Roux-en-Y gastric bypass (RYGB) results in rapid weight loss, reduced adiposity, and improved glucose metabolism. These effects are not simply attributable to decreased caloric intake or absorption, but the mechanisms linking rearrangement of the gastrointestinal tract to these metabolic outcomes are largely unknown. Studies in humans and rats have shown that RYGB restructures the gut microbiota, prompting the hypothesis that some of the effects of RYGB are caused by altered host-microbial interactions. To test this hypothesis, we used a mouse model of RYGB that recapitulates many of the metabolic outcomes in humans. 16S ribosomal RNA gene sequencing of murine fecal samples collected after RYGB surgery, sham surgery, or sham surgery coupled to caloric restriction revealed that alterations to the gut microbiota after RYGB are conserved among humans, rats, and mice, resulting in a rapid and sustained increase in the relative abundance of Gammaproteobacteria (Escherichia) and Verrucomicrobia (Akkermansia). These changes were independent of weight change and caloric restriction, were detectable throughout the length of the gastrointestinal tract, and were most evident in the distal gut, downstream of the surgical manipulation site. Transfer of the gut microbiota from RYGB-treated mice to nonoperated, germ-free mice resulted in weight loss and decreased fat mass in the recipient animals relative to recipients of microbiota induced by sham surgery, potentially due to altered microbial production of short-chain fatty acids. These findings provide the first empirical support for the claim that changes in the gut microbiota contribute to reduced host weight and adiposity after RYGB surgery.

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.

There were 802 multiple-choice items containing obesity-related keywords identified by NBME, of which 289 (36%) were identified as being relevant to obesity and were coded into appropriate domains and subdomains. Among the individual domains, the Diagnosis& Evaluation domain comprised most of the items (174) for all 3 Step examinations. Fifty-eight percent of items were represented by 4 of 17 organ systems, and 80% of coded items were represented by 6 ABOM subdomains. The majority of obesity-coded items pertained to the diagnosis and management of obesity-related comorbid conditions rather than addressing the prevention, diagnosis, or management of obesity itself. Insights. The most important concepts of obesity prevention and treatment were not represented on the Step exams. Exam items primarily addressed the diagnosis and treatment of obesity-related comorbid conditions instead of obesity itself. The expert review panel identified numerous important obesity-related topics that were insufficiently addressed or entirely absent from the examinations. The reviewers recommend that the areas identified for improvement may promote a more balanced testing of knowledge in obesity.

Eliciting a weight history can provide clinically important information to aid in treatment decision‐making. This view is consistent with the life course perspective of obesity and the aim of patient‐centered care, one of six domains of health care quality. However, thus far, the value and practicality of including a weight history in the clinical assessment and treatment of patients with obesity have not been systematically explored. For these reasons, the Clinical Committee of The Obesity Society established a task force to review and assess the available evidence to address five key questions. It is concluded that weight history is an essential component of the medical history for patients presenting with overweight or obesity, and there are strong and emerging data that demonstrate the importance of life stage, duration of exposure to obesity, maximum BMI, and group‐based trajectory modeling in predicting risk for increased morbidity and mortality. Consideration of these and other patient‐specific factors may improve risk stratification and clinical decision‐making for screening, counseling, and management. Recommendations are provided for the key elements that should be included in a weight history, and several needs for future clinical research are outlined.

OBJECTIVE This analysis of 3,375 adults with overweight/obesity across the Semaglutide Treatment Effect in People with obesity (STEP) 1, 3, and 4 trials evaluated whether more participants with prediabetes had normoglycemia after 68 weeks’ treatment with once-weekly semaglutide 2.4 mg plus lifestyle intervention versus placebo and assessed changes in glucose metabolism in participants with prediabetes. RESEARCH DESIGN AND METHODS STEP 1, 3, and 4 were phase 3, 68-week, randomized, placebo-controlled, multinational trials; STEP 4 had a 20-week semaglutide run-in and 48-week randomized period. Analyses included changes (week 0–68; before the washout period) in glycemic status (prespecified: STEP 1 and 3; post hoc: STEP 4), and in HbA1c, fasting plasma glucose (FPG), and HOMA insulin resistance (HOMA-IR) among participants with prediabetes (post hoc). RESULTS Significantly more participants with baseline (week 0) prediabetes (n = 1,536) had normoglycemia at week 68 with semaglutide versus placebo (STEP 1, 84.1% vs. 47.8%; STEP 3, 89.5% vs. 55.0%; STEP 4, 89.8% vs. 70.4%; all P < 0.0001). Fewer participants with baseline normoglycemia had prediabetes at week 68 with semaglutide versus placebo (STEP 1, 2.9% vs. 10.9%; STEP 3, 3.2% vs. 5.8%; STEP 4, 1.1% vs. 5.0%). Semaglutide resulted in greater improvements in HbA1c, FPG, and HOMA-IR than placebo among participants with baseline prediabetes (all P < 0.01). CONCLUSIONS STEP 1, 3, and 4 collectively provide a robust assessment of the effects of semaglutide on glucose metabolism and prediabetes in a large cohort of adults with overweight/obesity while on treatment. Among participants with baseline prediabetes, 68 weeks’ treatment with semaglutide versus placebo led to significant improvements in glucose metabolism and a higher likelihood of normoglycemia.

Objective: Obesity is a growing global concern compounded by limited availability of effective treatment options. The SURMOUNT development program aims to evaluate the efficacy and safety of tirzepatide as an adjunct to lifestyle intervention compared with placebo on chronic weight management in adults with BMI ≥ 27 kg/m 2 with or without type 2 diabetes. Methods:The SURMOUNT program includes four global phase 3 trials NCT04184622 (SURMOUNT-1), NCT04657003 (SURMOUNT-2), NCT04657016 (SURMOUNT-3), and NCT04660643 (SURMOUNT-4). Participants are randomized to once-weekly subcutaneous tirzepatide versus placebo in a double-blind manner.The primary end point in all trials is the percentage change in body weight from randomization to end of treatment. Results for the primary end point for SURMOUNT-1 were published recently and results for the other trials are expected in 2023.Results: Across trials, participants have a mean age of 44.9 to 54.2 years, are mostly female (50.7% to 69.7%), and have a mean BMI of 36.1 to 38.9. Conclusions:The extensive assessment of once-weekly tirzepatide in the global SURMOUNT program will detail the clinical effects of this first-in-class glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist in chronic weight management.

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