Context: Gastric bypass surgery (GBP) results in rapid weight loss, improvement of type 2 diabetes (T2DM), and increase in incretins levels. Diet-induced weight loss also improves T2DM and may increase incretin levels.Objective: Our objective was to determine whether the magnitude of the change of the incretin levels and effect is greater after GBP compared with a low caloric diet, after equivalent weight loss. Design and Methods:Obese women with T2DM studied before and 1 month after GBP (n ϭ 9), or after a diet-induced equivalent weight loss (n ϭ 10), were included in the study. Patients from both groups were matched for age, body weight, body mass index, diabetes duration and control, and amount of weight loss. Setting: This outpatient study was conducted at the General Clinical Research Center.Main Outcome Measures: Glucose, insulin, proinsulin, glucagon, gastric inhibitory peptide (GIP), and glucagon-like peptide (GLP)-1 levels were measured after 50-g oral glucose. The incretin effect was measured as the difference in insulin levels in response to oral and to an isoglycemic iv glucose load.Results: At baseline, none of the outcome variables (fasting and stimulated values) were different between the GBP and diet groups. Total GLP-1 levels after oral glucose markedly increased six times (peak:17 Ϯ 6 to 112 Ϯ 54 pmol/liter; P Ͻ 0.001), and the incretin effect increased five times (9.4 Ϯ 27.5 to 44.8 Ϯ 12.7%; P Ͻ 0.001) after GBP, but not after diet. Postprandial glucose levels (P ϭ 0.001) decreased more after GBP. Conclusions:These data suggest that early after GBP, the greater GLP-1 and GIP release and improvement of incretin effect are related not to weight loss but rather to the surgical procedure. This could be responsible for better diabetes outcome after GBP. T ogether with the epidemic of obesity (1), the number of weight loss surgeries has surged in the last decade (2). Roux-en-Y gastric bypass surgery (GBP) results in significant and prolonged weight loss with resolution of type 2 diabetes (T2DM) in 80% of cases (3). The mechanism by which T2DM improves rapidly after GBP, often before significant weight loss, has not yet been elucidated. The hormonal changes described after GBP suggest a possible endocrine effect of this surgery. We (4) and others (5-10) have shown that the mealor glucose-stimulated incretin levels, which are blunted in T2DM, increase after GBP. In parallel with the increased levels of glucagon-like peptide (GLP)-1 and gastric inhibitory

OBJECTIVE -Limited data on patients undergoing Roux-en-Y gastric bypass surgery (RY-GBP) suggest that an improvement in insulin secretion after surgery occurs rapidly and thus may not be wholly accounted for by weight loss. We hypothesized that in obese patients with type 2 diabetes the impaired levels and effect of incretins changed as a consequence of RY-GBP. RESEARCH DESIGN AND METHODS -Incretin (gastric inhibitory peptide [GIP]and glucagon-like peptide-1 [GLP-1]) levels and their effect on insulin secretion were measured before and 1 month after RY-GBP in eight obese women with type 2 diabetes and in seven obese nondiabetic control subjects. The incretin effect was measured as the difference in insulin secretion (area under the curve [AUC]) in response to an oral glucose tolerance test (OGTT) and to an isoglycemic intravenous glucose test.RESULTS -Fasting and stimulated levels of GLP-1 and GIP were not different between control subjects and patients with type 2 diabetes before the surgery. One month after RY-GBP, body weight decreased by 9.2 Ϯ 7.0 kg, oral glucose-stimulated GLP-1 (AUC) and GIP peak levels increased significantly by 24.3 Ϯ 7.9 pmol ⅐ l Ϫ1 ⅐ min Ϫ1 (P Ͻ 0.0001) and 131 Ϯ 85 pg/ml (P ϭ 0.007), respectively. The blunted incretin effect markedly increased from 7.6 Ϯ 28.7 to 42.5 Ϯ 11.3 (P ϭ 0.005) after RY-GBP, at which it time was not different from that for the control subjects (53.6 Ϯ 23.5%, P ϭ 0.284).CONCLUSIONS -These data suggest that early after RY-GBP, greater GLP-1 and GIP release could be a potential mediator of improved insulin secretion.

Purpose of review Chronic stress, combined with positive energy balance, may be a contributor to the increased risk for obesity, especially upper body obesity, and other metabolic diseases. This association may be mediated by alterations in the hypothalamic–pituitary–adrenal (HPA) axis. In this review, we summarize the major research that has been conducted on the role of the HPA axis in obesity and metabolic disease. Recent findings Dysregulation in the HPA axis has been associated with upper body obesity, but data are inconsistent, possibly due to methodological differences across studies. In addition to systemic effects, changes in local cortisol metabolism in adipose tissue may also influence the risk for obesity. HPA axis dysregulation may be the causal link between conditions such as maternal malnutrition and sleep deprivation with metabolic disease. Summary The present review provides evidence for the relationship between chronic stress, alterations in HPA activity, and obesity. Understanding these associations and its interactions with other factors will be important in developing effective treatments for obesity and related metabolic diseases.

Gastric bypass surgery (GBP), in addition to weight loss, results in dramatic remission of type 2 diabetes (T2DM). The mechanisms by which this remission occurs are unclear. Besides weight loss and caloric restriction, the changes in gut hormones that occur after GBP are increasingly gaining recognition as key players in glucose control. Incretins are gut peptides that stimulate insulin secretion postprandially; the levels of these hormones, particularly glucagon-like peptide-1, increase after GBP in response to nutrient stimulation. Whether these changes are causal to changes in glucose homeostasis remain to be determined. The purpose of this review is to assess the evidence on incretin changes and T2DM remission after GBP, and the possible mechanisms by which these changes occur. Our goals are to provide a thorough update on this field of research so that recommendations for future research and criteria for bariatric surgery can be evaluated.

IntroductionOne of the major benefits of gastric bypass (GBP) surgery is the remission of Type 2 diabetes in 60-80% of cases.1 The rapidity of onset and the magnitude of the effect of GBP on diabetes remain incompletely explained. In addition to the effect of caloric restriction and weight loss, gut peptides, such as incretins, may play a role in the metabolic improvement after GBP.2,3 The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) enhance pancreatic insulin secretion (b-cell) and suppress glucagon secretion (a-cell) during meals. The resultant effect is maintenance of normal glucose homeostasis with a reduction in excess endogenous glucose production and better insulin sensitivity. The incretin effect on insulin secretion is impaired in diabetes. 4 We have shown that both incretin levels and effects on insulin secretion are markedly increased 1 month after GBP in patients with diabetes, 2 but not after a matched weight loss by diet.3 Moreover, although fasting levels of glucose and insulin decrease AbstractBackground: The aim of the present study was to determine the mechanisms underlying Type 2 diabetes remission after gastric bypass (GBP) surgery by characterizing the short-and long-term changes in hormonal determinants of blood glucose. Methods: Eleven morbidly obese women with diabetes were studied before and 1, 6, and 12 months after GBP; eight non-diabetic morbidly obese women were used as controls. The incretin effect was measured as the difference in insulin levels in response to oral glucose and to an isoglycemic intravenous challenge. Outcome measures were glucose, insulin, C-peptide, proinsulin, amylin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) levels and the incretin effect on insulin secretion. Results: The decrease in fasting glucose (r = 0.724) and insulin (r = 0.576) was associated with weight loss up to 12 months after GBP. In contrast, the blunted incretin effect (calculated at 22%) that improved at 1 month remained unchanged with further weight loss at 6 (52%) and 12 (52%) months. The blunted incretin (GLP-1 and GIP) levels, early phase insulin secretion, and other parameters of b-cell function (amylin, proinsulin ⁄ insulin) followed the same pattern, with rapid improvement at 1 month that remained unchanged at 1 year. Conclusions: The data suggest that weight loss and incretins may contribute independently to improved glucose levels in the first year after GBP surgery.

The goal of this study was to understand the mechanisms of greater weight loss by gastric bypass (GBP) compared to gastric banding (GB) surgery. Obese weight‐ and age‐matched subjects were studied before (T0), after a 12 kg weight loss (T1) by GBP (n = 11) or GB (n = 9), and at 1 year after surgery (T2). peptide YY3–36 (PYY3–36), ghrelin, glucagon‐like peptide‐1 (GLP‐1), leptin, and amylin were measured after an oral glucose challenge. At T1, glucose‐stimulated GLP‐1 and PYY levels increased significantly after GBP but not GB. Ghrelin levels did not change significantly after either surgery. In spite of equivalent weight loss, leptin and amylin decreased after GBP, but not after GB. At T2, weight loss was greater after GBP than GB (P = 0.003). GLP‐1, PYY, and amylin levels did not significantly change from T1 to T2; leptin levels continued to decrease after GBP, but not after GB at T2. Surprisingly, ghrelin area under the curve (AUC) increased 1 year after GBP (P = 0.03). These data show that, at equivalent weight loss, favorable GLP‐1 and PYY changes occur after GBP, but not GB, and could explain the difference in weight loss at 1 year. Mechanisms other than weight loss may explain changes of leptin and amylin after GBP.

Objective-To examine the effect of an equivalent weight loss, by gastric bypass surgery (GBP) or by diet, on peptide YY ), ghrelin, and leptin levels and to determine the effect of diabetes status on PYY 3-36 levels.Summary Background Data-The increased PYY 3-36 levels after GBP may be involved in the magnitude and the sustainability of weight loss after surgery.Methods-Of the 30 morbidly obese women who participated in the study, 21 had type 2 diabetes mellitus, and were studied before and after equivalent weight loss of 10 kg by either GBP (n = 11) or by diet (n = 10).Results-PYY 3-36 levels were higher in obese diabetic as compared with nondiabetic individuals (64.1 ± 34.4 pg/mL vs. 39.9 ± 21.1 pg/mL; P < 0.05). PYY 3-36 levels increased markedly in response to oral glucose after GBP (peak: 72.3 ± 20.5 pg/mL-132.7 ± 49.7 pg/mL; P < 0.001; AUC 0-180 : 51.5 ± 23.3 pg/mL.min −1 -91.1 ± 32.2 pg/mL.min −1 P < 0.001), but not after diet (peak: 85.5 ± 51.9 pg/ mL-84.8 ± 41.13 pg/mL; P = NS; AUC 0-180 : 68.3 ± 38.5 pg/mL.min −1 -61.1 ± 42.2 pg/mL.min −1 P = NS). Fasting ghrelin levels increased after diet (425 ± 91 pg/mL-519 ± 105 pg/mL; P < 0.05), but did not change after GBP (506 ± 121 pg/mL-482 ± 196 pg/mL; P = NS).Conclusions-Diabetes status seems to be a determinant of PYY 3-36 levels. GBP, but not dietinduced weight loss, resulted in markedly increased glucose-stimulated PYY 3-36 levels. The increase in stimulated PYY 3-36 levels after GBP is likely a result of the surgery rather than a secondary outcome of weight loss. Changes in PYY 3-36 levels and ghrelin could contribute to the success of GBP in sustaining weight loss.Weight loss by diet is often of small magnitude and difficult to sustain over time. On the contrary, bariatric surgery, particularly Roux-en-Y gastric bypass (GBP), typically results in loss of 50% excess body weight within the first year, and the effect is often sustained at 10 years. The rapid and dramatic resolution of type 2 diabetes mellitus (T2DM) after GBP has led to the hypothesis that some of the metabolic effects of the surgery may be independent of weight loss1 -3 and may be related to the changes in incretins, gut hormones that stimulate insulin secretion.4 , 5 The mechanisms by which GBP suppresses appetite are not clear. The NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript marked increase in levels of 2 anorexigenic hormones, peptide YY (PYY),6 -10 and glucagonlike peptide 1 (GLP-1),4 , 7 could explain the increased satiety after GBP. A greater PYY release is associated with greater weight loss after GBP11 and weight regain has been shown with lower PYY levels in a rodent model.12 Previous reports on change in PYY levels after diet intervention are scarce, report only fasting levels, and are inconsistent. 13,14 The gastric hormone ghrelin may also be implicated in meal-to-meal regulation.15 Its levels increase in anticipation of a meal and decrease after feeding, suggesting a role in short-term meal-to-meal regulation. 16 Ghrelin levels vary a...

Our data suggest that the observed changes in OXM primarily occur in response to GBP and not as a consequence of weight loss. These changes were observed early after surgery and occurred in parallel with previously reported increases in incretins and peptide YY. We speculate that the combination of gut hormone changes is essential for the improved glucose homeostasis and may partially explain the success of this surgery on diabetes resolution and weight loss.