Incretins, diabetes, and bariatric surgery: a review

Surgery for Obesity and Related Diseases 1 (2005) 589 –598

Review article

Incretins, diabetes, and bariatric surgery: a review Rachel Fetner, M.D.a,*, James McGinty, M.D.b, Colleen Russell, Ph.D.c, F. Xavier Pi-Sunyer, M.D., M.P.H.a,c, Blandine Laferrère, M.D.a,c a

Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, St. Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, New York b Department of Surgery, Division of Bariatric Surgery, St. Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, New York c Obesity Research Center, St. Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, New York Manuscript received April 28, 2005; revised August 5, 2005; accepted September 2, 2005

Keywords:

Incretin; Glucagon-like peptide 1; Gastric inhibitory polypeptide; Glucose-dependent insulinotropic polypeptide; Type 2 diabetes mellitus; Bariatric surgery; Obesity

The prevalence of type 2 diabetes mellitus is increasing rapidly in the United States, with almost 16 million adults currently affected [1]. Obesity is an independent risk factor for diabetes. Among diabetic individuals, 50% are obese, with a body mass index (BMI) ⬎ 30 kg/m2 [1]. Bariatric surgery (surgical weight loss) has become an effective treatment for morbid obesity in those patients who have failed medical management of their illness. Up to 30% of patients presenting for bariatric surgery have type 2 diabetes mellitus [2,3]. The most commonly performed surgical procedure for weight loss, the Roux-en-Y gastric bypass (GBP), results in a percentage of excess weight loss (%EWL) of 50% to 75% and “cures” diabetes in 70% to 100% of patients [2,4] by improving both insulin secretion and sensitivity [5]. The possible role of the gut hormones known as incretins in the improvement of diabetes after bariatric surgery has been hypothesized. The incretins, gut peptides secreted in response to meals, enhance insulin secretion. The impaired incretin secretion in obese type 2 diabetes mellitus is partially responsible for the defect in insulin secretion [6 –9]. In this article we review the role of incretins in insulin secretion and in type 2 diabetes mellitus and the role of bariatric surgery in the improvement of diabetes and the response of incretins after surgery. As more morbidly obese diabetic patients undergo bariatric surgery, understanding

ⴱReprint requests: Rachel Fetner, M.D., 29 Barstow Road—Suite 305, Great Neck, NY 11021. E-mail: [email protected]

the factors contributing to the improvement of their diabetes becomes increasingly important.

Incretins The incretin effect, defined by Creutzfeldt, describes “the phenomenon of oral glucose eliciting a greater insulin response than intravenous glucose, even when the same amount of glucose is infused or an equivalent rise in glycemia is caused by the parenteral route” [10]. Although several neurotransmitters and gut hormones have incretinlike activity, evidence suggests that gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are the dominant peptides responsible for nutrient-stimulated insulin secretion [11]. GIP A peptide of 42 amino acids belonging to the glucagonsecretin family of peptides, GIP is secreted from K cells in the duodenum in response to absorbable carbohydrates and lipids [12,13]. A 10- to 20-fold elevation in GIP levels occurs in response to meal ingestion [13,14], with an increase to several hundred pmol/L [12,15]. The half-life of intact GIP is between 3 and 7 minutes [12,16]; it is degraded by the enzyme dipeptidyl peptidase IV (DPP-IV). The metabolites of GIP are also eliminated rapidly, resulting in a half-life of about 17 minutes [12,17,18].

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Table 1 Properties of GIP and GLP-1 [11–13,115,116]

Secreted from Insulin secretion Gastric emptying Glucagon secretion Gastric acid secretion Beta cell proliferation and survival Food intake, weight gain NH2-terminal inactivation by DPP-IV Secretion in type 2 diabetes Response in type 2 diabetes

GIP

GLP-1

K cells, mostly in duodenum and proximal jejunum Stimulates Minimal effect No effect Inhibits Promotes No effect Yes Normal Defective

L cells, predominantly in ileum and colon Stimulates Inhibits Inhibits Inhibits Promotes Reduces Yes Reduced Preserved

GIP ⫽ gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide; GLP-1 ⫽ glucagon-like peptide.

GLP-1

Other effects

GLP-1 is a product of the glucagon gene expressed in the pancreatic alpha cells and the L cells of the intestinal mucosa. In the pancreas, the main product of posttranslational processing is glucagon. In the L cells, “enteroglucagon,” GLP-1, and GLP-2 are the main final products [19]. GLP-1 is released by the presence of nutrients in the gut, but in contrast to GIP, concentrations rarely exceed 50 pmol/L [12,15,20]. GLP-1 is one of the most potent insulin secretagogues, and its potency exceeds that of GIP [13]. Once it is secreted, GLP-1 (7-36)NH2, the predominantly secreted and active form of GLP-1, is metabolized and inactivated by DPP-IV to form GLP-1 (9-36)NH2. The half-life of the GLP-1 metabolites is short, about 4 to 5 minutes [12,18]. The inactive GLP-1 (9-36)NH2 is the most abundant form of GLP-1 in postprandial plasma [21]. GLP-1 (9-36)NH2 does not affect insulin or glucagon secretion or alter glucose disposal even when administered at supraphysiological levels [21].

GLP-1 and GIP have many other effects besides their incretin effects (Table 1). GLP-1 inhibits gastric emptying [23–25] and glucagon secretion [26,27]. It also inhibits food intake and has been shown to promote weight loss [28 –32]. GIP, in contrast, has no effect on glucagon secretion and a minimal, if any, effect on gastric emptying. The first identified role of GIP was inhibition of gastric acid secretion, which is how it got its name [33]. Both GLP-1 and GIP promote beta cell proliferation and cell survival [11,16].

Effects of GLP-1 and GIP on insulin secretion Many studies have examined the effects of GLP-1 and GIP on insulin secretion in healthy subjects. D’Alessio et al. [20] showed that intravenous GLP-1 enhanced glucosestimulated insulin release compared with saline solution in healthy subjects (n ⫽ 6). Elahi et al. [6] demonstrated in 22 normal subjects that intravenous GLP-1 stimulated insulin secretion during euglycemia, whereas GIP did not. During physiological hyperglycemia, GLP-1 caused a greater insulin response than GIP. This study also showed that the two hormones have an additive insulinotropic effect during hyperglycemia and significantly stimulated insulin release above that seen with either peptide alone in normal subjects [6]. Physiological amounts of GIP and GLP-1 given intravenously significantly stimulated insulin secretion at both fasting plasma glucose levels and postprandial levels in eight healthy patients [22]. As in previous studies, at higher glucose levels, the GLP-1 response was greater than the GIP response [22]. GLP-1 also inhibited glucagons, whereas GIP did not [22].

Incretin defect in type 2 diabetes mellitus The incretin effect is responsible for approximately 50% of the insulin secreted after meal absorption. It becomes progressively blunted during the development of type 2 diabetes mellitus [34,35]. Many comprehensive reviews have examined the incretins and their role in diabetes mellitus [11–13,16,27,36]. GLP-1 levels are decreased in obesity, with or without concomitant diabetes [37,38]. In patients with type 2 diabetes mellitus, impaired incretin secretion contributes to the defective insulin secretion [6,8,39] compared with matched obese patients [37]. The components of the incretin defect in type 2 diabetes mellitus are defective secretion of GLP-1 and defective insulinotropic activity of GIP [6 – 8]. Indirect evidence for the importance of an incretin defect as a major contributor to the insulin deficiency in type 2 diabetes mellitus is the observation that administration of exogenous incretin hormone can restore insulin secretion to near-normal levels [6,7]. Circulating levels of GIP are normal or slightly increased in subjects with type 2 diabetes mellitus in the basal and postprandial states. In contrast, these subjects show modest but significant reductions in levels of meal-stimulated GLP-1. In contrast to GIP, which loses its effect in diabetics [7], GLP-1 continues to promote insulin secretion and suppress glucagon production in patients with type 2 diabetes mellitus [39]. In a group of 11 patients with type 2 diabetes mellitus, Elahi et al. [6] also demonstrated that GLP-1 administration caused an increase

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in the incretin response during hyperglycemia, but GIP administration did not. Both GIP receptor and GLP-1 receptor knockout (KO) mice [GIPR(⫺/⫺) and GLP-1R(⫺/⫺)] have been generated to investigate the physiological importance of the enteroinsular axis. Studies have demonstrated that glucose intolerance is additively increased in mice with inactivated GIP receptor genes, GLP-1 receptor genes, or both [40]. Glucose intolerance is more severe in double-receptor KO mice than in single-receptor KO mice [40]. Pederson et al. [41] found that GLP-1R ⫺/⫺ mice have only modest glucose intolerance and exhibit compensatory changes in the enteroinsular axis with increased GIP secretion and enhanced GIP action. In contrast, GIPR KO mice have unaltered GLP-1 levels but a greater insulin response to GLP-1 compared with wildtype mice, despite a decrease in pancreatic insulin content and gene expression [42].

inhibitor, significantly reduced fasting and postprandial glucose, HgA1C, and glucagon levels [53]. The GLP-1 receptor agonists described here are all based on the native peptide and are not orally available, whereas DPP-IV inhibitors are low-molecular-weight compounds suitable for oral administration [54]. These “GLP-1–like” agents are of particular interest, because many decrease food intake and promote weight loss [43], whereas most of the drugs used to treat diabetes tend to cause weight again [55]. In summary, the incretin hormones are key elements in physiological insulin secretion, responsible for ⬎ 50% of the physiological insulin secretion in response to oral ingestion of nutrients. GLP-1 secretion is impaired in type 2 diabetes mellitus, but its effect is maintained. Multiple “incretin-like” agents are currently being developed for the treatment of type 2 diabetes mellitus and should be available soon.

Incretin hormones as therapeutic agents

Incretins and bariatric surgery

Because of the preserved effect of GLP-1 in type 2 diabetes mellitus, there is much interest in using GLP-1 as a therapeutic agent in patients with this disease. Intravenous infusions, continuous subcutaneous infusions, and large doses of subcutaneous GLP-1 have normalized hyperglycemia in patients with type 2 diabetes mellitus [39,43,44]. Because the insulinotropic effect of GLP-1 is glucose-dependent, it is unlikely to cause significant hypoglycemia [45]. Because it is degraded extremely rapidly, GLP-1 per se cannot be used for clinical treatment of type 2 diabetes mellitus. Alternative treatment options include GLP-1 receptor agonists, GLP-1 mimetics, DPP-IV–resistant analogues, DPP-IV inhibitors, and continuous subcutaneous infusion of GLP-1 [46]. The GLP-1 agonist exendin-4 has a longer biological half-life and seems to be considerably more potent than GLP-1 [47,48]. Intravenous infusion of exendin-4 caused a significant decrease in fasting and postprandial glucose levels and also decreased food intake in healthy and diabetic patients [47,48]. Buse [49] showed that significantly more patients with type 2 diabetes mellitus treated with subcutaneous exendin-4 achieved an HgA1C level 7% lower than that in the placebo group over a 30-week period (n ⫽ 377). The higher dose of exendin-4 (10 ␮g compared with 5 ␮g) significantly reduced body weight as well [49]. NN2211 (liraglutide), a DPP-IV–resistant derivative of GLP-1, can lower blood sugar in healthy individuals [50,51] and also improve blood glucose control in patients with type 2 diabetes mellitus, without causing hypoglycemia or changes in fasting glucagon levels [51]. NVP DPP728, an orally active and highly selective DPP-IV inhibitor, significantly reduced glucose concentrations and HgA1C after 4 weeks of treatment [52]. LAF237, a longer-acting DDP-IV

Bariatric surgery is indicated for patients with BMI ⱖ 40 kg/m2 or BMI &ge 35 kg/m2 with significant comorbidities [56,57]. Bariatric surgery leads to significant and prolonged weight loss and is associated with improvement or resolution of all major comorbidities, particularly diabetes [56]. Approximately 150,000 Americans underwent bariatric surgery in 2004; 20% to 30% of these patients had diabetes [2]. Both insulin secretion and insulin sensitivity improve with surgical weight loss [5]. Many factors are involved in the improvement of insulin secretion after surgical weight loss, including decreased caloric intake and decreased glucotoxicity and lipotoxicity. In addition, the role of incretins is drawing increasing attention. Limited data on bariatric surgery patients suggest that the improvement in insulin secretion after surgery occurs rapidly and may result from changes in the enteroinsular axis, particularly in incretins [58 – 61]. Bariatric surgical procedures Bariatric surgeries can be classified as malabsorptive, malabsorptive/restrictive, or purely restrictive procedures [62,63]. There are four operations currently in use in the United States within these classifications: GBP, laparoscopic adjustable gastric banding (LAGB), vertical banded gastroplasty (VBG), and biliopancreatic diversion (BPD) [56,64]. The first procedure performed for weight loss, jejunoileal bypass (JIB) [65,66] is a strictly malabsorptive procedure that was later abandoned because of its many significant life-threatening long-term complications [62,65,67– 69]. However, surgeries involving a limited degree of malabsorption have become the mainstay of weight loss surgery. BPD was developed in the 1970s by Scopinaro et al. [70] and was modified to BPD with duodenal switch in the 1990s

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[66]. After this procedure, patients may eat larger portions than with other procedures because of the greater stomach volume, and there is no dumping syndrome because the pylorus is left intact. Substantial fat and protein malabsorption occur with these procedures, which require additional therapy and monitoring [56,71]. This operation is associated with an %EWL of approximately 70% to 80%, which is maintained over 5 years [71]. One review found an operative mortality of 1.1% in patients undergoing BPD or duodenal switch procedures [56]. The procedure is more complex than other bariatric procedures and is associated with greater morbidity [57,67]. A small restrictive gastric pouch to produce early satiety combined with a Roux-en-Y limb to provide malabsorption characterizes GBP [71]. Mason and Ito [72] first reported the GBP procedure in 1967. The average %EWL with this surgery is 60% to 75% [56] at 2 years, with 10% to 15% regain of the excess weight in most patients at 5 years postoperatively [71]. The operative mortality was between 0.3% and 1.0% in several reviews [56,73,74]. Long-term complications include the dumping syndrome, stomal stenosis, ulcers, ventral and internal hernias, and vitamin deficiencies [63,74,75]. GBP is the most commonly performed weight loss surgery in the United States [67,74]. Two restrictive operations are currently in use for surgical weight control: VBG, introduced by Mason [76], and LAGB [68,77]. VBG is performed by stapling the stomach vertically, leaving a 10- to 30-cc pouch. A ring of synthetic material (eg, silastic or Marlex) is sutured around the pouch to restrict its outlet [67,68,77]. Weight loss is achieved by restricting the capacity of the stomach, limiting intake. Although the %EWL is approximately 50%, less than with GBP, advantages include the absence of dumping syndrome and the lack of vitamin and mineral deficiencies. Possible complications include persistent vomiting, band erosion, and exacerbation of gastroesophageal reflux [73,77]. After initial weight loss, weight regain often occurs secondary to patient noncompliance [68,77]. Gastroplasties currently account for about 10% of bariatric operations in the United States, and most are done laparoscopically [68,77]. LAGB involves placing a silicone band with an inner balloon around the upper stomach, creating a small proximal pouch [67,68,77,78]. Kuzmak [79] introduced the inflatable band in which the diameter of the band can be adjusted by infusion of saline solution through a subcutaneous reservoir. The weight loss profile is similar to that for VBG, but the adjustability reduces the incidence of persistent vomiting and erosion [56]. The reoperation rate is approximately 5%, and reoperation is usually due to slippage of the band on the stomach, causing obstruction, or port site problems, such as tubing breakage [62,68,80]. The operative mortality rate is 0.1% for these purely restrictive procedures [56]. Patient compliance and frequent follow-up visits are required for successful weight loss with these procedures [68,81].

More than two-thirds of bariatric surgical procedures are now being performed laparoscopically [77]. LAGB is associated with less postoperative pain, shorter hospitalization and overall recovery times, and fewer incisional hernias [82]. Effect of bariatric surgery on diabetes Animal models have examined the effects of bariatric surgery on weight loss and diabetes. Xu et al. [83] studied the effects of Roux-en-Y gastric bypass on obese Zucker rats and found significantly decreased serum glucose and insulin concentrations postoperatively compared with controls. In addition, Rubino and Marescaux [84] showed that Goto-Kakizki rats (a spontaneous nonobese model of type 2 diabetes mellitus) that underwent gastrojejunal bypass had significantly improved glucose tolerance compared with sham-operated, food-restricted, and rosiglitazone-treated rats. This effect seemed to be a direct effect of the duodenal jejunal exclusion rather than of weight loss, because these were nonobese rats [84]. Similar results have been found in human studies. Pories and coworkers [2,85– 88] have documented dramatic improvement in type 2 diabetes mellitus within several days of surgery, with reduced fasting blood glucose, serum insulin, and serum leptin levels, as well as a lower rate of progression to and mortality from type 2 diabetes mellitus. A recent meta-analysis found that diabetes was completely resolved in 76.8% of patients and resolved or improved in 86% of patients [56,57]. Not all surgical procedures were equally effective. Diabetes was resolved in 98.9% of cases after BPD or duodenal switch, 83.7% of cases after GBP, 71.6% of cases after LABG, and only 47.9% of cases after VBG [56,57]. Ex-obese weight-stable subjects after BPD showed a normalization of the insulin response to glucose compared with nonobese subjects [89]. Another study of 6 morbidly obese patients (including 2 diabetics) showed that insulin sensitivity (Si), measured by a euglycemic clamp, was only partially corrected 6 to 12 months after GBP (after BMI decreased by 15 kg/m2) compared with a control group of lean males [90]. A more recent study showed improvement of Si measured by Homeostatic Assessment Model in 20 nondiabetic patients after BPD as early as 4 days after the surgery, with further improvement at 2 months, suggesting that the recovery of Si is, at least in part, independent of weight loss [91]. A longitudinal study reported no difference in terms of Si index or %EWL between the normal glucose tolerance, impaired glucose tolerance, and diabetic groups 12 months after GPB [5]. Another study showed complete remission of diabetes with normalization of the acute insulin response to glucose and Si 3 months after GBP [92], whereas others failed to show improved insulin secretion despite increased Si [93].

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Table 2 Effects of bariatric surgery on GLP-1 and GIP Reference

n

Surgery type

Study type

Control group

GLP-1, EG*

GIP

IE†

Lauritsen 1980

44

JIB 3/1 (12) JIB 1/3 (5)

C-S

●

Not measured

2 GIP after oral glucose vs. obese

JIB (20) or BPD (38)

C-S

Obese (12) Nonobese s/p IAS for FHC (5) Nonobese (10) Lean (13) Obese (16)

1 fasting and postprandial EG

Before and 3– 4 months after GBP ● Lean (6) ● Nonoperated obese (6) ● Obese 9 months after JIB (6) Before, 3 weeks and 6 months after JIB

Not measured

1 fasting GIP vs. lean, 2 postprandial GIP vs. lean and obese 2 fasting and postglucose GIP 1 fasting and mealstimulated GIP

JIB 3/1 2 IE vs. obese ● JIB 1/31 IE vs. nonobese Not measured

● ●

Sarson 1981

87

● ● ●

Sirinek 1986

12

GBP

L

Naslund 1998

24

20 years after JIB (6)

C-S

Barry 1977

12

JIB

L

5

GBP

L

Jorde 1981

21

JIB

C-S and L

Kellum 1990

16

L

●

Clements 2004

20

GBP (9) or VBG (7) GBP

L

●

Rubino 2004

10

GBP

L

●

Morinigo 2003

Before and 1.5 months after surgery ● Before, 2 and 6 weeks s/p JIB (5) ● Lean (8) ● 2 years s/p JIB (8) Before and after surgery Before and 2, 6 and 12 weeks after surgery Before and 3 weeks after surgery

1 fasting and mealstimulated GLP-1

●

Not measured Not measured

1 EG 3 weeks and 6 months after oral glucose 1 GLP-1 after test meal

Not measured

Not measured

Not measured

Not measured

Not measured

Not measured

1 EG after glucose meal

2 GIP after liquid test meal (with less of a decrease 2 years after surgery vs. preoperative and lean) Not measured

No change in fasting levels No change in fasting levels

2 fasting GIP at 6 and 12 weeks 2 fasting GIP only in diabetics

Not measured

Not measured

Not measured

GLP-1, glucagon-like peptide-1; EG, enteroglucagon; GIP, gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide; IE, incretin effect; C-S, cross-sectional; L, longitudinal; JIB, jejunoileal bypass; JIB 3/1, jejunoileal bypass with a ratio of 3:1 between jejunal and ileal segment left in continuity; JIB 1/3, jejunoileal bypass with a ratio of 1:3 between jejunal and ileal segment left in continuity; BPD, biliopancreatic diversion; GBP, gastric bypass; IAS, ileoascendostomia; FHC, familial hypercholesterolemia. * Enteroglucagon and GLP-1 are fragments of the same proglucagon molecule103, and early studies measured enteroglucagon rather than GLP-1. Enteroglucagon and GLP-1 have been shown to be secreted in parallel.58 † Incretin effect is defined as the phenomenon of oral glucose eliciting a greater insulin response than intravenous glucose, even when the same amount of glucose is infused or an equivalent rise in glycemia is caused by the parental route.10,19

Bariatric surgery and incretins Weight loss by either medical or surgical means appears to modify the basal and meal-stimulated incretin levels in obese patients with and without type 2 diabetes mellitus, although study results are contradictory [58 – 61,94 –98]. Serum GLP-1 levels have been shown to be lower in obese nondiabetics compared with lean controls and to improve to 80% to 88% of that of lean subjects after a 15% dietinduced weight loss [38]. In the same study, the GIP response was similar in lean and obese subjects, but decreased after weight loss [38]. Several studies have reported decreased GIP release and effect after JIB [59,60,97,99] and after GBP [61,94,100] in obese subjects. One cross-sectional study showed that basal fasting levels of enteroglucagon (the hormone measured instead of GLP-1 in early studies) and GIP were higher in obese patients who underwent JIB or BPD than in lean subjects [59]. However, these patients had postprandial responses

that were lower for GIP and higher for enteroglucagon compared with those in lean controls [59]. This lower GIP response was observed after a mixed meal in post-JIB patients [59,99] and after a glucose load in post-GBP patients [94]. Other cross-sectional studies showed higher basal and meal-stimulated GLP-1 levels in obese women 20 years after JIB compared with obese patients who did not undergo surgery and with obese patients 9 months after surgery [58,101]. Changes in gastric emptying after bariatric surgery may also explain the increased incretin effect. The accelerated transit after GPB, secondary to anatomic changes, could be responsible for the more rapid release of GLP-1 [102]. The increase in incretins occurring after bariatric surgery may play a role in the improved insulin secretion after surgery. However, most of the studies to date have been cross-sectional [58 – 60,101] and compared postsurgical morbidly obese to nonsurgical or lean groups [58 – 60],

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making it difficult to isolate the role of surgery from that of weight loss. Also, of the studies reporting basal and mealstimulated incretin levels, very few reported the incretin effect on insulin secretion. Few studies examined long-term changes of gut peptides after surgical weight loss. Barry et al. [95] reported that the increased GLP-1 levels observed at 3 weeks after JIB surgery further increased 6 months later. Table 2 summarizes the effects of bariatric surgery on GLP-1 and GIP levels. By suppressing glucagon and causing reactive hypoglycemia [103–106], the enhanced GLP-1 secretion after bariatric surgery may also play a role in promoting the symptoms of the dumping syndrome, a group of vasomotor and/or gastrointestinal symptoms occurring after a carbohydrate meal in patients who have undergone gastric surgery [107]. In summary, not only is bariatric surgery gaining popularity as the treatment of choice for morbidly obese patients, but also its significant effect on weight loss and comorbidities in the long term make it the most effective therapy for morbid obesity. All surgical procedures, by decreasing food intake and inducing weight loss, decrease glucose levels and lipotoxicity and improve both insulin secretion and sensitivity, resulting in improved diabetes control. Among all surgical procedures, GBP, through its specific effect on the gut hormones, seems to have additional benefits for diabetes control. The mechanisms by which GBP considerably improves diabetes control could be related to the incretins. The GIP effect is impaired in type 2 diabetes mellitus, so although GIP release might change after bariatric surgery, the effect remains impaired. However, GLP-1 release (and subsequently the effect) is defective in diabetes, and the surgery may restore both the release and the effect. Conclusions The increasing prevalence of obesity has brought an increase in associated comorbidities, especially type 2 diabetes mellitus. Because of their immediate and long-term success of bariatric surgery in terms of weight loss and diabetes control, the number these procedures performed in the United States is also rising. The pathophysiology of obesity and type 2 diabetes mellitus remains unclear. The emerging role of the gut as an endocrine organ, with the development of incretins as new agents, is gaining interest. The incretins, gut hormones secreted in response to nutrients, play a key role in insulin secretion in response to these nutrients. Incretin analogues are actively being developed and soon should play a role in the treatment of type 2 diabetes mellitus. The incretins seem to play a role in the rapid improvement in diabetes after bariatric surgery. However, too few studies, mostly crosssectional rather than prospective, have been done to enable a thorough evaluation of this phenomenon. Moreover, although few studies have examined prospectively the

changes in incretin levels (the assays are technically quite difficult), no recent studies have evaluated the incretin effect. Therefore, the role of incretins in curing or improving diabetes after bariatric surgery remains speculative at this point. Future studies should address the contribution of incretins in the development, treatment, and rapid resolution (after bariatric surgery) of type 2 diabetes mellitus. The gut is a complex endocrine organ, and whether the incretins interact with other gut hormones, such as ghrelin [108 –113] and peptide YY [112–114], to control food intake and weight loss after bariatric surgery remains to be studied.

Acknowledgment We are grateful to Allison Hart for her help in formatting the references.

References [1] National Task Force on the Prevention and Treatment of Obesity. Overweight, obesity, and health risk. Arch Intern Med 2000;160: 898 –904. [2] Pories WJ, MacDonald KG Jr, Morgan EJ, et al. Surgical treatment of obesity and its effect on diabetes: 10-y follow-up. Am J Clin Nutr 1992;55:582S–5S. [3] Residori L, Garcia-Lorda P, Flancbaum L, Pi-Sunyer FX, Laferrère B. Prevalence of co-morbidities in obese patients before bariatric surgery: effect of race. Obes Surg 2003;13:333– 40. [4] Sjostrom CD, Lissner L, Wedel H, Sjostrom L. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obese Res 1999;7:477– 84. [5] Geloneze B, Tambascia MA, Pareja JC, Repetto EM, Magna LA. The insulin tolerance test in morbidly obese patients undergoing bariatric surgery. Obes Res 2001;9:763–9. [6] Elahi D, McAloon-Dyke M, Fukagawa NK, et al. The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (7-37) in normal and diabetic subjects. Regul Pept 1994;51:63–74. [7] Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 (7-36 amide) but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 1993;91: 301. [8] Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide in type 2 diabetic patients. J Clin Endocrinol Metab 2001;86:3717–23. [9] Lugari R, Dell’Anna C, Ugolotti D, et al. Effect of nutrient ingestion of glucagon-like peptide 1 (7-36 amide) secretion in human type 1 and type 2 diabetes. Horm Metab Res 2000;32:424 – 8. [10] Creutzfeldt W. The incretin concept today. Diabetologia 1979;16: 75– 85. [11] Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26:2929 – 40. [12] Vilsboll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia 2004;47:357– 66. [13] Holst JJ, Orskov C. Incretin hormones: an update. Scand J Clin Lab Invest 2001;234:75S– 85S.

R. Fetner et al. / Surgery for Obesity and Related Diseases 1 (2005) 589 –598 [14] Pederson RA, Gastric inhibitory polypeptide. In: Walsh, JH, Dockray GJ, editors. Gut peptides: biochemistry and physiology. New York: Raven Press; 1994. p. 217– 60. [15] Orskov C, Wettergren A, Holst JJ. Secretion of the incretin hormones glucagon-like peptide 1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man throughout the day. Scand J Gastroenterol 1996;31:665–70. [16] Gault VA, O’Harte FPM, Flatt PR. Glucose-dependent insulinotropic polypeptide (GIP): anti-diabetic and anti-obesity potential? Neuropeptides 2003;37:253– 63. [17] Deacon CF, Nauck MA, Meier J, Hucking K, Holst JJ. Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide. J Clin Endocrinol Metab 2000;85:3575– 81. [18] Vilsboll T, Agersoe H, Krarup T, Holst JJ. Similar elimination rates of GLP-1 in obese type 2 diabetic patients and healthy subjects. J Clin Endocrinol Metab 2003;88:220 – 4. [19] Nauck MA. Is glucagon-like peptide 1 an incretin hormone? Diabetologia 1999;42:373–9. [20] D’Alessio DA, Kahn SE, Leusner CR, Ensinck JW. Glucagon-like peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal. J Clin Invest 1994;93:2263– 6. [21] Vahl TP, Paty BW, Fuller BD, Prigeon RL, D’Alessio DA. Effects of GLP-1-(7-36)NH2, GLP-1-(7-37)NH2, and GLP-1-(9-36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans. J Clin Endocrinol Metab 2003;88:1772–9. [22] Vilsboll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept 2003;114:115–21. [23] Flint A, Rabin A, Ersboll AK, Holst JJ, Astrup A. The effect of physiological levels of glucagon-like peptide 1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes Relat Metab Disord 2001;25:781–92. [24] Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Truncated GLP-1 (proglucagon 78-107 amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci 1993;38:665– 73. [25] Wettergren A, Wojdemann M, Holst JJ. Glucagon-like peptide 1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol 1998;275:G984 –92. [26] Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002;122:531– 44. [27] Nauck MA, Meier JJ. Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. Regul Pept 2005;128:135– 48. [28] Flint A, Raben A, Astrup A, Holst J. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998;101:515–20. [29] Gutzwiller J, Goke B, Drew J, et al. Glucagon-like peptide 1: a potent regulator of food intake in humans. Gut 1999;44:81– 6. [30] Naslund E, Barkeling B, King N, et al. Energy intake and appetite are suppressed by glucagon-like peptide 1 (GLP-1) in obese men. Int J Obes Relat Metab Disord 1999;23:304 –11. [31] Toft-Nielsen MB, Madsbad S, Holst JJ. Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients. Diabetes Care 1999;22: 1137– 43. [32] Turton M, O’Shea D, Gunn I, et al. A role of glucagon-like peptide 1 in the central regulation of feeding. Nature 1996;379:69 –72. [33] Yip RG, Wolfe MM. GIP biology and fat metabolism. Life Sci 2000;66:91–103. [34] Ebert R, Creutzfeldt W. Gastrointestinal peptides and insulin secretion. Diabetes Metab Rev 1987;3:1–26.

595

[35] Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non–insulin-dependent) diabetes. Diabetologia 1986;29:46 –52. [36] Dupre J. Glycaemic effects of incretins in type 1 diabetes mellitus: a concise review, with emphasis on studies in humans. Regul Pept 2005;128:149 –57. [37] Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagonlike peptide 1 in type 2 diabetic patients. Diabetes 2001;50:609 –13. [38] Verdich C, Toubro S, Buemann B, Lysgard MJ, Juul Holst J, Astrup A. The role of postprandial releases of insulin and incretin hormones in meal-induced satiety: effect of obesity and weight reduction. Int J Obes Relat Metab Disord 2001;25:1206 –14. [39] Nauck MA, Kleine N, Orskov C, et al. Normalization of fasting hyperglycemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non–insulin-dependent) diabetic patients. Diabetologia 1993;36:741– 4. [40] Preitner E, Ibberson M, Franklin I, et al. Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J Clin Invest 2004;113:635– 45. [41] Pederson RA, Satkunarajah M, McIntosh CH, et al. Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor ⫺/⫺ mice. Diabetes 1998;47:1046 –52. [42] Pamir N, Lynn FC, Buchan AM, et al. Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis. Am J Physiol Endocrinol Metab 2003;282; E931–9. [43] Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002;359:824 –30. [44] Nauck MA, Holst JJ, Willms B. Glucagon-like peptide 1 and its potential in the treatment of non–insulin-dependent diabetes mellitus. Horm Metab Res 1997;29:411– 6. [45] Qualmann C, Nauck MA, Holst JJ, Orskov C, Creutzfeldt W. Insulinotropic actions of intravenous glucagon-like peptide 1 (GLP-1) (7-36 amide) in the fasting state in healthy subjects. Acta Diabetol 1995;32:13– 6. [46] Holst JJ. Glucagon-like peptide 1: a gastrointestinal hormone with a pharmaceutical potential. Curr Med Chem 1999;6:1005–17. [47] Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab 2002;87:1282–90. [48] Edwards MB, Stanley SA, Davis R, et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Endocrinol Metab 2001;281:E155– 61. [49] Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004;27:2628 –35. [50] Agerso H, Jensen LB, Elbrond B, Rolan P, Zdravkovis M. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 2002;45:195–202. [51] Juhl CB, Hollingdal M, Sturis J, et al. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes 2002;51: 424 –9. [52] Ahren B, Simonsson E, Karssib H, et al. Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes. Diabetes Care 2002;25:869 –75. [53] Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia,

596

[54] [55] [56] [57]

[58]

[59]

[60]

[61]

[62] [63]

[64] [65]

[66] [67] [68] [69] [70]

[71]

[72] [73]

[74] [75]

[76] [77]

R. Fetner et al. / Surgery for Obesity and Related Diseases 1 (2005) 589 –598 sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 2004;89:2078 – 84. Deacon CF. Therapeutic strategies based on glucagon-like peptide 1. Diabetes 2004;53:2181–9. Turner RC, Holman RR. Lessons from UK prospective diabetes study. Diabetes Res Clin Pract 1995;28:S151–7. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724 –37. Kalfarentzos F, Parabolas S, Scrubs G, Khakis I, Looked A, Mead N. Prospective evaluation of biliopancreatic diversion with Rouxen-Y gastric bypass in the super obese. J Gastrointestinal Surg 2004;8:479 – 88. Naslund E, Backman L, Holst JJ, Theodorsson E, Hellstrom PM. Importance of small bowel peptides for the improved glucose metabolism 20 years after jejunoileal bypass for obesity. Obes Surg 1998;8:253– 60. Sarson DL, Scopinaro N, Bloom SR. Gut hormone changes after jejunoileal (JIB) or biliopancreatic (BPB) bypass surgery for morbid obesity. Int J Obes 1981;5:471– 80. Lauritsen KB, Christensen KC, Stokholm KH. Gastric inhibitory polypeptide (GIP) release and incretin effect after oral glucose in obesity and after jejunoileal bypass. Scand J Gastroenterol 1980;15: 489 –95. Rubino F, Gagner M, Gentileschi P, 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;240:236 – 42. Buchwald H. Overview of bariatric surgery. J Am Coll Surg 2002; 194:367–75. Gonzalez R, Nelson LG, Gallagher SF, Moor MM. Anastomatic leaks after laparoscopic gastric bypass. Obes Surg 2004;12:1299 – 1307. Profumo RJ. Bariatric surgery: review of common procedures and mortality analyses. J Insur Med 2004;36:187–93. Kremen AJ, Linner JH, Nelson CH. An experimental evaluation of the nutritional importance of proximal and distal small intestine. Ann Surg 1954;140:439 – 48. Marceau P, Biron S, Bourque RA, et al. Biliopancreatic diversion with a new type of gastrectomy. Obes Surg 1993;3:29 –35. Herron DM. The surgical management of severe obesity. Mt Sinai J Med 2004;71:63–71. Fobi MA. Surgical treatment of obesity: a review. J Natl Med Assoc 2004;96:61–75. Griffen WO Jr, Bivins BA, Bell RM. The decline and fall of the jejunoileal bypass. Surg Gynecol Obstetr 1983;157:301– 8. Scopinaro N, Gianetta E, Civalleri D, Bonalumi U, Bachi V. Biliopancreatic bypass for obesity II: initial experience in man. Br J Surg 1979;66:618 –20. Greenway SE, Greenway FL III, Klein S. Effects of obesity surgery on non–insulin-dependent diabetes mellitus. Arch Surg 2002;137: 1109 –17. Mason EE, Ito CC. Gastric bypass in obesity. Surg Clin North Am 1967;47:1345–54. Snow V, Barry P, Fitterman N, Qaseem A, Weiss K. Pharmacological and surgical management of obesity in primary care: a clinical practice guideline from the ACP. Ann Intern Med 2005;142:525–32. Maggard MA, Shugarman LR, Suttorp M, et al. Meta-analysis: surgical treatment of obesity. Ann Intern Med 2005;142:547–59. Fernandez AZ Jr, Demaria EJ, Tichansky DS, et al. Multivariate analysis of risk factors for death following gastric bypass for treatment of morbid obesity. Ann Surg 2004;239:698 –702. Mason EE. Vertical banded gastroplasty for obesity. Arch Surg 1982;117:701– 6. Brolin RE. Bariatric surgery and long-term control of morbid obesity. JAMA 2002;288:2793– 6.

[78] Fielding GA, Ran CJ. Laparoscopic adjustable gastric band. Surg Clin North Am 2005;129 – 40. [79] Kuzmak LI. Gastric banding. In: Dietel M, editor. Surgery for the morbidly obese patient. Philadelphia: Lea & Febiger; 1989. p. 225. [80] Peterli R, Donadini A, Peters T, Ackermann C, Tondelli P. Reoperations following laparoscopic adjustable gastric banding. Obes Surg 2002;12:851– 6. [81] Kuzmak LI. Silicone gastric banding: a single and effective operation for morbid obesity. Contemp Surg 1986;28:13–18. [82] Cottam DR, Nguyen NT, Eid GM, Schauer PR. The impact of laparoscopy on bariatric surgery. Surg Endosc 2005;19:621–7. [83] Xu Y, Ohinata K, Meguid MM, et al. Gastric bypass model in the obese rat to study metabolic mechanisms of weight loss. J Surg Res 2002;107:56 – 63. [84] 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. [85] Pories WJ, Caro JF, Flicking EG, Meelheum HD, Swanson MS. The control of diabetes mellitus (NIDDM) in the morbidly obese with the Greenville gastric bypass. Ann Surg 1987;206:316 –23. [86] Pories WJ, Swanson MS, MacDonald KG, 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. [87] MacDonald KG Jr, Long SD, Swanson MS, et al. The gastric bypass operation reduces the progression and mortality of non–insulindependent diabetes mellitus. J Gastrointest Surg 1997;1:213–20. [88] Hickey MS, Pories WJ, MacDonald KG, et al. A new paradigm for type 2 diabetes mellitus: could it be a disease of the foregut? Ann Surg 1998;55:1025–34. [89] Castagneto M, De Gaetano A, Mingrone G, et al. Normalization of insulin sensitivity in the obese patient after stable weight reduction with biliopancreatic diversion. Obes Surg 1994;4:161– 8. [90] Burstein R, Epstein Y, Charuzi I, Suessholz A, Karnieli E, Shapiro Y. Glucose utilization in morbidly obese subjects before and after weight loss by gastric bypass operation. Int J Obes Relat Metab Disord 1995;19:558 – 61. [91] Adami GF, Cordera R, Marinari G, Lamerini G, Andraghetti G, Scopinaro N. Plasma ghrelin concentration in the short-term following biliopancreatic diversion. Obes Surg 2003;13:889 –92. [92] 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. [93] Hughes TA, Gwynne JT, Switzer BR, Herbst C, White G. Effects of caloric restriction and weight loss on glycemic control, insulin release and resistance, and atherosclerotic risk in obese patients with type II diabetes mellitus. Am J Med 1984;77:7–17. [94] Sirinek KR, O’Dorisio TM, Hill D, McFee AS. Hyperinsulinism, glucose-dependent insulinotropic polypeptide, and the enteroinsular axis in morbidly obese patients before and after gastric bypass. Surgery 1986;100:781–7. [95] Barry RE, Barisch J, Bray GA, Sperling MA, Morin RJ, Benfield J. Intestinal adaptation after jejunoileal bypass in man. Am J Clin Nutr 1977;30:32– 42. [96] Morinigo R, Casamitjana R, Moize V, Gomis R, Vidal J. Determinants and relevance of GLP-1 secretion changes following gastric bypass in morbidly obese patients. Int J Obes 2003;T3:P3– 046, S87. [97] Jorde R, Burhol PG, Johnson JA. The effect of jejunoileal bypass on postprandial release of plasma gastric inhibitory polypeptide (GIP). Scand J Gastroenterol 1981;16:313–9. [98] Kellum JM, Kuemmerle JF, O’Dorisio TM, et al. Gastrointestinal hormone responses to meals before and after gastric bypass and vertical banded gastroplasty. Ann Surg 1990;211:763–70.

R. Fetner et al. / Surgery for Obesity and Related Diseases 1 (2005) 589 –598 [99] Sarson DL, Besterman HS, Bloom SR. Radioimmunassay of gastric inhibitory polypeptide and its release in morbid obesity and after jejuno-ileal bypass (proceedings). J Endocrinol 1979;81:155P– 6P. [100] 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 II diabetes mellitus. Am Surg 2004;70:1– 4. [101] Naslund E, Gryback P, Hellstrom PM, et al. Gastrointestinal hormones and gastric emptying 20 years after jejunoileal bypass for massive obesity. Int J Obes Relat Metab Disord 1997;21:387–92. [102] Horowitz M, Collins P, Harding P, Shearman D. Gastric emptying after gastric bypass. Int J Obes 1986;10:117–21. [103] Miholic J, Orskov C, Holst JJ, Kotzerke J, Meyer HJ. Emptying of the gastric substitute, glucagon-like peptide 1 (GLP-1), and reactive hypoglycemia after total gastrectomy. Dig Dis Sci 1991;36:1361–70. [104] Miholic J, Orskov C, Holst JJ, Kotzerke J, Pichlmayr R. Postprandial release of glucagon-like peptide 1, pancreatic glucagon, and insulin after esophageal resection. Digestion 1993;54:73– 8. [105] Naito H, Sakaki I, Matsuno S. Surgical aspect of enteroinsular axis after gastrointestinal surgery with reference to incretin secretion. Pancreas 1998;16:370 – 8. [106] Schirra J, Katschinski M, Weidman C, et al. Gastric emptying and the release of glucagon-like peptide 1, pancreatic glucagon, and insulin after esophageal resection. Digestion 1993;54:73– 8. [107] Vecht J, Masclee AA, Lamers CB. The dumping syndrome: current insights into pathophysiology, diagnosis and treatment. Scand J Gastroenterol 1997;223:21–7. [108] Katsuki A, Urakawa H, Gabazza EC, et al. Circulating levels of active ghrelin is associated with abdominal adiposity, hyperinsulin-

[109]

[110]

[111]

[112] [113]

[114] [115]

[116]

597

emia and insulin resistance in patients with type 2 diabetes mellitus. Eur J Endocrinol 2004;151:573–7. Poykko SM, Kellokosi E, Horkko S, Kaumma H, Kesaniemi YA, Ukkola O. Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes 2003; 52:2546 –53. Anderwald C, Brabant G, Bernoider E, et al. Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients. Diabetes 2003;52:1792– 8. Geloneze B, Tambascia MA, Pilla VF, Geloneze SR, Repetto EM, Pareja JC. Ghrelin, a gut-brain hormone: effect of gastric bypass surgery. Obes Surg 2003;13:17–22. Dhillo WS, Bloom SR. Gastrointestinal hormones and regulation of food intake. Horm Metab Res 2004;36:846 –51. Korner J, Bessler M, Cirilo LJ, 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 – 65. Renshaw D, Batterham RI. Peptide YY: a potential therapy for obesity. Curr Drug Targets 2005;6:171–9. Wettergren A, Wodjeman M, Meisner S, Stadil F, Holst JJ. The inhibitory effect of glucagon-like peptide 1 (GLP-1) 7-36 amide on gastric acid secretion in humans depends on an intact vagal innervation. Gut 1997;40:597– 600. Wettergren A, Petersen H, Orskov C, Christiansen J, Sheikh SP, Holst JJ. Glucagon-like peptide 1 7-36 amide and peptide YY from the L-cell of the ileal mucosa are potent inhibitors of vagally induced gastric acid secretion in man. Scand J Gastroenterol 1994;29:501–5.

Editorial Comment The review by Fetner et al. [1] of incretins, diabetes, and bariatric surgery provides additional support for the hindgut stimulation of glucagon-like peptide-1 (GLP-1) secretion to better manage type 2 diabetes mellitus. Valverde et al. [2] have provided additional supporting data in a longitudinal study of the effect of biliopancreatic diversion (BPD) on the secretion of GLP-1. They showed that the area under the curve for plasma GLP-1 doubled during an oral glucose tolerance test at 1 month after BPD and continued to rise at 3 and 6 months. A mild increase occurred in GLP-1 secretion at 6 months after vertical banded gastroplasty, which may have been due to weight loss. It seemed to me, after reviewing the pertinent literature in 1999, that the most logical explanation for the improvement in glucose metabolism after bypass operations was stimulation of the distal ileum to secrete GLP-1, which I understood to result from bypass of the pyloric muscle [3]. Because the pyloric muscle controls emptying of the stomach, it also controls stimulation of GLP-1 secretion. In 1948, during my surgical training at the University of Minnesota, Clarence Dennis taught us that, after gastric bypass, ingested food arrives in the distal small bowel within 5 minutes and that if we made a small gastroenterostomy stoma, dumping symptoms would be less frequent. Verhagen et al. [4] have shown that infusion of 25% glucose into the duodenum increases the tone of the pyloric muscle and slows

motility of the antrum. The teleologic hypothesis is that the digestive tract maintains isotonicity of the intestinal contents so that the contents will move slowly enough to allow digestion and absorption. If pyloric control of gastric emptying is lost (bypassed) and glucose or fat reach the distal ileum, the ileal brake hormone (GLP-1) is secreted and slows both gastric emptying and intestinal peristalsis. Strader et al. [5] has shown that ileal transposition (in normal-weight rats) causes a marked rise in GLP-1 without changing the glucose levels in the glucose tolerance test. Koopmans and Sclafani [6] warned about using ileal transposition in humans for the treatment of obesity because they had observed unexplained deaths in rats during their short-term studies. The report by Service et al. [7] of hypoglycemia and nesidioblastosis in 6 patients who underwent RYGB 6 months to 8 years after surgery adds another complication to bypass operations. This would also be a likely complication of ileal transposition. Näslund et al. [8] reported that the stimulation of GLP-1 production was greatest 20 years after intestinal bypass. This was when I became interested in the possible use of ileal transposition for the treatment of type 2 diabetes mellitus and was reassured at the time. However, now, with the report of hypoglycemia due to nesidioblastosis, an added need for caution exists about the use of any operation that frequently exposes the distal ileum to glucose and/or fat. My interest in restric-