Nutritional Challenges and Treatment After Bariatric Surgery.

Bariatric surgery is an important weight loss tool in individuals with severe obesity. It is currently the most effective long-term weight loss treatment that lowers obesity-related comorbidities. It also has significant physiological and nutritional consequences that can result in gastrointestinal complications and micronutrient deficiencies. After gastric bypass, common clinical events that negatively affect nutritional status include malabsorption, dumping syndrome, kidney stones, altered intestinal bile acid availability, bowel obstruction, ulcer, gastroesophageal reflux, and bacterial overgrowth. Risk factors for poor nutritional status and excessive loss of lean body mass and bone include reduced dietary quality and inadequate intake, altered nutrient absorption, and poor patient compliance with nutrient supplementation. There are unique concerns in adolescents, older individuals, and individuals who become pregnant postoperatively. With careful management, health-care professionals can assist with long-term weight loss success and minimize the risk of acute and long-term nutrition complications after bariatric surgery.

Remission of type 2 diabetes: always more questions, but enough answers for action.

The concept of type 2 diabetes remission is evolving rapidly, and gaining wide public and professional interest, following demonstration that with substantial intentional weight loss almost nine in ten people with type 2 diabetes can reduce their HbA1c level below the diagnostic criterion (48 mmol/mol [6.5%]) without glucose-lowering medications, and improve all features of the metabolic syndrome. Pursuing nomoglycaemia with older drugs was dangerous because of the risk of side effects and hypoglycaemia, so the conventional treatment target was an HbA1c concentration of 53 mmol/mol (7%), meaning that diabetes was still present and allowing disease progression. Newer agents may achieve a normal HbA1c safely and, by analogy with treatments that send cancers or inflammatory diseases into remission, this might also be considered remission. However, although modern glucagon-like peptide-1 receptor agonists and related medications are highly effective for weight loss and glycaemic improvement, and generally safe, many people do not want to take drugs indefinitely, and their cost means that they are not available across much of the world. Therefore, there are strong reasons to explore and research dietary approaches for the treatment of type 2 diabetes. All interventions that achieve sustained weight loss of >10-15 kg improve HbA1c, potentially resulting in remission if sufficient beta cell capacity can be preserved or restored, which occurs with loss of the ectopic fat in liver and pancreas that is found with type 2 diabetes. Remission is most likely with type 2 diabetes of short duration, lower HbA1c and a low requirement for glucose-lowering medications. Relapse is likely with weight regain and among those with a poor beta cell reserve. On current evidence, effective weight management should be provided to all people with type 2 diabetes as soon as possible after diagnosis (or even earlier, at the stage of prediabetes, defined in Europe, Australasia, Canada [and most of the world] as ≥42 and <48 mmol/mol [≥6.0 and <6.5%], and in the USA as HbA1c ≥39 and <48 mmol/mol [≥5.7 and <6.5%]). Raising awareness among people with type 2 diabetes and their healthcare providers that remission is possible will enable earlier intervention. Weight loss of >10 kg and remission lasting 1-2 years may also delay vascular complications, although more evidence is needed. The greatest challenge for research is to improve long-term weight loss maintenance, defining cost-effective approaches tailored to the preferences and needs of people living with type 2 diabetes.

Metabolite signature of diabetes remission in individuals with obesity undergoing weight loss interventions.

OBJECTIVE: This observational study investigated metabolomic changes in individuals with type 2 diabetes (T2D) after weight loss. We hypothesized that metabolite changes associated with T2D-relevant phenotypes are signatures of improved health. METHODS: Fasting plasma samples from individuals undergoing bariatric surgery (n = 71 Roux-en-Y gastric bypass [RYGB], n = 22 gastric banding), lifestyle intervention (n = 66), or usual care (n = 14) were profiled for 139 metabolites before and 2 years after weight loss. Principal component analysis grouped correlated metabolites into factors. Association of preintervention metabolites was tested with preintervention clinical features and changes in T2D markers. Association between change in metabolites/metabolite factors and change in T2D remission markers, homeostasis model assessment of ß-cell function, homeostasis model assessment of insulin resistance, and glycated hemoglobin (HbA1c) was assessed. RESULTS: Branched-chain amino acids (BCAAs) were associated with preintervention adiposity. Changes in BCAAs (valine, leucine/isoleucine) and branched-chain ketoacids were positively associated with change in HbA1c (false discovery rate q value ≤ 0.001) that persisted after adjustment for percentage weight change and RYGB (p ≤ 0.02). In analyses stratified by RYGB or other weight loss method, some metabolites showed association with non-RYGB weight loss. CONCLUSIONS: This study confirmed known metabolite associations with obesity/T2D and showed an association of BCAAs with HbA1c change after weight loss, independent of the method or magnitude of weight loss.

Racial and Ethnic Disparities in Glycemic Control Among Insured US Adults.

Importance: Poor access to care and lack of health insurance are important contributors to disparities in glycemic control. However expanding health insurance coverage may not be enough to fully address the high burden of poor glycemic control for some groups. Objective: To characterize racial and ethnic disparities in glycemic control among adults with private and public insurance in the US over a 15-year timeframe and to evaluate whether social, health care, and behavioral or health status factors attenuate estimates of disparities. Design, Setting, and Participants: This cross-sectional study used data from the National Health and Nutrition Examination Survey from 2003 to 2018. Participants included Hispanic or Latino, non-Hispanic Black, and non-Hispanic White adults aged 25 to 80 years with self-reported diabetes and health insurance. Data were analyzed from January 15 to August 23, 2023. Exposure: Participants self-identified as Hispanic or Latino, non-Hispanic Black, or non-Hispanic White. Main Outcomes and Measures: The main outcome, poor glycemic control, was defined as glycated hemoglobin A1c (HbA1c) of 7.0% or greater. Information about social (education, food security, and nativity), health care (insurance type, routine place for health care, insurance gap in past year, and use of diabetes medications), and behavioral or health status (years with diabetes, waist circumference, and smoking) factors were collected via questionnaires. Results: A total of 4070 individuals (weighted mean [SE] age, 61.4 [0.27] years; 1970 [weighted proportion, 49.3%] were women) were included, representing 16 337 362 US adults, including 1146 Hispanic or Latino individuals (weighted proportion, 13.2%), 1196 non-Hispanic Black individuals (weighted proportion, 15.7%), and 1728 non-Hispanic White individuals (weighted proportion, 71.1%). In models adjusted for age, sex, and survey year, Hispanic or Latino and non-Hispanic Black individuals had significantly higher odds of poor glycemic control than non-Hispanic White individuals (Hispanic or Latino: odds ratio [OR], 1.46; 95% CI, 1.16-1.83; Black: OR, 1.28; 95% CI, 1.04-1.57). There was some attenuation after adjustment for social factors, especially food security (Hispanic or Latino: OR, 1.39; 95% CI, 1.08-1.81); Black: OR, 1.39; 95% CI, 1.08-1.81). However, accounting for health care and behavioral or health status factors increased disparities, especially for Hispanic or Latino individuals (OR, 1.63; 95% CI, 1.24-2.16), with racial and ethnic disparities persisting even among those with private insurance (OR, 1.66; 95% CI, 1.10-2.52). Conclusions and Relevance: In this cross-sectional study of insured adults with diabetes in the US, disparities in poor glycemic control persisted despite adjustment for social, health care, and behavioral factors. Research is needed to identify the barriers contributing to poor control even in populations with access to care.

Glucagon-like peptide-1 effect on ß-cell function varies according to diabetes remission status after Roux-en-Y gastric bypass.

AIMS: The contribution of endogenous glucagon-like peptide (GLP)-1 to ß-cell function after Roux-en-Y gastric bypass surgery (RYGB) is well established in normoglycaemic individuals, but not in those with postoperative hyperglycaemia. We, therefore, studied the effect of GLP-1 on ß-cell function in individuals with varying degrees of type 2 diabetes mellitus (T2D) control after RYGB. MATERIALS AND METHODS: Glucose, insulin secretion rates, ß-cell glucose sensitivity and glucagon were measured during an oral glucose tolerance test before (saline only) and at 3, 12 and 24 months after RYGB with and without infusion of the GLP-1 receptor blocker exendin9-39 (EX9). The cohort was retrospectively classified based on T2D remission (REM) status at the latest study time point: REM (n = 5), persistent T2D (n = 8), or impaired glucose tolerance (n = 16). RESULTS: EX9 blunted the increase in ß-cell glucose sensitivity at 3 months (-44.1%, p < .001) and 12 months (-43.3%, p < .001), but not at 24 months (-12.4%, p = .243). EX9 enhanced postprandial glucagon concentrations by 62.0% at 3 months (p = .008), 46.5% at 12 months (p = .055), and 30.4% at 24 months (p = .017). EX9 counterintuitively decreased glucose concentrations at 3 months in the entire cohort (p < .001) but had no effect on glycaemia at 12 and 24 months in persistent T2D and impaired glucose tolerance; it minimally worsened glycaemia in REM at 12 months. CONCLUSIONS: GLP-1 blockade reversed the improvement in ß-cell function observed after RYGB, but this effect varied temporally and by REM status. GLP-1 blockade transiently and minimally worsened glycaemia only in REM, and lowered postprandial glucose values at 3 months, regardless of REM status.

Data-driven subgroups of type 2 diabetes, metabolic response, and renal risk profile after bariatric surgery: a retrospective cohort study.

BACKGROUND: A novel data-driven classification of type 2 diabetes has been proposed to personalise anti-diabetic treatment according to phenotype. One subgroup, severe insulin-resistant diabetes (SIRD), is characterised by mild hyperglycaemia but marked hyperinsulinaemia, and presents an increased risk of diabetic nephropathy. We hypothesised that patients with SIRD could particularly benefit from metabolic surgery. METHODS: We retrospectively related the newly defined clusters with the response to metabolic surgery in participants with type 2 diabetes from independent cohorts in France (the Atlas Biologique de l'Obésite Sévère [ABOS] cohort, n=368; participants underwent Roux-en-Y gastric bypass or sleeve gastrectomy between Jan 1, 2006, and Dec 12, 2017) and Brazil (the metabolic surgery cohort of the German Hospital of San Paulo, n=121; participants underwent Roux-en-Y gastric bypass between April 1, 2008, and March 20, 2016). The study outcomes were type 2 diabetes remission and improvement of estimated glomerular filtration rate (eGFR). FINDINGS: At baseline, 34 (9%) of 368 patients, 314 (85%) of 368 patients, and 17 (5%) of 368 patients were classified as having SIRD, mild obesity-related diabetes (MOD), and severe insulin deficient diabetes (SIDD) in the ABOS cohort, respectively, and in the São Paulo cohort, ten (8%) of 121 patients, 83 (69%) of 121 patients, and 25 (21%) of 121 patients were classified as having SIRD, MOD, and SIDD, respectively. At 1 year, type 2 diabetes remission was reported in 26 (81%) of 32 and nine (90%) of ten patients with SIRD, 167 (55%) of 306 and 42 (51%) of 83 patients with MOD, and two (13%) of 16 and nine (36%) of 25 patients with SIDD, in the ABOS and São Paulo cohorts, respectively. The mean eGFR was lower in patients with SIRD at baseline and increased postoperatively in these patients in both cohorts. In multivariable analysis, SIRD was associated with more frequent type 2 diabetes remission (odds ratio 4·3, 95% CI 1·8-11·2; p=0·0015), and an increase in eGFR (mean effect size 13·1 ml/min per 1·73 m2, 95% CI 3·6-22·7; p=0·0070). INTERPRETATION: Patients in the SIRD subgroup had better outcomes after metabolic surgery, both in terms of type 2 diabetes remission and renal function, with no additional surgical risk. Data-driven classification might help to refine the indications for metabolic surgery. FUNDING: Agence Nationale de la Recherche, Investissement d'Avenir, Innovative Medecines Initiative, Fondation Cœur et Artères, and Fondation Francophone pour la Recherche sur le Diabète.

Role of the Gut in the Temporal Changes of ß-Cell Function After Gastric Bypass in Individuals With and Without Diabetes Remission.

OBJECTIVE: The role of the gut in diabetes remission after Roux-en-Y gastric bypass (RYGB) is incompletely understood. We assessed the temporal change in insulin secretory capacity after RYGB, using oral and intravenous (IV) glucose, in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Longitudinal, prospective measures of ß-cell function were assessed after oral glucose intake and graded glucose infusion in individuals with severe obesity and diabetes studied at 0, 3 (n = 29), 12 (n = 24), and 24 (n = 20) months after RYGB. Data were collected between 2015 and 2019 in an academic clinical research center. RESULTS: The decreases in body weight, fat mass, waist circumference, and insulin resistance after surgery (all P < 0.001 at 12 and 24 months) did not differ according to diabetes remission status. In contrast, both the magnitude and temporal changes in ß-cell glucose sensitivity after oral glucose intake differed by remission status (P = 0.04): greater (6.5-fold; P < 0.01) and sustained in those in full remission, moderate and not sustained past 12 months in those with partial remission (3.3-fold; P < 0.001), and minimal in those not experiencing remission (2.7-fold; P = not significant). The improvement in ß-cell function after IV glucose administration was not apparent until 12 months, significant only in those in full remission, and only ∼33% of that observed after oral glucose intake. Preintervention ß-cell function and its change after surgery predicted remission; weight loss and insulin sensitivity did not. CONCLUSIONS: Our data show the time course of changes in ß-cell function after RYGB. The improvement in ß-cell function after RYGB, but not changes in weight loss or insulin sensitivity, drives diabetes remission.

Preintervention Clinical Determinants and Measured ß-Cell Function As Predictors of Type 2 Diabetes Remission After Roux-en-Y Gastric Bypass Surgery.

BACKGROUND: Bariatric surgery results in improved glycemic control in individuals with type 2 diabetes. Single and clusters of clinical determinants have been identified as presurgery predictors of postsurgery diabetes remission. Our goal was to assess whether the addition of measured preoperative ß-cell function would improve established clinical models of prediction of diabetes remission. RESEARCH DESIGN AND METHODS: Presurgery clinical characteristics, metabolic markers, and ß-cell function after oral and intravenous (IV) glucose challenges were assessed in 73 individuals with severe obesity and type 2 diabetes and again 1 year after gastric bypass surgery. Single and multivariate analyses were conducted with preoperative variables to determine the best predictive models of remission. RESULTS: Presurgery ß-cell glucose sensitivity, a surrogate of ß-cell function, was negatively correlated with known diabetes duration, HbA1c, insulin use, and the diabetes remission scores DiaRem and advanced (Ad)-DiaRem (all P < 0.001). Measured ß-cell function after oral glucose was 1.6-fold greater than after the IV glucose challenge and more strongly correlated with preoperative clinical and metabolic characteristics. The addition of preoperative ß-cell function to clinical models containing well-defined diabetes remission scores did not improve the model's ability to predict diabetes remission after Roux-en-Y gastric bypass. CONCLUSIONS: The addition of measured ß-cell function does not add predictive value to defined clinical models of diabetes remission 1 year after surgical weight loss.

Metabolites and diabetes remission after weight loss.

There is marked heterogeneity in the response to weight loss interventions with regards to weight loss amount and metabolic improvement. We sought to identify biomarkers predictive of type 2 diabetes remission and amount of weight loss in individuals with severe obesity enrolled in the Longitudinal Assessment of Bariatric Surgery (LABS) and the Look AHEAD (Action for Health in Diabetes) studies. Targeted mass spectrometry-based profiling of 135 metabolites was performed in pre-intervention blood samples using a nested design for diabetes remission over five years (n = 93 LABS, n = 80 Look AHEAD; n = 87 remitters), and for extremes of weight loss at five years (n = 151 LABS; n = 75 with high weight loss). Principal components analysis (PCA) was used for dimensionality reduction, with PCA-derived metabolite factors tested for association with both diabetes remission and weight loss. Metabolic markers were tested for incremental improvement to clinical models, including the DiaRem score. Two metabolite factors were associated with diabetes remission: one primarily composed of branched chain amino acids (BCAA) and tyrosine (odds ratio (95% confidence interval) [OR (95% CI)] = 1.4 [1.0-1.9], p = 0.045), and one with betaine and choline (OR [95% CI] = 0.7 [0.5-0.9], p = 0.02).These results were not significant after adjustment for multiple tests. Inclusion of these two factors in clinical models yielded modest improvements in model fit and performance: in a constructed clinical model, the C-statistic improved from 0.87 to 0.90 (p = 0.02), while the net reclassification index showed improvement in prediction compared to the DiaRem score (NRI = 0.26, p = 0.0013). No metabolite factors associated with weight loss at five years. Baseline levels of metabolites in the BCAA and trimethylamine-N-oxide (TMAO)-microbiome-related pathways are independently and incrementally associated with sustained diabetes remission after weight loss interventions in individuals with severe obesity. These metabolites could serve as clinically useful biomarkers to identify individuals who will benefit the most from weight loss interventions.

Characterization of one anastomosis gastric bypass and impact of biliary and common limbs on bile acid and postprandial glucose metabolism in a minipig model.

The alimentary limb has been proposed to be a key driver of the weight-loss-independent metabolic improvements that occur upon bariatric surgery. However, the one anastomosis gastric bypass (OAGB) procedure, consisting of one long biliary limb and a short common limb, induces similar beneficial metabolic effects compared to Roux-en-Y Gastric Bypass (RYGB) in humans, despite the lack of an alimentary limb. The aim of this study was to assess the role of the length of biliary and common limbs in the weight loss and metabolic effects that occur upon OAGB. OAGB and sham surgery, with or without modifications of the length of either the biliary limb or the common limb, were performed in Gottingen minipigs. Weight loss, metabolic changes, and the effects on plasma and intestinal bile acids (BAs) were assessed 15 days after surgery. OAGB significantly decreased body weight, improved glucose homeostasis, increased postprandial GLP-1 and fasting plasma BAs, and qualitatively changed the intestinal BA species composition. Resection of the biliary limb prevented the body weight loss effects of OAGB and attenuated the postprandial GLP-1 increase. Improvements in glucose homeostasis along with changes in plasma and intestinal BAs occurred after OAGB regardless of the biliary limb length. Resection of only the common limb reproduced the glucose homeostasis effects and the changes in intestinal BAs. Our results suggest that the changes in glucose metabolism and BAs after OAGB are mainly mediated by the length of the common limb, whereas the length of the biliary limb contributes to body weight loss.NEW & NOTEWORTHY Common limb mediates postprandial glucose metabolism change after gastric bypass whereas biliary limb contributes to weight loss.

Per- and polyfluoroalkyl substance plasma concentrations and metabolomic markers of type 2 diabetes in the Diabetes Prevention Program trial.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are widely used chemicals, some of which have been linked to type 2 diabetes. We tested whether PFAS concentrations were cross-sectionally associated with metabolites previously shown to predict incident type 2 diabetes using the Diabetes Prevention Program (DPP), a trial of individuals at high risk of type 2 diabetes. METHODS: We evaluated 691 participants enrolled in the DPP with baseline measures of 10 PFAS (including total perfluorooctanesulfonic acid (PFOS), total perfluorooctanoic acid (PFOA), and Sb-PFOA [branched isomers of PFOA]) and 77 metabolites. We used log2-transformed PFAS concentrations as exposures and standardized metabolite concentrations as outcomes in linear regression models adjusted for age, sex, race/ethnicity, use of anti-hyperlipidemic or triglyceride-lowering medication, income, years of education, marital status, smoking, and family history of diabetes, with Benjamini-Hochberg linear step-up false discovery rate correction. RESULTS: Sb-PFOA was associated with the largest number of tested metabolites (29 of 77). Each doubling in Sb-PFOA was associated with higher leucine (ß = 0.07 [95%CI: 0.02, 0.11] SD) and lower glycine (-0.08 [95%CI: 0.03, -0.13] SD). Each doubling of either total PFOA or n-PFOA was associated with -0.13 [95%CI: 0.04, -0.22] SD lower glycine. PFOA and Sb-PFOA were positively associated with multiple triacylglycerols and diacylglycerols, and total PFOS, total PFOA, and Sb-PFOA were positively associated with phosphatidylethanolamines. CONCLUSIONS: PFAS concentrations are associated with metabolites linked to type 2 diabetes (particularly amino acid, glycerolipid and glycerophospholipid pathways). Further prospective research is needed to test whether these metabolites mediate associations of PFAS and type 2 diabetes.

Diabetes Remission Status During Seven-year Follow-up of the Longitudinal Assessment of Bariatric Surgery Study.

CONTEXT: Few studies have examined the clinical characteristics that predict durable, long-term diabetes remission after bariatric surgery. OBJECTIVE: To compare diabetes prevalence and remission rates during 7-year follow-up after Roux-en-Y gastric bypass (RYGB) and laparoscopic gastric banding (LAGB). DESIGN: An observational cohort of adults with severe obesity recruited between 2006 and 2009 who completed annual research assessments for up to 7 years after RYGB or LAGB. SETTING: Ten US hospitals. PARTICIPANTS: A total sample of 2256 participants, 827 with known diabetes status at both baseline and at least 1 follow-up visit. INTERVENTIONS: Roux-en-Y gastric bypass or LAGB. MAIN OUTCOME MEASURES: Diabetes rates and associations of patient characteristics with remission status. RESULTS: Diabetes remission occurred in 57% (46% complete, 11% partial) after RYGB and 22.5% (16.9% complete, 5.6% partial) after LAGB. Following both procedures, remission was greater in younger participants and those with shorter diabetes duration, higher C-peptide levels, higher homeostatic model assessment of ß-cell function (HOMA %B), and lower insulin usage at baseline, and with greater postsurgical weight loss. After LAGB, reduced HOMA insulin resistance (IR) was associated with a greater likelihood of diabetes remission, whereas increased HOMA-%B predicted remission after RYGB. Controlling for weight lost, diabetes remission remained nearly 4-fold higher compared with LAGB. CONCLUSIONS: Durable, long-term diabetes remission following bariatric surgery is more likely when performed soon after diagnosis when diabetes medication burden is low and beta-cell function is preserved. A greater weight-independent likelihood of diabetes remission after RYGB than LAGB suggests mechanisms beyond weight loss contribute to improved beta-cell function after RYGB.Trial Registration clinicaltrials.gov Identifier: NCT00465829.

Anthropometrics by Three-Dimensional Photonic Scanner in Patients with Obesity Before and After Bariatric Surgery.

BACKGROUND: We studied body composition by three-dimensional photonic scanning (3DPS) and metabolic biomarkers in a large ethnically diverse cohort of individuals with severe obesity before and after weight loss by Roux-en-Y gastric bypass (RYGB) or adjustable gastric banding (AGB) surgery. MATERIALS AND METHODS: Male and female participants (n = 95) underwent 3DPS testing in the weeks preceding bariatric surgery (baseline), and 1 year after either RYGB (n = 34) or AGB (n = 9). RESULTS: Principal component analysis showed that A1C and HDL cholesterol clustered with waist-to-hip ratio (WHR). Both RYGB and AGB surgeries led to similar improvements in A1C and lipids after 1 year. RYGB led to greater decreases in body weight, and in most anthropometric measures, compared with AGB at 1 year. However, after accounting for weight loss differences, RYGB and AGB groups did not differ in regional decreases in circumferences or volumes; the exception was a greater reduction in lean mass in RYGB compared with AGB. CONCLUSION: Distribution of weight loss, assessed by 3DPS, did not differ between RYGB and AGB, but surgery type predicted change in lean mass at 1 year.

Lipocalin-2 is an anorexigenic signal in primates.

In the mouse, the osteoblast-derived hormone Lipocalin-2 (LCN2) suppresses food intake and acts as a satiety signal. We show here that meal challenges increase serum LCN2 levels in persons with normal or overweight, but not in individuals with obesity. Postprandial LCN2 serum levels correlate inversely with hunger sensation in challenged subjects. We further show through brain PET scans of monkeys injected with radiolabeled recombinant human LCN2 (rh-LCN2) and autoradiography in baboon, macaque, and human brain sections, that LCN2 crosses the blood-brain barrier and localizes to the hypothalamus in primates. In addition, daily treatment of lean monkeys with rh-LCN2 decreases food intake by 21%, without overt side effects. These studies demonstrate the biology of LCN2 as a satiety factor and indicator and anorexigenic signal in primates. Failure to stimulate postprandial LCN2 in individuals with obesity may contribute to metabolic dysregulation, suggesting that LCN2 may be a novel target for obesity treatment.

Obesity has reached epidemic proportions worldwide and affects more than 40% of adults in the United States. People with obesity have a greater likelihood of developing type 2 diabetes, cardiovascular disease or chronic kidney disease. Changes in diet and exercise can be difficult to follow and result in minimal weight loss that is rarely sustained overtime. In fact, in people with obesity, weight loss can lower the metabolism leading to increased weight gain. New drugs may help some individuals achieve 5 to 10% weight loss but have side effects that prevent long-term use. Previous studies in mice show that a hormone called Lipocalin-2 (LCN2) suppresses appetite. It also reduces body weight and improves sugar metabolism in the animals. But whether this hormone has the same effects in humans or other primates is unclear. If it does, LCN2 might be a potential obesity treatment. Now, Petropoulou et al. show that LCN2 suppressed appetite in humans and monkeys. In human studies, LCN2 levels increased after a meal in individuals with normal weight or overweight, but not in individuals with obesity. Higher levels of LCN2 in a person's blood were also associated with a feeling of reduced hunger. Using brain scans, Petropoulou et al. showed that LCN2 crossed the blood-brain barrier in monkeys and bound to the hypothalamus, the brain center regulating appetite and energy balance. LCN2 also bound to human and monkey hypothalamus tissue in laboratory experiments. When injected into monkeys, the hormone suppressed food intake and lowered body weight without toxic effects in short-term studies. The experiments lay the initial groundwork for testing whether LCN2 might be a useful treatment for obesity. More studies in animals will help scientists understand how LCN2 works, which patients might benefit, how it would be given to patients and for how long. Clinical trials would also be needed to verify whether it is an effective and safe treatment for obesity.

Reliability and responsiveness of virtual portion size creation tasks: Influences of context, foods, and a bariatric surgical procedure.

Food portion size influences energy intake and sustained high-energy intake often leads to obesity. Virtual portion creation tasks (VPCTs), in which a participant creates portions of food on a computer screen, predict intake in healthy individuals. The objective of this study was to determine whether portions created in VPCTs are stable over time (test-retest reliability) and responsive to factors known to influence food intake, such as eating contexts and food types, and to determine if virtual portions can predict weight loss. Patients with obesity scheduled for bariatric surgery (n = 29), and individuals with a normal BMI (18.5-24.9 kg/m2, controls, n = 29), were instructed to create virtual portions of eight snack foods, which varied in energy density (low and high) and taste (sweet and salty). Portions were created in response to the following eating situations, or "contexts": What they would a) eat to stay healthy (healthy), b) typically eat (typical), c) eat to feel comfortably satisfied (satisfied), d) consider the most that they could tolerate eating (maximum), and e) eat if nothing was limiting them (desired). Tasks were completed before, and 3 months after, surgery in patients, and at two visits, 3 months apart, in controls. Body weight (kg) was recorded at both visits. Virtual portions differed significantly across groups, visits, eating contexts, energy densities (low vs. high), and tastes (sweet vs. salty). Portions created by controls did not change over time, while portions created by patients decreased significantly after surgery, for all contexts except healthy. For patients, desired and healthy portions predicted 3-month weight loss. VPCTs are replicable, responsive to foods and eating contexts, and predict surgical weight loss. These tasks could be useful for individual assessment of expectations of amounts that are eaten in health and disease and for prediction of weight loss.

Proinsulin associates with poor ß-cell function, glucose-dependent insulinotropic peptide, and insulin resistance in persistent type 2 diabetes after Roux-en-Y gastric bypass in humans.

BACKGROUND: The determinants of type 2 diabetes (T2D) remission and/or relapse after gastric bypass (RYGB) remain fully unknown. This study characterized ß- and α-cell function, in cretin hormone release and insulin sensitivity in individuals with (remitters) or without (non-remitters) diabetes remission after RYGB. METHODS: This is a cross-sectional study of two distinct cohorts of individuals with or without diabetes remission at least 2 years after RYGB. Each individual underwent-either an oral glucose (remitters) or a mixed meal (non-remitters) test; glucose, proinsulin, insulin, C-peptide, glucagon, incretins and leptin were measured. RESULTS: Compared to remitters (n = 23), non-remitters (n = 31) were older (mean [±SD] age 56.1 ± 8.2 vs. 46.0 ± 8.9 years, P < 0.001), had longer diabetes duration (13.1 ± 10.1 vs. 2.2 ± 2.4 years, P < 0.001), were further out from the surgery (5.6 ± 3.3 vs. 3.5 ± 1.7 years, P < 0.01), were more insulin resistant (HOMA-IR 4.01 ± 3.65 vs. 2.08 ± 1.22, P < 0.001), but did not differ for body weight. As predicted, remitters had higher ß-cell glucose sensitivity (1.95 ± 1.23 vs. 0.86 ± 0.55 pmol/kg/min/mmol, P < 0.001) and disposition index (1.55 ± 1.75 vs 0.33 ± 0.27, P = 0.003), compared to non-remitters, who showed non-suppressibility of glucagon during the oral challenge (time × group P = 0.001). Higher proinsulin (16.55 ± 10.45 vs. 6.62 ± 3.50 PM, P < 0.0001), and proinsulin: C-peptide (40.83 ± 29.43 vs. 17.13 ± 7.16, P < 0.001) were strongly associated with non-remission status, while differences in incretins between remitters and non-remitters were minimal. CONCLUSIONS: Individual without diabetes remission after gastric bypass have poorer ß-cell response and lesser suppression of glucagon to an oral challenge; body weight and incretins differ minimally according to remission status.

Preoperative liking and wanting for sweet beverages as predictors of body weight loss after Roux-en-Y gastric bypass and sleeve gastrectomy.

BACKGROUND/OBJECTIVES: Patients who receive Roux-en-Y gastric bypass (RYGB) lose more weight than those who receive vertical sleeve gastrectomy (VSG). RYGB and VSG alter hedonic responses to sweet flavor, but whether baseline differences in hedonic responses modulate weight loss after RYGB or VSG remains untested. PARTICIPANTS/METHODS: Male and female candidates (n = 66) for RYGB or VSG were recruited and tested for their subjective liking and wanting ratings of sucrose solutions and flavored beverages sweetened with aspartame. Participants were classified by unsupervised hierarchical clustering for their liking and wanting ratings of sucrose and aspartame. Participant liking ratings were also used in a supervised classification using pre-established categories of liking ratings (liker, disliker, and inverted u-shape). Effects of categories obtained from unsupervised or supervised classification on body weight loss and their interaction with surgery type were analyzed separately at 3 and 12 months after surgery using linear models corrected for sex and age. RESULTS: RYGB participants lost more body weight compared with VSG participants at 3 and 12 months after surgery (P < 0.001 for both time points). Unsupervised clustering analysis identified clusters corresponding to high and low wanting or liking ratings for sucrose or aspartame. RYGB participants in high-wanting clusters based on sucrose, but not aspartame, lost more weight than VSG at both 3 (P = 0.01) and 12 months (P = 0.03), yielding a significant cluster by surgery interaction. Categories based on supervised classification using liking ratings for sucrose or aspartame showed no significant effects on body weight loss between RYGB and VSG participants. CONCLUSIONS: Classification of patients into high/low-wanting ratings for sucrose before surgery can predict differential body weight loss after RYGB or VSG in adults and could be used to advise on surgery type.

A Gut Check Explains Improved Glucose Metabolism after Surgery.

Biliopancreatic diversion (BPD) surgery leads to more frequent diabetes remission than Roux-en-Y gastric bypass (RYGB). In this issue, Harris et al. (2019) compare each surgery after careful matching for percentage weight loss and find the gut as a major site of difference between the effects of the two surgeries.

Longitudinal changes of microbiome composition and microbial metabolomics after surgical weight loss in individuals with obesity.

BACKGROUND: Some of the metabolic effects of bariatric surgery may be mediated by the gut microbiome. OBJECTIVES: To study the effect of bariatric surgery on changes to gut microbiota composition and bacterial pathways, and their relation to metabolic parameters after bariatric surgery. SETTINGS: University hospitals in the United States and Spain. METHODS: Microbial diversity and composition by 16 S rRNA sequencing, putative bacterial pathways, and targeted circulating metabolites were studied in 26 individuals with severe obesity, with and without type 2 diabetes, before and at 3, 6, and 12 months after either gastric bypass or sleeve gastrectomy. RESULTS: Bariatric surgery tended to increase alpha diversity, and significantly altered beta diversity, microbiota composition, and function up to 6 months after surgery, but these changes tend to regress to presurgery levels by 12 months. Twelve of 15 bacterial pathways enriched after surgery also regressed to presurgery levels at 12 months. Network analysis identified groups of bacteria significantly correlated with levels of circulating metabolites over time. There were no differences between study sites, surgery type, or diabetes status in terms of microbial diversity and composition at baseline and after surgery. CONCLUSIONS: The association among changes in microbiome with decreased circulating biomarkers of inflammation, increased bile acids, and products of choline metabolism and other bacterial pathways suggest that the microbiome partially mediates improvement of metabolism during the first year after bariatric surgery.