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Summary Prolonged intervention studies investigating molecular metabolism are necessary for a deeper understanding of dietary effects on health. Here we provide mechanistic information about metabolic adaptation to fat-rich diets. Healthy, slightly overweight men ingested saturated or polyunsaturated fat-rich diets for 6 weeks during weight maintenance. Hyperinsulinemic clamps combined with leg balance technique revealed unchanged peripheral insulin sensitivity, independent of fatty acid type. Both diets increased fat oxidation potential in muscle. Hepatic insulin clearance increased, while glucose production, de novo lipogenesis, and plasma triacylglycerol decreased. High fat intake changed the plasma proteome in the immune-supporting direction and the gut microbiome displayed changes at taxonomical and functional level with polyunsaturated fatty acid (PUFA). In mice, eucaloric feeding of human PUFA and saturated fatty acid diets lowered hepatic triacylglycerol content compared with low-fat-fed control mice, and induced adaptations in the liver supportive of decreased gluconeogenesis and lipogenesis. Intake of fat-rich diets thus induces extensive metabolic adaptations enabling disposition of dietary fat without metabolic complications.

Obesity-related diseases affect half of the global population, and bariatric surgery is one of the few interventions with long-lasting weight loss and cardio-metabolic effects. Here, we investigated the effect of Roux-en-Y gastric bypass surgery on the plasma proteome, hypothesizing that specific proteins or protein patterns may serve as key mediators and markers of the metabolic response. We performed mass spectrometry (MS)-based proteomics on two longitudinal studies encompassing 47 morbidly obese patients, generating quantitative information on more than 1,700 proteins. A global correlation matrix incorporating about 200,000 relationships revealed functional connections between proteins and assigned them to physiological processes. The main classes of significantly altered proteins were markers of systemic inflammation and those involved in lipid metabolism. Our data highlight robust correlative and anti-correlative behaviors of circulating proteins to each other and to clinical parameters. A group of inflammation-related proteins showed distinct inverse relationships to proteins consistently associated with insulin sensitivity.

BACKGROUND Roux-en-Y gastric bypass (RYGB) involves exclusion of major parts of the stomach and changes in admixture of gastro-pancreatic enzymes, which could have a major impact on protein digestion and amino acid absorption. OBJECTIVE We investigated the effect of RYGB on amino acid appearance in the systemic circulation from orally ingested protein and from endogenous release. DESIGN Nine obese glucose-tolerant subjects, with a mean body mass index (in kg/m(2)) of 39.2 (95% CI: 35.2, 43.3) and mean glycated hemoglobin of 5.3% (95% CI: 4.9%, 5.6%), were studied before and 3 mo after RYGB. Leucine and phenylalanine kinetics were determined under basal conditions and during 4 postprandial hours by intravenous infusions of [3,3,3-(2)H3]-leucine and [ring-(2)D5]-phenylalanine combined with ingestion of [1-(13)C]-leucine intrinsically labeled caseinate as the sole protein source of the meal. Changes in body composition were assessed by dual-energy X-ray absorptiometry. RESULTS After RYGB, basal plasma leucine concentration did not change, but marked changes were seen postprandially with 1.7-fold increased peak concentrations (before—mean: 217 μmol/L; 95% CI: 191, 243 μmol/L; 3 mo—mean: 377 μmol/L; 95% CI: 252, 502 μmol/L; P = 0.012) and 2-fold increased incremental AUC (before-mean: 4.1 mmol ∙ min/L; 95% CI: 2.7, 5.5 mmol ∙ min/L; 3 mo-mean: 9.5 mmol ∙ min/L; 95% CI: 4.9, 14.2 mmol ∙ min/L; P = 0.032). However, the postprandial hyperleucinemia was transient, and concentrations were below basal concentrations in the fourth postprandial hour. These concentration differences were mainly caused by changes in leucine appearance rate from orally ingested caseinate: peak rate increased nearly 3-fold [before—mean: 0.5 μmol/(kg fat-free mass ∙ min); 95% CI: 0.4, 0.5 μmol/(kg fat-free mass ∙ min); 3 mo—mean 1.4 μmol/(kg fat-free mass ∙ min); 95% CI: 0.8, 1.9 μmol/(kg fat-free mass ∙ min); P = 0.002], and time to peak was much shorter (before—mean: 173 min; 95% CI: 137, 209 min; 3 mo—mean: 65 min; 95% CI: 46, 84 min; P < 0.001). Only minor changes were seen in endogenous leucine release after RYGB. CONCLUSIONS RYGB accelerates caseinate digestion and amino acid absorption, resulting in faster and higher but more transient postprandial elevation of plasma amino acids. Changes are likely mediated by accelerated intestinal nutrient entry and clearly demonstrate that protein digestion is not impaired after RYGB. This trial was registered at clinicaltrials.gov as NCT01559792.

Summary Glucagon is secreted from pancreatic α cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in β cells demonstrated that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in vivo. We conclude that glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion., Graphical Abstract, Highlights • PG 1-61 is a glucagon-like peptide in humans • Hyperglucagonemia may include PG 1-61, as well as glucagon • PG 1-61 stimulates insulin secretion and activates human hepatocytes • PG 1-61 may be a surrogate marker of alpha cell dysfunction, Wewer Albrechtsen et al. identify a glucagon-like molecule, PG 1-61, in humans using mass-spectrometry-based proteomics. PG 1-61 activates the glucagon receptor, stimulates insulin secretion, and activates key gluconeogenic enzymes. In dysmetabolic conditions, PG 1-61 is upregulated and may therefore serve as a marker of alpha cell stress.

Roux-en-Y gastric bypass (RYGB) improves glycemic control within days after surgery, and changes in insulin sensitivity and β-cell function are likely to be involved. We studied 10 obese patients with type 2 diabetes (T2D) and 10 obese glucose-tolerant subjects before and 1 week, 3 months, and 1 year after RYGB. Participants were included after a preoperative diet-induced total weight loss of −9.2 ± 1.2%. Hepatic and peripheral insulin sensitivity were assessed using the hyperinsulinemic- euglycemic clamp combined with the glucose tracer technique, and β-cell function was evaluated in response to an intravenous glucose-glucagon challenge as well as an oral glucose load. Within 1 week, RYGB reduced basal glucose production, improved basal hepatic insulin sensitivity, and increased insulin clearance, highlighting the liver as an important organ responsible for early effects on glucose metabolism after surgery. Insulin-mediated glucose disposal and suppression of fatty acids did not improve immediately after surgery but increased at 3 months and 1 year; this increase likely was related to the reduction in body weight. Insulin secretion increased after RYGB only in patients with T2D and only in response to oral glucose, underscoring the importance of the changed gut anatomy.

Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) induce substantial weight loss and improve glycemic control in patients with type 2 diabetes, but it is not clear whether these occur via the same mechanisms. We compared absorption rates of glucose and protein, as well as profiles of gastro-entero-pancreatic hormones, in patients who had undergone SG or RYGB vs controls.We performed a cross-sectional study of 12 patients who had undergone sleeve gastrectomy, 12 patients who had undergone RYGB, and 12 individuals who had undergone neither surgery (controls), all in Denmark. Study participants were matched for body mass index, age, sex, and postoperative weight loss, and all had stable weights. They received continuous infusions of stable isotopes of glucose, glycerol, phenylalanine, tyrosine, and urea before and during a mixed meal containing labeled glucose and intrinsically phenylalanine-labeled caseinate. Blood samples were collected for 6 hours, at 10- to 60-minute intervals, and analyzed.The systemic appearance of ingested glucose was faster after RYGB and SG vs controls; the peak glucose appearance rate was 64% higher after RYGB, and 23% higher after SG (both P.05); the peak phenylalanine appearance rate from ingested casein was 118% higher after RYGB (P.01), but similar between patients who had undergone SG and controls. Larger, but more transient increases in levels of plasma glucose and amino acids were accompanied by higher secretion of insulin, glucagon-like peptide 1, peptide YY, and cholecystokinin after RYGB, whereas levels of ghrelin were lower after SG, compared with RYGB and controls. Total 6-hour oral recovery of ingested glucose and protein was comparable among groups.Postprandial glucose and protein absorption and gastro-entero-pancreatic hormone secretions differ after SG and RYGB. RYGB was characterized by accelerated absorption of glucose and amino acids, whereas protein metabolism after SG did not differ significantly from controls, suggesting that different mechanisms explain improved glycemic control and weight loss after these surgical procedures. ClinicalTrials.gov ID NCT03046186.

Summary Experience with Roux-en-Y gastric bypass in patients with type 1 diabetes is very limited, despite an increasing prevalence of obesity also in this population. We describe changes in anthropometric measures, insulin dose, HbA1c, blood pressure, lipid status, and metabolic response to a liquid mixed meal throughout the first year after RYGB in an obese patient with type 1 diabetes. No change in HbA1c was observed, but a 48% reduction in weight-adjusted insulin dose and improvements in cardiovascular risk factors was seen 1 year after surgery. Exaggerated secretions of anorexigenic gut hormones were seen during the meals.

Roux-en-Y gastric bypass (RYGB) improves glucose tolerance and ameliorates fasting hyperinsulinemia within days after surgery. Improvements in hepatic insulin sensitivity and insulin clearance could contribute importantly to these effects.The objective of the investigation was to study changes in insulin clearance after RYGB.This was a prospective study of fasting hepatic insulin clearance and, in a subgroup of patients, postprandial insulin clearance after a meal test before and 1 week, 3 months, and 1 year after RYGB.The study was conducted at Hvidovre Hospital (Hvidovre, Denmark).Patients included 2 groups of obese RYGB-patients: 1) type 2 diabetes (T2D) group: 32 patients with T2D (meal test, n = 13), 2) normal glucose tolerance (NGT) group: 32 patients with NGT (meal test, n = 12).The intervention was RYGB.Fasting hepatic insulin clearance (fasting C-peptide/fasting insulin). Postprandial insulin clearance (incremental areas under the curve of insulin secretion rates/incremental areas under the curve of insulin).Fasting hepatic insulin clearance increased after 1 week (P.01) and further at 3 months (P.01), remaining elevated 1 year postoperatively (P.01) with no difference between the T2D and NGT groups. Postprandial insulin clearance changed only in the T2D group with an increase at 1 week (P.01) that was maintained at 3 months (P = .06) and 1 year (P.01).RYGB increases insulin clearance within 1 week after surgery, highlighting the liver as a key organ involved in the early beneficial effect on glucose metabolism. Postprandial insulin secretion may be underestimated postoperatively in patients with type 2 diabetes when evaluated by peripheral insulin concentrations instead of insulin secretion rates or C-peptide.

Postprandial secretion of glucagon-like peptide-1 (GLP-1) is enhanced after Roux-en-Y gastric bypass (RYGB), but the precise molecular mechanisms explaining this remain poorly understood. Plasma concentrations of bile acids (BAs) increase after RYGB, and BAs may act as molecular enhancers of GLP-1 secretion through activation of TGR5-receptors. We aimed to evaluate GLP-1 secretion after oral administration of the primary bile acid chenodeoxycholic acid (CDCA) and the secondary bile acid ursodeoxycholic acid (UDCA) (which are available for oral use) in RYGB-operated participants. Eleven participants (BMI 29.1 ± 1.2, age 37.0 ± 3.2 years, time from RYGB 32.3 ± 1.1 months, weight loss after RYGB 37.0 ± 3.1 kg) were studied in a placebo-controlled, crossover-study. On three different days, participants ingested (1) placebo (water), (2) UDCA 750 mg, (3) CDCA 1250 mg (highest recommended doses). Oral intake of CDCA increased plasma concentrations of GLP-1, C-peptide, glucagon, peptide YY, neurotensin, total bile acids, and fibroblast growth factor 19 significantly compared with placebo (all P < 0.05 for peak and positive incremental area-under-the-curve (piAUC)). All plasma hormone concentrations were unaffected by UDCA Neither UDCA nor CDCA changed glucose, cholecystokinin or glucose-dependent insulinotropic polypeptide (GIP) concentrations. In conclusion, our findings demonstrate that the primary bile acid chenodeoxycholic acid is able to enhance secretion of gut hormones when administered orally in RYGB-operated patients-even in the absence of nutrients.

Background Roux-en-Y gastric bypass (RYGB) is an effective means to achieve sustained weight loss for morbidly obese individuals. Besides rapid weight reduction, patients achieve major improvements of insulin sensitivity and glucose homeostasis. Dysbiosis of gut microbiota has been associated with obesity and some of its co-morbidities, like type 2 diabetes, and major changes of gut microbial communities have been hypothesized to mediate part of the beneficial metabolic effects observed after RYGB. Here we describe changes in gut microbial taxonomic composition and functional potential following RYGB. Methods We recruited 13 morbidly obese patients who underwent RYGB, carefully phenotyped them, and had their gut microbiomes quantified before (n = 13) and 3 months (n = 12) and 12 months (n = 8) after RYGB. Following shotgun metagenomic sequencing of the fecal microbial DNA purified from stools, we characterized the gut microbial composition at species and gene levels followed by functional annotation. Results In parallel with the weight loss and metabolic improvements, gut microbial diversity increased within the first 3 months after RYGB and remained high 1 year later. RYGB led to altered relative abundances of 31 species (P

Exaggerated postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may explain appetite reduction and weight loss after Roux-en-Y gastric bypass (RYGB), but causality has not been established. We hypothesized that food intake decreases after surgery through combined actions from GLP-1 and PYY. GLP-1 actions can be blocked using the GLP-1 receptor antagonist Exendin 9-39 (Ex-9), whereas PYY actions can be inhibited by the administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor preventing the formation of PYYAppetite-regulating gut hormones and appetite ratings during a standard mixed-meal test and effects on subsequent ad libitum food intake were evaluated in two studies: in study 1, nine patients with type 2 diabetes were examined prospectively before and 3 months after RYGB with and without Ex-9. In study 2, 12 RYGB-operated patients were examined in a randomized, placebo-controlled, crossover design on four experimental days with: (1) placebo, (2) Ex-9, (3) the DPP-4 inhibitor, sitagliptin, to reduce formation of PYYIn study 1, food intake decreased by 35% following RYGB compared with before surgery. Before surgery, GLP-1 receptor blockage increased food intake but no effect was seen postoperatively, whereas PYY secretion was markedly increased. In study 2, combined GLP-1 receptor blockage and DPP-4 inhibitor mediated lowering of PYYBlockade of actions from only one of the two L-cell hormones, GLP-1 and PYY

Roux-en-Y gastric bypass (RYGB) surgery causes profound changes in secretion of gastrointestinal hormones and glucose metabolism. We present a detailed analysis of the early hormone changes after RYGB in response to three different oral test meals designed to provide this information without causing side effects (such as dumping). We examined eight obese non-diabetic patients before and within 2 weeks after RYGB. On separate days, oral glucose tolerance tests (25 or 50 g glucose dissolved in 200 mL of water) and a liquid mixed meal test (200 mL 300 kcal) were performed. We measured fasting and postprandial glucose, insulin, C-peptide, glucagon, total and intact glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY3-36 (PYY), cholecystokinin (CCK), total and active ghrelin, gastrin, somatostatin, pancreatic polypeptide (PP), amylin, leptin, free fatty acids (FFA), and registered postprandial dumping. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance. Fasting glucose, insulin, ghrelin, and PYY were significantly decreased and FFA was elevated postoperatively. Insulin sensitivity increased after surgery. The postprandial response increased for C-peptide, GLP-1, GLP-2, PYY, CCK, and glucagon (in response to the mixed meal) and decreased for total and active ghrelin, leptin, and gastrin, but were unchanged for GIP, amylin, PP, and somatostatin after surgery. Dumping symptoms did not differ before and after the operation or between the tests. Within 2 weeks after RYGB, we found an increase in insulin secretion and insulin sensitivity. Responses of appetite-regulating intestinal hormones changed dramatically, all in the direction of reducing hunger.

Roux-en-Y gastric bypass (RYGB) leads to increased peripheral insulin sensitivity. The aim of this study was to investigate the effect of RYGB on expression and regulation of proteins involved in regulation of peripheral glucose metabolism. Skeletal muscle and adipose tissue biopsies from glucose-tolerant and type 2 diabetic subjects at fasting and during a hyperinsulinemic-euglycemic clamp before as well as 1 wk and 3 and 12 mo after RYGB were analyzed for relevant insulin effector proteins/signaling components. Improvement in peripheral insulin sensitivity mainly occurred at 12 mo postsurgery when major weight loss was evident and occurred concomitantly with alterations in plasma adiponectin and in protein expression/signaling in peripheral tissues. In skeletal muscle, protein expression of GLUT4, phosphorylated levels of TBC1D4, as well as insulin-induced changes in phosphorylation of Akt and glycogen synthase activity were enhanced 12 mo postsurgery. In adipose tissue, protein expression of GLUT4, Akt2, TBC1D4, and acetyl-CoA carboxylase (ACC), phosphorylated levels of AMP-activated protein kinase and ACC, as well as insulin-induced changes in phosphorylation of Akt and TBC1D4, were enhanced 12 mo postsurgery. Adipose tissue from glucose-tolerant subjects was the most responsive to RYGB compared with type 2 diabetic patients, whereas changes in skeletal muscle were largely similar in these two groups. In conclusion, an improved molecular insulin-sensitive phenotype of skeletal muscle and adipose tissue appears to contribute to the improved whole body insulin action following a substantial weight loss after RYGB.

Roux-en-Y gastric bypass surgery (RYGB) in patients with type 2 diabetes often leads to early disease remission, and it is unknown to what extent this involves improved pancreatic β-cell function per se and/or enhanced insulin- and non-insulin-mediated glucose disposal (glucose effectiveness). We studied 30 obese patients, including 10 with type 2 diabetes, 8 with impaired glucose tolerance, and 12 with normal glucose tolerance before, 1 wk, and 3 mo after RYGB, using an intravenous glucose tolerance test (IVGTT) to estimate first-phase insulin response, insulin sensitivity (Si), and glucose effectiveness with Bergman's minimal model. In the fasting state, insulin sensitivity was estimated by HOMA-S and β-cell function by HOMA-β. Moreover, mixed-meal tests and oral GTTs were performed. In patients with type 2 diabetes, glucose levels normalized after RYGB, first-phase insulin secretion in response to iv glucose increased twofold, and HOMA-β already improved 1 wk postoperatively, with further enhancements at 3 mo. Insulin sensitivity increased in the liver (HOMA-S) at 1 wk and at 3 mo in peripheral tissues (Si), whereas glucose effectiveness did not improve significantly. During oral testing, GLP-1 responses and insulin secretion increased regardless of glucose tolerance. Therefore, in addition to increased insulin sensitivity and exaggerated postprandial GLP-1 levels, diabetes remission after RYGB involves early improvement of pancreatic β-cell function per se, reflected in enhanced first-phase insulin secretion to iv glucose and increased HOMA-β. A major role for improved glucose effectiveness after RYGB was not supported by this study.

Bile acids and fibroblast growth factor 19 (FGF19) have been suggested as key mediators of the improvements in glucose metabolism after Roux-en-Y gastric bypass (RYGB).To describe fasting and postprandial state total bile acid (TBA) and FGF19 concentrations before and after RYGB and relate them to parameters of glucose metabolism, glucagon-like peptide-1, cholecystokinin, and cholesterol fractions.A prospective descriptive study was performed at the Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.Thirteen type 2 diabetic (T2D) patients and 12 normal glucose tolerant (NGT) subjects participated in the study.A 4-hour liquid meal test was performed before and 1 week, 3 months, and 1 year after RYGB.We measured fasting and postprandial TBA and FGF19 concentrations.Fasting TBA concentrations decreased in NGT subjects (P.001) and were unchanged in T2D patients 1 week after surgery, but then increased gradually in both groups with time from surgery (ANOVA Ptime.001). Area under the curve (AUC) TBA was decreased in NGT subjects 1 week after RYGB (before surgery, 567 mmol * min/L [interquartile range, 481-826]; 1 wk, 419 [381-508]; P = .009) and was unchanged in T2D patients (894 [573-1002]; 695 [349-1147]; P = .97) but then increased with time from surgery in both groups (Ptime.001). Fasting FGF19 concentrations were unchanged acutely after RYGB (NGT, 140 pg/mL [100-162], 134 [119-204], P = .42; T2D, 162 [130-196], 154 [104-164], P = .68) and remained unchanged throughout the follow-up period. AUC FGF19 increased gradually with time after surgery (Ptime.001), resembling the changes seen with AUC TBA. One week after RYGB, glucose metabolism improved, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol decreased, and cholecystokinin and glucagon-like peptide-1 secretion increased, whereas FFA concentrations were unchanged.TBA and FGF19 do not explain acute changes in glucose metabolism, cholesterol fractions, and gut hormone secretion after RYGB.

Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy are referred to as 'metabolic surgery' due to hormonal shifts with impacts on diabetes remission and weight loss. The purpose of this review is to summarize recent findings in mechanisms underlying beneficial effects of weight loss surgery.Importantly, gut hormone secretion is altered after RYGB and sleeve gastrectomy due to accelerated transit of nutrients to distal parts of the small intestine, leading to excessive release of L-cell peptide hormones [e.g. glucagon-like peptide-1 (GLP-1), peptide YY].Improved glucose metabolism after RYGB and sleeve gastrectomy involves several mechanisms: early increased hepatic insulin sensitivity, resulting from reduced liver fat content in response to the postoperative caloric restriction, improved beta-cell function mediated by exaggerated postprandial GLP-1 secretion; as demonstrated by relapse of impaired glucose tolerance in studies blocking the GLP-1 receptor by exendin 9-39, and later after major weight loss increased peripheral insulin sensitivity. Gut hormone secretion changes towards a more anorectic profile and is likely important for less caloric intake and weight loss.Changes in gut hormone secretion after RYGB and sleeve gastrectomy surgery induce the beneficial effects on weight and glycemic control through the influence on appetite regulation and insulin secretion.

Aim/hypothesis Hyperglucagonaemia is a characteristic of several clinical conditions (e.g. end-stage renal disease (ESRD), type 2 diabetes, obesity before and after Roux-en-Y gastric bypass (RYGB) and vagotomy with pyloroplasty), but the molecular nature of ‘immunoreactive’ glucagon is poorly characterised. The specific determination of fully processed, intact glucagon requires a ‘sandwich’ assay employing a combination of antibodies directed against both N- and C-termini. We compared a novel assay for intact glucagon with a highly sensitive C-terminal RIA (hitherto considered specific) to determine the extent to which the hyperglucagonaemia measured in clinical samples was caused by authentic glucagon. Methods We examined the performance of three commercial glucagon ‘sandwich’ ELISAs. The ELISAwith the best overall performance was selected to compare glucagon measurements in clinical samples with an established glucagon RIA. Results The first assay performed poorly: there was high cross-reactivity with glicentin (22%) and a lack of sensitivity for glucagon. The second and third assays showed minor cross-reactivity (1–5%) with oxyntomodulin and glicentin; however, the second assay had insufficient sensitivity for glucagon in plasma (>10–20 pmol/l). Thus, only the third assay was suitable for measuring glucagon concentrations in clinical samples. The ELISA and RIA measured similar glucagon levels in healthy individuals. Measurements of samples from individuals with abnormally high (type 2 diabetes or obese) or very elevated (post vagotomy with pyloroplasty, post-RYGB) glucagon levels were also similar in both assays. However, glucagon levels in participants with ESRD were much lower when measured by ELISA than by RIA, indicating that the apparent hyperglucagonaemia is not caused by fully processed intact glucagon. Conclusions/interpretation For most purposes, sensitive Cterminal glucagon RIAs are accurate. However, measurements may be spuriously high, at least in patients with renal disease. Trial Registration Samples from type 2 diabetic and normoglucose-tolerant patients before and 1 year after RYGB were from a study by Bojsen-Moller et al (trial registration number NCT 01202526). Samples from vagotomised and control individuals were from a study by Plamboeck et al (NCT01176890). Samples from ESRD patients were from a study by Idorn et al (NCT01327378).

Bariatric surgery is the most effective treatment for severe obesity. The mean weight loss is approximately 30-40 kg/11-15 BMI units or approximately 60 % of excess body weight. Many patients pursue bariatric surgery for improvement in their physical image and self-esteem rather than somatic health improvement. Health-related quality of life improves after bariatric surgery and the long-term improvements are positively associated with the long-term amount of weight reduction. After the major weight loss, excess skin present problems for the patients and many patients want body contouring by plastic surgery. Plastic surgery adds to further improvement in health-related quality of life

Roux-en-Y gastric bypass surgery (RYGB) improves glucose tolerance in patients with type 2 diabetes, but also changes the glucose profile in response to a meal in glucose-tolerant individuals. We hypothesised that the driving force for the changed postprandial glucose profiles after RYGB is rapid entry of glucose into the systemic circulation due to modified gastrointestinal anatomy, causing hypersecretion of insulin and other hormones influencing glucose disappearance and endogenous glucose production.We determined glucose absorption and metabolism and the rate of lipolysis before and 3 months after RYGB in obese glucose-tolerant individuals using the double-tracer technique during a mixed meal.After RYGB, the postprandial plasma glucose profile changed, with a higher peak glucose concentration followed by a faster return to lower than basal levels. These changes were brought about by changes in glucose kinetics: (1) a more rapid appearance of ingested glucose in the systemic circulation, and a concomitant increase in insulin and glucagon-like peptide-1 secretion; (2) postprandial glucose disappearance was maintained at a high rate for a longer time after RYGB. Endogenous glucose production was similar before and after surgery. Postoperative glucagon secretion increased and showed a biphasic response after RYGB. Adipose tissue basal rate of lipolysis was higher after RYGB.A rapid rate of absorption of ingested glucose into the systemic circulation, followed by increased insulin secretion and glucose disappearance appears to drive the changes in the glucose profile observed after RYGB, while endogenous glucose production remains unchanged.ClinicalTrials.gov NCT01559792.The study was part of the UNIK program: Food, FitnessPharma for Health and Disease (see www.foodfitnesspharma.ku.dk ). Funding was received from the Novo Nordisk foundation and the Strategic Research Counsel for the Capital Area and Danish Research Agency. The primary investigator received a PhD scholarship from the University of Copenhagen, which was one-third funded by Novo Nordisk.

Roux-en-Y gastric bypass (RYGB) improves glycaemic control in part by increasing postprandial insulin secretion through exaggerated glucagon-like peptide (GLP)-1 release. However, it is unknown whether islet cell responsiveness to i.v. glucose, non-glucose (arginine) and incretin hormones, including GLP-1, is altered. Eleven severely obese glucose-tolerant individuals underwent three hyperglycaemic clamps with arginine bolus and co-infusion of either GLP-1, glucose-dependent insulinotropic polypeptide (GIP) or saline before, and at 1 week and 3 months after RYGB. In addition, an OGTT was performed before and 3 months after surgery. After RYGB, insulin sensitivity improved at 1 week and 3 months, while insulin stimulation and glucagon suppression in response to the clamp with saline co-infusion were largely unaltered. The influence of i.v. GLP-1 and GIP on insulin and glucagon secretion was also unchanged postoperatively. In response to the postoperative OGTT at 3 months, insulin and GLP-1, but not GIP, secretion increased. Furthermore, the glucose profile during the OGTT was altered, with a substantial reduction in 2 h plasma glucose and a paradoxical hypersecretion of glucagon. After RYGB, insulin hypersecretion is linked to the oral, but not the i.v., route of administration and is associated with exaggerated release and preserved insulinotropic action of GLP-1, while both the secretion and action of GIP are unchanged. The results highlight the importance of increased GLP-1 secretion for improving postoperative glucose metabolism. ClinicalTrials.gov NCT01559779.

β-Cell function improves in patients with type 2 diabetes in response to an oral glucose stimulus after Roux-en-Y gastric bypass (RYGB) surgery. This has been linked to the exaggerated secretion of glucagon-like peptide 1 (GLP-1), but causality has not been established. The aim of this study was to investigate the role of GLP-1 in improving β-cell function and glucose tolerance and regulating glucagon release after RYGB using exendin(9-39) (Ex-9), a GLP-1 receptor (GLP-1R)–specific antagonist. Nine patients with type 2 diabetes were examined before and 1 week and 3 months after surgery. Each visit consisted of two experimental days, allowing a meal test with randomized infusion of saline or Ex-9. After RYGB, glucose tolerance improved, β-cell glucose sensitivity (β-GS) doubled, the GLP-1 response greatly increased, and glucagon secretion was augmented. GLP-1R blockade did not affect β-cell function or meal-induced glucagon release before the operation but did impair glucose tolerance. After RYGB, β-GS decreased to preoperative levels, glucagon secretion increased, and glucose tolerance was impaired by Ex-9 infusion. Thus, the exaggerated effect of GLP-1 after RYGB is of major importance for the improvement in β-cell function, control of glucagon release, and glucose tolerance in patients with type 2 diabetes.

To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (RYGB). Cross-sectional study of patients with good (excess body mass index lost (EBL) >60%) and poor weight loss response (EBL 12 months after RYGB and a lean control group matched for age and gender. Sixteen patients with good weight loss response, 17 patients with poor weight loss response, and eight control subjects were included in the study. Participants underwent dual energy X-ray absorptiometry scan, indirect calorimetry and a 9 h multiple-meal test with measurements of glucose, insulin, total bile acids (TBA), glucagon-like peptide (GLP)-1, peptide YY3–36 (PYY), cholecystokinin (CCK), ghrelin, neurotensin and pancreatic polypeptide (PP) as well as assessment of early dumping and appetite. Suppression of hunger was more pronounced in the good than the poor responders in response to the multiple-meal test (P=0.006). In addition, the good responders had a larger release of GLP-1 (P=0.009) and a greater suppression of ghrelin (P=0.037) during the test, whereas the postprandial secretion of CCK was highest in the poor responders (P=0.005). PYY, neurotensin, PP and TBA release did not differ between the RYGB-operated groups. Compared with control subjects, patients had exaggerated release of GLP-1 (P

Our aim was to study the potential mechanisms responsible for the improvement in glucose control in Type 2 diabetes (T2D) within days after Roux-en-Y gastric bypass (RYGB). Thirteen obese subjects with T2D and twelve matched subjects with normal glucose tolerance (NGT) were examined during a liquid meal before (Pre), 1 wk, 3 mo, and 1 yr after RYGB. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent-insulinotropic polypeptide (GIP), and glucagon concentrations were measured. Insulin resistance (HOMA-IR), β-cell glucose sensitivity (β-GS), and disposition index (Dβ-GS: β-GS × 1/HOMA-IR) were calculated. Within the first week after RYGB, fasting glucose [T2D Pre: 8.8 ± 2.3, 1 wk: 7.0 ± 1.2 ( P < 0.001)], and insulin concentrations decreased significantly in both groups. At 129 min, glucose concentrations decreased in T2D [Pre: 11.4 ± 3, 1 wk: 8.2 ± 2 ( P = 0.003)] but not in NGT. HOMA-IR decreased by 50% in both groups. β-GS increased in T2D [Pre: 1.03 ± 0.49, 1 wk: 1.70 ± 1.2, ( P = 0.012)] but did not change in NGT. The increase in DIβ-GSwas 3-fold in T2D and 1.5-fold in NGT. After RYGB, glucagon secretion was increased in response to the meal. GIP secretion was unchanged, while GLP-1 secretion increased more than 10-fold in both groups. The changes induced by RYGB were sustained or further enhanced 3 mo and 1 yr after surgery. Improvement in glycemic control in T2D after RYGB occurs within days after surgery and is associated with increased insulin sensitivity and improved β-cell function, the latter of which may be explained by dramatic increases in GLP-1 secretion.

Roux-en-Y gastric bypass (RYGB) greatly improves glycaemic control in morbidly obese patients with type 2 diabetes, in many even before significant weight loss. Understanding the responsible mechanisms may contribute to our knowledge of the pathophysiology of type 2 diabetes and help identify new drug targets or improve surgical techniques. This review summarises the present knowledge based on pathophysiological studies published during the last decade. Taken together, two main mechanisms seem to be responsible for the early improvement in glycaemic control after RYGB: (1) an increase in hepatic insulin sensitivity induced, at least in part, by energy restriction and (2) improved beta cell function associated with an exaggerated postprandial glucagon-like peptide 1 secretion owing to the altered transit of nutrients. Later a weight loss induced improvement in peripheral insulin sensitivity follows.

Background Roux-en-Y gastric bypass (RYGB) causes extensive changes in gastrointestinal anatomy and leads to reduced appetite and large weight loss, which partly is due to an exaggerated release of anorexigenic gut hormones. Methods To examine whether the altered passage of foods through the gastrointestinal tract after RYGB could be responsible for the changes in gut hormone release, we studied gastrointestinal motility with a scintigraphic technique as well as the secretion of the gut hormones glucagon-like peptide (GLP)-1 and peptide YY3-36 (PYY3-36) in 17 patients>1 year after RYGB and in nine healthy control subjects. Key Results At meal completion, a smaller fraction of liquid and solid radiolabeled marker was retained in the pouch of RYGB patients than in the stomach of control subjects (P = 0.002 and P

Gastric bypass surgery leads to profound changes in the secretion of gut hormones with effects on metabolism, appetite, and food intake. Here, we discuss their contributions to the improvement in glucose tolerance and the weight loss that results from the operations. We find that the improved glucose tolerance is due the following events: a negative energy balance and resulting weight loss, which improve first hepatic and later peripheral insulin sensitivity, in combination with increased postprandial insulin secretion elicited particularly by exaggerated glucagon-like peptide-1 responses. The weight loss is due to loss of appetite resulting in reduced energy intake, and we find it probable that this process is driven by exaggerated secretion of appetite-regulating gut hormones including, but probably not limited to, glucagon-like peptide-1 and peptide-YY. The increased secretion is due to an accelerated exposure to and absorption of nutrients in the small intestine. This places the weight loss and the gut hormones in key positions with respect to the metabolic improvements after bypass surgery.