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.

Glycemic control is improved more after gastric bypass surgery (GBP) than after equivalent diet-induced weight loss in patients with morbid obesity and type 2 diabetes mellitus. We applied metabolomic profiling to understand the mechanisms of this better metabolic response after GBP. Circulating amino acids (AAs) and acylcarnitines (ACs) were measured in plasma from fasted subjects by targeted tandem mass spectrometry before and after a matched 10-kilogram weight loss induced by GBP or diet. Total AAs and branched-chain AAs (BCAAs) decreased after GBP, but not after dietary intervention. Metabolites derived from BCAA oxidation also decreased only after GBP. Principal components (PC) analysis identified two major PCs, one composed almost exclusively of ACs (PC1) and another with BCAAs and their metabolites as major contributors (PC2). PC1 and PC2 were inversely correlated with pro-insulin concentrations, the C-peptide response to oral glucose, and the insulin sensitivity index after weight loss, whereas PC2 was uniquely correlated with levels of insulin resistance (HOMA-IR). These data suggest that the enhanced decrease in circulating AAs after GBP occurs by mechanisms other than weight loss and may contribute to the better improvement in glucose homeostasis observed with the surgical intervention.