,
Dohm
L
:
Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus
.
Ann Surg
222
:
339
350
,
1995
8.
Vetter
ML
,
Cardillo
S
,
Rickels
MR
,
Iqbal
N
:
Narrative review: effect of bariatric surgery on type 2 diabetes mellitus
.
Ann Intern Med
150
:
94
103
,
2009
9.
NIDDK Weight Information Network
:
Bariatric surgery for severe obesity [article online]
. Available from www.win.niddk.nih.gov/publications/gastric.htm.
Accessed 3 April 2012
10.
Cummings
DE
,
Overduin
J
,
Shannon
MH
,
Foster-Schubert
KE
:
Hormonal mechanisms of weight loss and diabetes resolution after bariatric surgery
.
Surg Obes Rel Dis
1
:
358
368
,
2005
11.
Perugini
RA
,
Malkani
S
:
Remission of type diabetes following bariatric surgery: review of mechanisms and concept of ‘reversibility.’
Curr Opin Endocrinol Diabetes Obes
18
:
119
128
,
2011
12.
Buchwald
H
,
Oien
DM
:
Metabolic/bariatric surgery worldwide 2008
.
Obes Surg
19
:
1605
1611
,
2008
13.
de Jong
JR
,
van Ramshorst
B
,
Gooszen
HG
,
Smout
AJ
,
Tiel-Van Buul
MM
:
Weight loss after laparoscopic adjustable gastric banding is not caused by altered gastric emptying
.
Obes Surg
19
:
287
292
,
2009
14.
Data Laparoscopy Research Team (iData Research)
:
US market for laparoscopic devices
.
Vancouver, B.C.
,
iData Research Inc.
,
2009
15.
Braghetto
I
,
Davanzo
C
,
Korn
O
,
Csendes
A
,
Valladares
H
,
Herrera
E
,
Gonzalez
P
,
Papapietro
K
:
Scintigraphic evaluation of gastric emptying in obese patients submitted to sleeve gastrectomy compared to normal subjects
.
Obes Surg
19
:
1515
1521
,
2009
16.
Melissas
J
,
Koukouraki
S
,
Askoxylakis
J
,
Stathaki
M
,
Daskalakis
M
,
Perisinakis
K
,
Karkavitsas
N
:
Sleeve gastrectomy: a restrictive procedure?
Obes Surg
17
:
57
62
,
2007
17.
Rubino
F
:
Bariatric surgery: effects on glucose homeostasis
.
Curr Opin Clin Nutr Metab Care
9
:
497
507
,
2006
18.
Buchwald
H
,
Avidor
Y
,
Braunwald
E
,
Jensen
MD
,
Pories
W
,
Fahrbach
K
,
Schoelles
K
:
Bariatric surgery: a systematic review and meta-analysis
.
JAMA
292
:
1724
1737
,
2004
19.
Ferchak
CV
,
Meneghini
LF
:
Obesity, bariatric surgery, and type 2 diabetes: a systematic review
.
Diabetes Metab Res Rev
20
:
438
445
,
2004
20.
Maggard
MA
,
Shugarman
LR
,
Suttorp
M
,
Maglione
M
,
Sugerman
HJ
,
Livingston
EH
,
Nguyen
NT
,
Li
Z
,
Mojica
WA
,
Hilton
L
,
Rhodes
S
,
Morton
SC
,
Shekelle
PG
:
Meta-analysis: surgical treatment of obesity
.
Ann Intern Med
142
:
547
559
,
2005
21.
Shah
M
,
Simha
V
,
Garg
A
:
Review: long-term impact of bariatric surgery on body weight, comorbidities, and nutritional status
.
J Clin Endocrinol Metab
91
:
4223
4231
,
2006
22.
Buchwald
H
,
Estok
R
,
Fahrbach
K
,
Banel
D
,
Jensen
MD
,
Pories
WJ
,
Bantle
JP
,
Sledge
I
:
Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis
.
Am J Med
122
:
248
256
,
2009
23.
Angrisani
L
,
Lorenzo
M
,
Borrelli
V
:
Laparoscopic adjustable gastric banding versus Roux-en-Y gastric bypass: 5-year results of a prospective randomized trial
.
Surg Obes Relat Dis
3
:
127
132
,
2007
24.
Nguyen
NT
,
Slone
JA
,
Nguyen
XM
,
Hartman
JS
,
Hoyt
DB
:
A prospective randomized trial of laparoscopic gastric bypass versus laparoscopic adjustable gastric banding for the treatment of morbid obesity: outcomes, quality of life, and costs
.
Ann Surg
250
:
631
641
,
2009
25.
Himpens
J
,
Dapri
G
,
Cadière
GB
:
A prospective randomized study between laparoscopic gastric banding and laparoscopic isolated sleeve gastrectomy: results after 1 and 3 years
.
Obes Surg
16
:
1450
1456
,
2006
26.
Peterli
R
,
Wölnerhanssen
B
,
Peters
T
,
Devaux
N
,
Kern
B
,
Christoffel-Courtin
C
,
Drewe
J
,
von Flüe
M
,
Beglinger
C
:
Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: a prospective randomized trial
.
Ann Surg
250
:
234
241
,
2009
27.
Lee
WJ
,
Ser
KH
,
Chong
K
,
Lee
YC
,
Chen
SC
,
Tsou
JJ
,
Chen
JC
,
Chen
CM
:
Laparoscopic sleeve gastrectomy for diabetes treatment in nonmorbidly obese patients: efficacy and change in insulin secretion
.
Surgery
147
:
664
669
,
2010
28.
Kehagias
I
,
Karamanakos
SN
,
Argentou
M
,
Kalfarentzos
F
:
Randomized clinical trial of laparoscopic Roux-en-Y gastric bypass versus laparoscopic sleeve gastrectomy for the management of patients with BMI < 50 kg/m2
.
Obes Surg
21
:
1650
1656
,
2011
29.
Sjöström
L
,
Lindroos
AK
,
Peltonen
M
,
Torgerson
J
,
Bouchard
C
,
Carlsson
B
,
Dahlgren
S
,
Larsson
B
,
Narbro
K
,
Sjöström
CD
,
Sullivan
M
,
Wedel
H
:
Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery
.
N Engl J Med
351
:
2683
2693
,
2004
30.
Buse
JB
,
Caprio
S
,
Cefalu
WT
,
Ceriello
A
,
DelPrato
S
,
Inzucchi
SE
,
McLaughlin
S
,
Phillips
GL
 2nd
,
Robertson
RP
,
Rubino
F
,
Kahn
R
,
Kirkman
MS
:
How do we define cure of diabetes?
Diabetes Care
32
:
2133
2135
,
2009
31.
Dixon
JB
,
Pories
WJ
,
O'Brien
PE
,
Schauer
PR
,
Zimmet
P
:
Surgery as an effective early intervention for diabesity: why the reluctance?
Diabetes Care
28
:
472
474
,
2005
32.
Pournaras
DJ
,
Aasheim
ET
,
Søvik
TT
,
Andrews
R
,
Mahon
D
,
Welbourn
R
,
Olbers
T
,
le Roux
CW
:
Effect of definition of type II diabetes remission in the evaluation for bariatric surgery for metabolic disorders
.
Br J Surg
99
:
100
103
,
2012
33.
Dixon
JB
,
O'Brien
PE
,
Playfair
J
,
Chapman
L
,
Schachter
LM
,
Skinner
S
,
Proietto
J
,
Bailey
M
,
Anderson
M
:
Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial
.
JAMA
299
:
316
323
,
2008
34.
Schauer
PR
,
Kashyap
SR
,
Wolski
K
,
Brethauer
SA
,
Kirwan
JP
,
Pothier
CE
,
Thomas
S
,
Abood
B
,
Nissen
SE
,
Bhatt
DL
:
Bariatric surgery versus intensive medical therapy in obese patients with diabetes
.
N Engl J Med
366
:
1567
1576
,
2012
35.
Mingrone
G
,
Panunzi
S
,
De Gaetano
A
,
Guidone
C
,
Iaconelli
A
,
Leccesi
L
,
Nanni
G
,
Pomp
A
,
Castagneto
M
,
Ghirlanda
G
,
Rubino
F
:
Bariatric surgery versus conventional medical therapy for type 2 diabetes
.
N Engl J Med
366
:
1577
1585
,
2012
36.
Wadden
TA
,
Volger
S
,
Sarwer
DB
,
Vetter
ML
,
Tsai
AG
,
Berkowitz
RI
,
Kumanyika
S
,
Schmitz
KH
,
Diewald
LK
,
Barg
R
,
Chittams
J
,
Moore
RH
:
A two-year randomized trial of obesity treatment in primary care practice
.
N Engl J Med
365
:
1969
1979
,
2011
37.
Appel
LJ
,
Clark
JM
,
Yeh
HC
,
Wang
NY
,
Coughlin
JW
,
Daumit
G
,
Miller
ER
 3rd
,
Dalcin
A
,
Jerome
GJ
,
Geller
S
,
Noronha
G
,
Pozefsky
T
,
Charleston
J
,
Reynolds
JB
,
Durkin
N
,
Rubin
RR
,
Louis
TA
,
Brancati
FL
:
Comparative effectiveness of weight-loss interventions in clinical practice
.
N Engl J Med
365
:
1959
1968
,
2011
38.
Bennett
GG
,
Warner
ET
,
Glasgow
RE
,
Askew
S
,
Goldman
J
,
Ritzwoller
DP
,
Emmons
KM
,
Rosner
BA
,
Colditz
GA
:
Obesity treatment for socioeconomically disadvantaged patients in primary care practice
.
Arch Intern Med
172
:
565
574
,
2012
39.
Torquati
A
,
Lutfi
R
,
Abumrad
N
,
Richards
WO
:
Is Roux-en-Y gastric bypass surgery the most effective treatment for type 2 diabetes mellitus in morbidly obese patients?
J Gastrointest Surg
9
:
1112
1116
,
2005
40.
Schauer
PR
,
Burguera
B
,
Ikramuddin
S
,
Cottam
D
,
Gourash
W
,
Hamad
G
,
Eid
GM
,
Mattar
S
,
Ramanathan
R
,
Barinas-Mitchel
E
,
Rao
RH
,
Kuller
L
,
Kelley
D
:
Effect of lapaoroscopic Roux-en-Y gastric bypass on type 2 diabetes mellitus
.
Ann Surg
238
:
467
484
,
2003
41.
Sugerman
HJ
,
Wolfe
LG
,
Sica
DA
,
Clore
JN
:
Diabetes and hypertension in severe obesity and effects of gastric bypass-induced weight loss
.
Ann Surg
237
:
751
756
,
2003
42.
Sarwer
DB
,
Wadden
TA
,
Moore
RH
,
Baker
AW
,
Gibbons
LM
,
Raper
SE
,
Williams
NN
:
Preoperative eating behavior, postoperative dietary adherence, and weight loss after gastric bypass surgery
.
Surg Obes Relat Dis
4
:
640
646
,
2008
43.
Kelley
DE
,
Wing
R
,
Buonocore
C
,
Sturis
J
,
Polonsky
K
,
Fitzsimmons
M
:
Relative effects of calorie restriction and weight loss in noninsulin-dependent diabetes mellitus
.
J Clin Endocrinol Metab
77
:
1287
1293
,
1993
44.
Isbell
JM
,
Tamboli
RA
,
Hansen
EN
,
Saliba
J
,
Dunn
JP
,
Phillips
SE
,
Marks-Shulman
PA
,
Abumrad
NN
:
The importance of caloric restriction in the early improvements in insulin sensitivity after Roux-en-Y gastric bypass
.
Diabetes Care
33
:
1438
1442
,
2010
45.
Ozer
K
,
Abdelnour
S
,
Alva
AS
:
The importance of caloric restriction in the early improvements in insulin sensitivity after Roux-en-Y gastric by-pass surgery: comment on Isbell et al
.
Diabetes Care
33
:
e176
,
2010
46.
Holst
JJ
:
The physiology of glucagon-like peptide 1
.
Physiol Rev
87
:
1409
1439
,
2007
47.
Flint
A
,
Raben
A
,
Ersbøll
AK
,
Holst
JJ
,
Astrup
A
:
The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric empyting, energy and substrate metabolism in obesity
.
Int J Obes Relat Metab Disord
25
:
781
792
,
2001
48.
Legakis
IN
,
Tzioras
C
,
Phenekos
C
:
Decreased glucagon-like peptide 1 fasting levels in type 2 diabetes
.
Diabetes Care
26
:
252
,
2003
49.
Laferrère
B
,
Heshka
S
,
Wang
K
,
Khan
Y
,
McGinty
J
,
Teixeira
J
,
Hart
AB
,
Olivan
B
:
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
30
:
1709
1716
,
2007
50.
Laferrère
B
,
Tran
H
,
Egger
JR
,
Teixeira
J
,
McGinty
J
,
Yap
K
,
Bawa
B
,
Olivan
B
:
The increase in GLP-1 levels and incretin effect after Roux-en-Y gastric bypass surgery (RYGBP) persists up to 1 year in patients with type 2 diabetes mellitus (T2DM) [Abstract]
.
Obesity
15
:
7
,
2007
51.
Korner
J
,
Bessler
M
,
Inabnet
W
,
Taveras
C
,
Holst
JJ
:
Exaggerated glucagon-like peptide 1 and blunted glucose-dependent insulinotropic peptide secretion are associated with Rouxen-Y gastric bypass but not adjustable gastric banding
.
Surg Obes Relat Dis
3
:
597
601
,
2007
52.
Laferrère
B
,
Teixeira
J
,
McGinty
J
,
Tran
H
,
Egger
JR
,
Colarusso
A
,
Kovack
B
,
Bawa
B
,
Koshy
N
,
Lee
H
,
Yapp
K
,
Olivan
B
:
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
93
:
2479
2485
,
2008
53.
Mingrone
G
,
Nolfe
G
,
Gissey
GC
,
Iaconelli
A
,
Leccesi
L
,
Guidone
C
,
Nanni
G
,
Holst
JJ
:
Circadian rhythms of GIP and GLP-1 in glucose tolerant and in type 2 diabetics after biliopancreatic diversion
.
Diabetologia
52
:
873
881
,
2009
54.
Salinary
S
,
Bertuzzi
A
,
Asnaghi
S
,
Guidone
C
,
Manco
M
,
Mingrone
G
:
First-phase insulin secretion and restoration and differential response to glucose load depending on the route of administration in type 2 diabetic subjects after bariatric surgery
.
Diabetes Care
32
:
375
380
,
2009
55.
Karamanakos
SN
,
Vagenas
K
,
Kalfarentzos
F
,
Alexandrides
TK
:
Weight loss, appetite suppression, and changes and in fasting and postprandial ghrelin and peptide-YY after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study
.
Ann Surg
247
:
401
407
,
2008
56.
Raufman
JP
,
Singh
L
,
Eng
J
:
Exendin-3, a novel peptide from Heloderma horridum venom, interacts with vasoactive intestinal peptide receptors and a newly described receptor on dispersed acini from guinea pig pancreas: description of exendin-3(9-39) amide, a specific exendin receptor antagonist
.
J Biol Chem
266
:
2897
2902
,
1991
57.
Eng
J
,
Kleiman
WA
,
Singh
L
,
Singh
G
,
Raufman
JP
:
Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom
.
J Biol Chem
267
:
7402
7405
,
1992
58.
Wang
Z
,
Wang
RM
,
Owji
AA
,
Smith
DM
,
Ghatel
MA
,
Bloom
SR
:
Glucagon-like peptide-1 is a physiological incretin in rat
.
J Clin Invest
95
:
417
421
,
1995
59.
D'Alessio
DA
,
Vogel
R
,
Prigeon
R
,
Laschansky
E
,
Koerker
D
,
Eng
J
,
Ensinck
JW
:
Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons
.
J Clin Invest
97
:
133
138
,
1996
60.
Schirra
J
,
Sturm
K
,
Leicht
P
,
Arnold
R
,
Göke
B
,
Katschinski
M
:
Exendin (9-39) amide is an antagonist of glucagon-like peptide-1 (7-36) amide in humans
.
J Clin Invest
101
:
1421
1430
,
1998
61.
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
13
:
1762
1772
,
2009
62.
Salehi
M
,
Prigeon
RL
,
D'Alessio
DA
:
Gastric bypass surgery enhances glucagon-like peptide-1 stimulated postprandial insulin secretion in humans
.
Diabetes
60
:
2308
2314
,
2011
63.
Meier
JJ
,
Nauck
MA
,
Schmidt
WE
,
Gallwitz
B
:
Gastric inhibitory polypeptide: the neglected incretin revisited
.
Regul Pept
107
:
1
13
,
2002
64.
Krarup
T
:
Immunoreactive gastric inhibitory polypeptide
.
Endocr Rev
9
:
122
134
,
1988
65.
Ross
SA
,
Brown
JC
,
Dupré
J
:
Hypersecretion of gastric inhibitory polypeptide following oral glucose in diabetes mellitus
.
Diabetes
26
:
525
529
,
1977
66.
Vollmer
K
,
Holst
JJ
,
Baller
B
,
Ellrichmann
M
,
Nauck
MA
,
Schmidt
WE
,
Meier
JJ
:
Predictors of incretin concentrations in subjects with normal, impaired, and diabetic glucose tolerance
.
Diabetes
57
:
678
687
,
2008
67.
Vilsbøll
T
,
Krarup
T
,
Madsbad
S
,
Holst
JJ
:
Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients
.
Diabetologia
45
:
1111
1119
,
2002
68.
Vilsbøll
T
,
Knop
FK
,
Krarup
T
,
Johansen
A
,
Madsbad
S
,
Larsen
S
,
Hansen
T
,
Pedersen
O
,
Holst
JJ
:
The pathophysiology of diabetes involves a defective amplification of late phase insulin response to glucose by glucose-dependent insulkinotropic polypeptide-regardless of etiology and phenotype
.
J Clin Endocrinol Metab
88
:
4897
4903
,
2003
69.
Clements
RH
,
Gonzalez
QH
,
Long
CI
,
Wittert
G
,
Laws
HL
:
Hormonal changes after Roux-en-Y gastric bypass for morbid obesity and the control of type 2 diabetes mellitus
.
Am Surg
70
:
1
4
,
2004
70.
Näslund
E
,
Backman
L
,
Holst
JJ
,
Theodorsson
E
,
Hellström
PM
:
Importance of small bowel peptides for the improved glucose metabolism 20 years after jejunoileal bypass for obesity
.
Obes Surg
8
:
253
260
,
1998
71.
Shak
JR
,
Roper
J
,
Perez-Perez
GI
,
Tseng
CH
,
Francois
F
,
Gamagaris
Z
,
Patterson
C
,
Weinshel
E
,
Fielding
GA
,
Ren
C
,
Blaser
MJ
:
The effect of laparoscopic gastric banding surgery on plasma levels of appetite-control, insulinotropic, and digestive hormones
.
Obes Surg
18
:
1089
1096
,
2008
72.
Ballantyne
GH
:
Peptide YY (1–36) and peptide YY (3–36): Part I: distribution, release, and actions
.
Obes Surg
16
:
651
658
,
2006
73.
Batterham
RL
,
Cohen
MA
,
Ellis
SM
,
Le Roux
CW
,
Withers
DJ
,
Frost
GS
,
Ghatei
MA
,
Bloom
SR
:
Inhibition of food intake in obese subjects by peptide YY3–36N
.
N Engl J Med
349
:
941
948
,
2003
74.
Korner
J
,
Leibel
RL
:
To eat or not to eat: how the gut talks to the brain
.
N Engl J Med
349
:
926
928
,
2003
75.
Korner
J
,
Inabnet
W
,
Conwell
IM
,
Taveras
C
,
Daud
A
,
Olivero-Rivera
L
,
Restuccia
NL
,
Bessler
M
:
Differential effects of gastric bypass and banding on circulating gut hormone and leptin levels
.
Obesity
14
:
1553
1561
,
2006
76.
Morínigo
R
,
Moizé
V
,
Musri
M
,
Lacy
AM
,
Navarro
S
,
Marín
JL
,
Delgado
S
,
Casamitjana
R
,
Vidal
J
:
Glucagon-like peptide-1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects
.
J Clin Endocrinol Metab
91
:
1735
1740
,
2006
77.
Dezaki
K
,
Sone
H
,
Koizumi
M
,
Nakata
M
,
Kakei
M
,
Nagai
H
,
Hosoda
H
,
Kangawa
K
,
Yada
T
:
Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance
.
Diabetes
55
:
3486
3493
,
2006
78.
Cummings
DE
,
Foster-Schubert
KE
,
Overduin
J
:
Ghrelin and energy balance: focus on current controversies
.
Curr Drug Targets
6
:
153
169
,
2005
79.
Cummings
DE
,
Weigle
DS
,
Frayo
RS
,
Breen
PA
,
Ma
MK
,
Dellinger
EP
,
Purnell
JQ
:
Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery
.
N Engl J Med
346
:
1623
1630
,
2002
80.
Geloneze
B
,
Tambascia
MA
,
Pilla
VF
,
Geloneze
SR
,
Repetto
EM
,
Pareja
JC
:
Ghrelin: a gut-brain hormone: effect of gastric bypass surgery
.
Obes Surg
13
:
17
22
,
2003
81.
Faraj
M
,
Havel
PJ
,
Phélis
S
,
Blank
D
,
Sniderman
AD
,
Cianflone
K
:
Plasma acylation-stimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects
.
J Clin Endocrinol Metab
88
:
1594
1602
,
2003
82.
Holdstock
C
,
Engström
BE
,
Ohrvall
M
,
Lind
L
,
Sundbom
M
,
Karlsson
FA
:
Ghrelin and adipose tissue regulatory peptides: effect of gastric bypass surgery in obese humans
.
J Clin Endocrinol Metab
88
:
3177
3183
,
2003
83.
Sundbom
M
,
Holdstock
C
,
Engström
BE
,
Karlsson
FA
:
Early changes in ghrelin following Roux-en-Y gastric bypass: influence of vagal nerve functionality?
Obes Surg
17
:
304
310
,
2007
84.
Rubino
F
,
Gagner
M
:
Potential of surgery for curing type 2 diabetes mellitus
.
Ann Surg
236
:
554
559
,
2002
85.
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
239
:
1
11
,
2004
86.
Rubino
F
,
Forgione
A
,
Cummings
DE
,
Vix
M
,
Gnuli
D
,
Mingrone
G
,
Castagneto
M
,
Marescaux
J
:
The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes
.
Ann Surg
244
:
741
749
,
2006
87.
Ramos
AC
,
Galväo Neto
MP
,
de Souza
YM
,
Galväo
M
,
Murakami
AH
,
Silva
AC
,
Canseco
EG
,
Santamaría
R
,
Zambrano
TA
:
Laparoscopic duodenal-jejunal exclusion in the treatment of type 2 diabetes mellitus in patients with BMI < 30 kg/m2 (LBMI)
.
Obes Surg
19
:
307
312
,
2009
88.
Rodriguez-Grunert
L
,
Galvao Neto
MP
,
Alamo
M
,
Ramos
AC
,
Baez
PB
,
Tarnoff
M
:
First human experience with endoscopically delivered and retrieved duodenal-jejunal bypass sleeve
.
Surg Obes Relat Dis
4
:
55
59
,
2008
89.
Koopmans
HS
,
Ferri
GL
,
Sarson
DL
,
Polak
JM
,
Bloom
SR
:
The effects of ileal transposition and ileal bypass on food intake and GI hormone levels in rats
.
Physiol Behav
33
:
601
609
,
1984
90.
Ohtani
N
,
Sasaki
I
,
Naito
H
,
Shibata
C
,
Tsuchiya
T
,
Matsuno
S
:
Effect of ileojejunal transposition of gastrointestinal motility, gastric emptying, and small intestinal transit in dogs
.
J Gastrointest Surg
3
:
516
523
,
1999
91.
Sarson
DL
,
Scopinaro
N
,
Bloom
SR
:
Gut hormone changes after jejunoileal (JIB) or biliopancreatic (BPB) bypass surgery for morbid obesity
.
Int J Obes
5
:
471
480
,
1981
92.
Strader
AD
,
Vahl
TP
,
Jandacek
RJ
,
Woods
SC
,
D'Alessio
DA
,
Seeley
RJ
:
Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats
.
Am J Physiol Endocrinol Metab
288
:
E447
E453
,
2005
93.
Kahn
SE
,
Prigeon
RL
,
McCulloch
DK
,
Boyko
EJ
,
Bergman
RN
,
Schwartz
MW
,
Neifing
JL
,
Ward
WK
,
Beard
JC
,
Palmer
JP
:
The contribution of insulin-dependent and insulin-independent glucose uptake to intravenous glucose tolerance in healthy human subjects
.
Diabetes
43
:
587
592
,
1994
94.
Guidone
C
,
Manco
M
,
Valera-Mora
E
,
Iaconelli
A
,
Gniuli
D
,
Mari
A
,
Nanni
G
,
Castagneto
M
,
Calvani
M
,
Mingrone
G
:
Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery
.
Diabetes
55
:
2025
2031
,
2006
95.
Mari
A
,
Manco
M
,
Guidone
C
,
Nanni
G
,
Castagneto
M
,
Mingrone
G
,
Ferrannini
E
:
Restoration of normal glucose tolerance in severely obese patients after bilio-pancreatic diversion: role of insulin sensitivity and beta cell function
.
Diabetologia
49
:
2136
2143
,
2006
96.
Muscelli
E
,
Mingrone
G
,
Camastra
S
,
Manco
M
,
Pereira
JA
,
Pareja
JC
,
Ferrannini
E
:
Differential effect of weight loss on insulin resistance in surgically treated obese patients
.
Am J Med
118
:
51
57
,
2005
97.
Camastra
S
,
Gastaldelli
A
,
Mari
A
,
Bonuccelli
S
,
Scartabelli
G
,
Frascerra
S
,
Baldi
S
,
Nannipieri
M
,
Rebelos
E
,
Anselmino
M
,
Muscelli
E
,
Ferrannini
E
:
Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes
.
Diabetologia
54
:
2093
2102
,
2011
98.
Campos
GM
,
Rabl
C
,
Peeva
S
,
Ciovica
R
,
Rao
M
,
Schwarz
JM
,
Havel
P
,
Schambelan
M
,
Mulligan
K
:
Improvement in peripheral glucose uptake after gastric bypass surgery is observed only after substantial weight loss has occurred and correlates with the magnitude of weight lost
.
J Gastrointest Surg
14
:
15
23
,
2010
99.
Lima
MM
,
Pareja
JC
,
Alegre
SM
,
Geloneze
SR
,
Kahn
SE
,
Astiarraga
BD
,
Chaim
EA
,
Geloneze
B
:
Acute effect of Roux-en-Y gastric bypass on whole-body insulin sensitivity: a study with the euglycemic hyperinsulinemic clamp
.
J Clin Endocrinol Metab
95
:
3871
3875
,
2010
100.
Kashyap
SR
,
Daud
S
,
Kelly
KR
,
Gastaldelli
A
,
Win
H
,
Brethauer
S
,
Kirwan
JP
,
Schauer
PR
:
Acute effects of gastric bypass versus gastric restrictive surgery on beta-cell function and insulinotropic hormones in severely obese patients with type 2 diabetes
.
Int J Obes
34
:
462
471
,
2010
101.
Sultan
S
,
Parikh
M
,
Youn
H
,
Kurian
M
,
Fielding
G
,
Ren
C
:
Early U.S. outcomes afer laparoscopic adjustable gastric banding in patients with a body mass índex less than 35 kg/m2
.
Surg Endosc
23
:
1569
1573
,
2009
102.
Cohen
R
,
Pinheiro
JS
,
Correa
JL
,
Schiavon
CA
:
Laparoscopic Roux-en-Y gastric bypass for BMI < 35 kg/m2: a tailored approach
.
Surg Obes Relat Dis
2
:
401
404
,
2006
103.
Yermilov
I
,
McGory
ML
,
Shekelle
PW
,
Ko
CY
,
Maggard
MA
:
Appropriateness criteria for bariatric surgery: beyond the NIH guidelines
.
Obesity
17
:
1521
1527
,
2009
104.
Sarwer
DB
,
Ritter
S
,
Wadden
TA
,
Spitzer
JC
,
Vetter
ML
,
Moore
RH
:
Physicians' attitudes about referring their type 2 diabetes patients for bariatric surgery
.
Surg Obes Relat Dis.
Electronically Published ahead of print on 30 January 2012 (doi: 10.1016/j. soard.2011.12.013)
105.
Sjöström
L
,
Narbro
K
,
Sjöström
CD
,
Karason
K
,
Larsson
B
,
Wedel
H
,
Lystig
T
,
Sullivan
M
,
Bouchard
C
,
Carlsson
B
,
Bengtsson
C
,
Dahlgren
S
,
Gummesson
A
,
Jacobson
P
,
Karlsson
J
,
Lindroos
AK
,
Lönroth
H
,
Näslund
I
,
Olbers
T
,
Stenlöf
K
,
Torgerson
J
,
Agren
G
,
Carlsson
LM
:
Effects of bariatric surgery on mortality in Swedish obese subjects
.
N Engl J Med
357
:
741
752
,
2007
106.
DiGiorgi
M
,
Rosen
DJ
,
Choi
JJ
,
Milone
L
,
Schrope
B
,
Olivero-Rivera
L
,
Restuccia
N
,
Yuen
S
,
Fisk
M
,
Inabnet
WB
,
Bessler
M
:
Re-emergence of diabetes after gastric by-pass in patients with mid- to long-term follow-up
.
Surg Obes Relat Dis
6
:
249
253
,
2010
107.
Chikunguwo
SM
,
Wolfe
LG
,
Dodson
P
,
Meador
JG
,
Baugh
N
,
Clore
JN
,
Kellum
JM
,
Maher
JW
:
Analysis of factors associated with durable remission of diabetes after Rouxen-Y gastric by-pass
.
Surg Obes Relat Dis
6
:
254
259
,
2010
108.
Laferrère
B
:
Do we really know why diabetes remits after gastric bypass surgery?
Endocrine
40
:
162
167
,
2011