Short-term effects of obesity surgery versus low-energy diet on body composition and tissue-specific glucose uptake: a randomised clinical study using whole-body integrated 18F-FDG-PET/MRI.

AIMS/HYPOTHESIS: Obesity surgery (OS) and diet-induced weight loss rapidly improve insulin resistance. We aim to investigate the impact of either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery compared with a diet low in energy (low-calorie diet; LCD) on body composition, glucose control and insulin sensitivity, assessed both at the global and tissue-specific level in individuals with obesity but not diabetes. METHODS: In this parallel group randomised controlled trial, patients on a waiting list for OS were randomised (no blinding, sealed envelopes) to either undergo surgery directly or undergo an LCD before surgery. At baseline and 4 weeks after surgery (n=15, 11 RYGB and 4 SG) or 4 weeks after the start of LCD (n=9), investigations were carried out, including an OGTT and hyperinsulinaemic-euglycaemic clamps during which concomitant simultaneous whole-body [18F]fluorodeoxyglucose-positron emission tomography (PET)/MRI was performed. The primary outcome was HOMA-IR change. RESULTS: One month after bariatric surgery and initiation of LCD, both treatments induced similar reductions in body weight (mean ± SD: -7.7±1.4 kg and -7.4±2.2 kg, respectively), adipose tissue volume (7%) and liver fat content (2% units). HOMA-IR, a main endpoint, was significantly reduced following OS (-26.3% [95% CI -49.5, -3.0], p=0.009) and non-significantly following LCD (-20.9% [95% CI -58.2, 16.5). For both groups, there were similar reductions in triglycerides and LDL-cholesterol. Fasting plasma glucose and insulin were also significantly reduced only following OS. There was an increase in glucose AUC in response to an OGTT in the OS group (by 20%) but not in the LCD group. During hyperinsulinaemia, only the OS group showed a significantly increased PET-derived glucose uptake rate in skeletal muscle but a reduced uptake in the heart and abdominal adipose tissue. Both liver and brain glucose uptake rates were unchanged after surgery or LCD. Whole-body glucose disposal and endogenous glucose production were not significantly affected. CONCLUSIONS/INTERPRETATION: The short-term metabolic effects seen 4 weeks after OS are not explained by loss of body fat alone. Thus OS, but not LCD, led to reductions in fasting plasma glucose and insulin resistance as well as to distinct changes in insulin-stimulated glucose fluxes to different tissues. Such effects may contribute to the prevention or reversal of type 2 diabetes following OS. Moreover, the full effects on whole-body insulin resistance and plasma glucose require a longer time than 4 weeks. TRIAL REGISTRATION: ClinicalTrials.gov NCT02988011 FUNDING: This work was supported by AstraZeneca R&D, the Swedish Diabetes Foundation, the European Union's Horizon Europe Research project PAS GRAS, the European Commission via the Marie Sklodowska Curie Innovative Training Network TREATMENT, EXODIAB, the Family Ernfors Foundation, the P.O. Zetterling Foundation, Novo Nordisk Foundation, the Agnes and Mac Rudberg Foundation and the Uppsala University Hospital ALF grants.

Hypovitaminosis D and hyperparathyroidism: a 5-year postoperative follow-up of 30,458 gastric bypass and sleeve gastrectomy patients.

BACKGROUND: Bariatric procedures are associated with nutrient deficiencies. Studies show an association between gastric bypass (Roux-en-Y gastric bypass [RYGB]) and hypovitaminosis D as well as hyperparathyroidism, yet few compare RYGB to sleeve gastrectomy (SG), and large long-term analyses are scarce. OBJECTIVE: Evaluate trends of vitamin D and parathyroid hormone (PTH) levels in RYGB and SG. SETTING: National quality register. METHOD: The Scandinavian Obesity Surgery Registry records all bariatric surgeries in Sweden. Data from 2008 to 2021 on primary RYGB or SG with reported 25-hydroxy vitamin D (25-OH-D) and/or PTH levels were included. Individuals with an estimated glomerular filtration rate of <60 mL/min/1.73 m2 were excluded, leaving a study population of 25,385 RYGB and 5073 SG patients. RESULTS: A decrease in 25-OH-D, mirrored by an increase in PTH, was observed after the first year for both procedures, but more pronounced in RYGB. At 5 years, 25-OH-D levels were still higher than at baseline. Regular supplementation resulted in better 25-OH-D and PTH levels. Linear regression found that procedure type (RYGB versus SG), 25-OH-D levels, and time since surgery were significant factors in predicting PTH levels. The risk of pathologic PTH levels (>7 pmol/L) at 2 and 5 years postoperatively was roughly three times higher in RYGB (odds ratios = 3.41 and 2.84, respectively). CONCLUSIONS: Previous studies alongside these results suggest that RYGB, more so than SG, may cause hypovitaminosis D and thereby hyperparathyroidism, which could lead to osteopenia. The threshold for 25-OH-D should be >75 nmol/L, and despite higher levels, current vitamin D supplementation may not be sufficient. Follow-up should include screening for hyperparathyroidism and hypovitaminosis D.

Time trends and outcomes of gastrostomy placement in a Swedish national cohort over two decades.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) and laparoscopically inserted gastrostomy have become the gold standard for adult patients and children, respectively, requiring long-term enteral nutrition support. Procedure-related mortality is a rare event, often reported to be zero in smaller studies. National data on 30-d mortality and long-term survival rates after gastrostomy placement are scarce in the literature. AIM: To study the use of gastrostomies in Sweden from 1998-2019 and to analyze procedure-related mortality and short-term (< 30 d) and long-term survival. METHODS: In this retrospective, population-based cohort study, individuals that had received a gastrostomy between 1998-2019 in Sweden were included. Individuals were identified in the Swedish National Patient Register, and survival analysis was possible by cross-referencing the Swedish Death Register. The cohort was divided into three age groups: Children (0-18 years); adults (19-64 years); and elderly (≥ 65 years). Kaplan-Meier with log-rank test and Cox regression were used for survival analysis. RESULTS: In total 48682 individuals (52% males, average age 60.9 ± 25.3 years) were identified. The cohort consisted of 12.0% children, 29.5% adults, and 58.5% elderly. An increased use of gastrostomies was observed during the study period, from 13.7/100000 to 22.3/100000 individuals (P < 0.001). The use of PEG more than doubled (about 800 to 1800/year), with a corresponding decrease in open gastrostomy (about 700 to 340/year). Laparoscopic gastrostomy increased more than ten-fold (about 20 to 240/year). Overall, PEG, open gastrostomy, and laparoscopic gastrostomy constituted 70.0% (n = 34060), 23.3% (n = 11336), and 4.9% (n = 2404), respectively. Procedure-related mortality was 0.1% (n = 44) overall (PEG: 0.05%, open: 0.24%, laparoscopic: 0.04%). The overall 30-d mortality rate was 10.0% (PEG: 9.8%, open: 12.4%, laparoscopic: 1.7%) and decreased from 11.6% in 1998-2009 vs 8.5% in 2010-2019 (P < 0.001). One-year and ten-year survival rates for children, adults, and elderly were 93.7%, 67.5%, and 42.1% and 79.9%, 39.2%, and 6.8%, respectively. The most common causes of death were malignancies and cardiovascular and respiratory diseases. CONCLUSION: The annual use of gastrostomies in Sweden increased during the study period, with a shift towards more minimally invasive procedures. Although procedure-related death was rare, the overall 30-d mortality rate was high (10%). To overcome this, we believe that patient selection should be improved.

Surgical Aspects of Sleeve Gastrectomy Are Related to Weight Loss and Gastro-esophageal Reflux Symptoms.

INTRODUCTION: A large variation in outcome has been reported after sleeve gastrectomy (SG) across countries and institutions. We aimed to evaluate the effect of surgical technique on total weight loss (TWL) and gastro-esophageal reflux disease (GERD). METHODS: Observational cohort study based on data from the national registries for bariatric surgery in the Netherlands, Norway, and Sweden. A retrospective analysis of prospectively obtained data from surgeries during 2015-2017 was performed based on 2-year follow-up. GERD was defined as continuous use of acid-reducing medication. The relationship between TWL, de novo GERD and operation technical variables were analyzed with regression methods. RESULTS: A total of 5927 patients were included. The average TWL was 25.6% in Sweden, 28.6% in the Netherlands, and 30.6% in Norway (p < 0.001 pairwise). Bougie size, distance from the resection line to the pylorus and the angle of His differed between hospitals. A minimized sleeve increased the expected total weight loss by 5-10 percentage points. Reducing the distance to the angle of His from 3 to just above 0 cm increased the risk of de novo GERD five-fold (from 3.5 to 17.8%). CONCLUSION: Smaller bougie size, a shorter distance to pylorus and to the angle of His were all associated with greater weight loss, whereas a shorter distance to angle of His was associated with more de novo reflux.

Randomized controlled trial of nasogastric tube use after esophagectomy: study protocol for the kinetic trial.

Esophagectomy is a complex and complication laden procedure. Despite centralization, variations in perioparative strategies reflect a paucity of evidence regarding optimal routines. The use of nasogastric (NG) tubes post esophagectomy is typically associated with significant discomfort for the patients. We hypothesize that immediate postoperative removal of the NG tube is non-inferior to current routines. All Nordic Upper Gastrointestinal Cancer centers were invited to participate in this open-label pragmatic randomized controlled trial (RCT). Inclusion criteria include resection for locally advanced esophageal cancer with gastric tube reconstruction. A pretrial survey was undertaken and was the foundation for a consensus process resulting in the Kinetic trial, an RCT allocating patients to either no use of a NG tube (intervention) or 5 days of postoperative NG tube use (control) with anastomotic leakage as primary endpoint. Secondary endpoints include pulmonary complications, overall complications, length of stay, health related quality of life. A sample size of 450 patients is planned (Kinetic trial: https://www.isrctn.com/ISRCTN39935085). Thirteen Nordic centers with a combined catchment area of 17 million inhabitants have entered the trial and ethical approval was granted in Sweden, Norway, Finland, and Denmark. All centers routinely use NG tube and all but one center use total or hybrid minimally invasive-surgical approach. Inclusion began in January 2022 and the first annual safety board assessment has deemed the trial safe and recommended continuation. We have launched the first adequately powered multi-center pragmatic controlled randomized clinical trial regarding NG tube use after esophagectomy with gastric conduit reconstruction.

Systematic Development of National Guidelines for Obesity Care: The Swedish Approach.

INTRODUCTION: With the rapid development of treatment modalities for obesity management, there is an increasing demand for guidance to facilitate the prioritization of interventions. In 2020, the Swedish National Board of Health and Welfare started the process of producing the first national guidelines for obesity care directed to decision makers who allocate resources to the best knowledge-based care. The main aim of this paper was to describe the systematic development of these guidelines, designed to guarantee uniformly high standards of care throughout the whole country. METHODS: The standardized procedures of the National Board of Health and Welfare were applied to construct guidelines in a systematic and transparent way, including priority setting of recommendations and quality indicators to evaluate the progress of implementation. The process involved independent expert committees including professionals and patient representatives, and the guidelines were reviewed through an open public consultation. RESULTS: National guidelines were issued in 2023, encompassing a broad scope, from identification and diagnosis to multiple treatment modalities, embedded in a life-course perspective from pregnancy to the elderly, as well as highlighting the need for improved knowledge and competence of health care providers. CONCLUSIONS: National guidelines for improved standard care and evidence-based and efficient use of health care resources for obesity treatment can be developed in a systematic way with professionals and patient representatives.

Glycemic variability and hypoglycemia before and after Roux-en-Y Gastric Bypass and Sleeve Gastrectomy - A cohort study of females without diabetes.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) lead to lower fasting glucose concentrations, but might cause higher glycemic variability (GV) and increased risk of hypoglycemia. However, it has been sparsely studied in patients without preoperative diabetes under normal living conditions. OBJECTIVES: To study 24-hour interstitial glucose (IG) concentrations, GV, the occurrence of hypoglycemia and dietary intake before and after laparoscopic RYGB and SG in females without diabetes. SETTING: Outpatient bariatric units at a community and a university hospital. METHODS: Continuous glucose monitoring and open-ended food recording over 4 days in 4 study periods: at baseline, during the preoperative low-energy diet (LED) regimen, and at 6 and 12 months postoperatively. RESULTS: Of 47 patients included at baseline, 83%, 81%, and 79% completed the remaining 3 study periods. The mean 24-hour IG concentration was similar during the preoperative LED regimen and after surgery and significantly lower compared to baseline in both surgical groups. GV was significantly increased 6 and 12 months after surgery compared to baseline. The self-reported carbohydrate intake was positively associated with GV after surgery. IG concentrations below 3.9 mmol/L were observed in 14/25 (56%) of RYGB- and 9/12 (75%) of SG-treated patients 12 months after surgery. About 70% of patients with low IG concentrations also reported hypoglycemic symptoms. CONCLUSIONS: The lower IG concentration in combination with the higher GV after surgery, might create a lower margin to hypoglycemia. This could help explain the increased occurrence of hypoglycemic episodes after RYGB and SG.

Results from the Scandinavian Obesity Surgery Registry: A narrative review.

In 2007, the Scandinavian Obesity Surgery Registry (SOReg) was started by the profession to monitor the results of bariatric surgery and to provide a high-quality database for research. In the end of August 2023, SOReg contains 88,379 patients (body mass index [BMI] 41.7 kg/m2 , 41.2 years, 77.1% females, gastric bypass 76.8%). In this narrative review, we demonstrate that preoperative weight loss is of value and that the laparoscopic double omega-loop technique is highly suitable for gastric bypass. Closing the mesenteric openings is, however, important. Swedish bariatric surgery has low mortality, and our results are comparative to those of other countries. Significant long-term improvements are found in common obesity-related diseases such as diabetes, hypertension, and sleep apnea. Furthermore, the risk for cardiac failure and major adverse cardiovascular events is significantly reduced. Pregnancy-related outcomes are also improved. Gastric bypass results in significant improvements in quality of life and seems to be cost saving. We have revealed that low socioeconomic status is associated with reduced chance of undergoing bariatric surgery and inferior outcomes. Of note, we have performed several randomized clinical trials within the registry database. In conclusion, high-quality national registry databases, such as SOReg, are important for maintaining high-quality care and present a platform for extensive research.

Long-term Follow-up 15 Years After Duodenal Switch or Gastric Bypass for Super Obesity: a Randomized Controlled Trial.

BACKGROUND: In super obesity, Roux-en-Y gastric bypass (RYGB) may be insufficient why some surgeons advocate biliopancreatic diversion with duodenal switch (BPD/DS), a more malabsorptive procedure. There is a paucity of evidence regarding results beyond 10 years, especially after BPD/DS. The aim of this randomized controlled trial was to compare the long-term outcome of BPD/DS, and RYGB in patients with super obesity, i.e., body mass index (BMI) > 50 kg/m2. METHODS: This is a 13- to 17-year follow-up study of a single-center, single-blinded randomized trial in which 47 patients (BMI > 48 and eligible for bariatric surgery) were randomized 1:1 to BPD/DS and RYGB (25 men, 24 BPD/DS, 39.1 ± 9.9 years, BMI 54.5 ± 6.1 kg/m2). The primary outcome was weight loss. The study was financed by Swedish governmental funding of clinical research (ALF). TRIAL REGISTRATION NUMBER: ISRCTN10940791. RESULTS: Thirty-four (18 BPD/DS) of the living 42 patients (81.0%) participated. BPD/DS resulted in higher BMI loss (20.4 ± 7.9 vs. 12.4 ± 8.6, p = .008) and higher percent of total body weight loss (37.5% ± 12.2 vs. 22.8% ± 14.8, p = .004). BPD/DS was associated with lower fasting glucose, glycated hemoglobin (HbA1c), and low-density lipoprotein (LDL) as well as lower hemoglobin. Adverse events were more common after BPD/DS (2.7 vs. 0.9 per patient, p = .004). The global assessment tool BAROS (Bariatric Analysis and Reporting Outcome System) demonstrated superior scores for BPD/DS (p = .047). CONCLUSION: When compared to RYGB, BPD/DS results in superior weight loss and metabolic control as well as superior BAROS score, however, at the cost of more adverse events.

Complementary elements of support after gastric-bypass surgery perceived by adults with previous type 2 diabetes: A qualitative study 2 years after bariatric surgery.

Bariatric surgery is the most medically and cost-effective treatment for adults with obesity and type 2 diabetes mellitus (T2DM). Our findings suggest initial improvements in health-related quality of life that may decline as support from follow-up care ends. How patients experience long-term support is not well described. This study therefore aimed to investigate how adults with previous T2DM perceived different sources of support 2 years after bariatric surgery. In this qualitative study, individual interviews were conducted with 13 adults (10 women) 2 years after surgery. Using thematic analysis, one overarching theme (compiling complementary elements of support after gastric-bypass surgery), four themes and nine subthemes emerged. The results show that support was given and received from various sources, support needs varied over time depending on where the patient was in the process and that the sources of support were complementary. To conclude, our results show that support needs change in adults who have undergone bariatric surgery. Long-term professional and day-to-day support from family and other networks are essential and complementary elements of support. Healthcare staff should consider these findings, especially during the early follow-up period.

Trophozoite fitness dictates the intestinal epithelial cell response to Giardia intestinalis infection.

Giardia intestinalis is a non-invasive, protozoan parasite infecting the upper small intestine of most mammals. Symptomatic infections cause the diarrhoeal disease giardiasis in humans and animals, but at least half of the infections are asymptomatic. However, the molecular underpinnings of these different outcomes of the infection are still poorly defined. Here, we studied the early transcriptional response to G. intestinalis trophozoites, the disease-causing life-cycle stage, in human enteroid-derived, 2-dimensional intestinal epithelial cell (IEC) monolayers. Trophozoites preconditioned in media that maximise parasite fitness triggered only neglectable inflammatory transcription in the IECs during the first hours of co-incubation. By sharp contrast, "non-fit" or lysed trophozoites induced a vigorous IEC transcriptional response, including high up-regulation of many inflammatory cytokines and chemokines. Furthermore, "fit" trophozoites could even suppress the stimulatory effect of lysed trophozoites in mixed infections, suggesting active G. intestinalis suppression of the IEC response. By dual-species RNA-sequencing, we defined the IEC and G. intestinalis gene expression programs associated with these differential outcomes of the infection. Taken together, our results inform on how G. intestinalis infection can lead to such highly variable effects on the host, and pinpoints trophozoite fitness as a key determinant of the IEC response to this common parasite.

Incidence of Kidney Stones After Metabolic and Bariatric Surgery-Data from the Scandinavian Obesity Surgery Registry.

PURPOSE: Obesity is associated with increased incidence of kidney stones, a risk further increased by metabolic and bariatric surgery, particularly after procedures with a malabsorptive component. However, there is a paucity in reports on baseline risk factor and on larger population-based cohorts. The objective was to evaluate incidence and risk factors for kidney stones after bariatric surgery by comparing them to an age-, sex-, and geographically matched cohort from the normal population. MATERIAL AND METHODS: Patients operated with primary Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or biliopancreatic diversion with duodenal switch (BPD-DS) from 2007 until 2017 within the Scandinavian Obesity Surgery registry were matched 1:10 to controls from the normal population. Hospital admission or outpatient visits due to kidney stones registered in the National Patient Registry were considered as endpoint. RESULTS: The study included 58,366 surgical patients (mean age 41.0±11.1, BMI 42.0±5.68, 76% women) with median follow-up time 5.0 [IQR 2.9-7.0] years and 583,660 controls. All surgical procedures were associated with a significantly increased risk for kidney stones (RYGB, HR 6.16, [95% CI 5.37-7.06]; SG, HR 6.33, [95% CI 3.57-11.25]; BPD/DS, HR 10.16, [95% CI 2.94-35.09]). Higher age, type 2 diabetes hypertension at baseline, and a preoperative history of kidney stones were risk factors for having a postoperative diagnosis of kidney stones. CONCLUSION: Primary RYGB, SG, and BPD/DS were all associated with a more than sixfold increased risk for postoperative kidney stones. The risk increased with advancing age, two common obesity-related conditions, and among patients with preoperative history of kidney stones.

A randomized trial comparing percutaneous endoscopic gastrostomy (PEG) and radiologically inserted percutaneous gastrostomy (RIG).

BACKGROUND AND OBJECTIVE: At present, percutaneous endoscopic gastrostomy (PEG) is the procedure of choice in establishing a permanent feeding tube in patients with chronic severe dysphagia. This is the first prospective randomized study in adults comparing PEG with radiologically inserted gastrostomy (RIG). METHODS: Randomization of 106 patients, eligible for both techniques, to PEG (pull method) or RIG. The groups were comparable in terms of age, body mass index, and underlying diseases. Adverse events were reported 10 and 30 days after the operative procedure, and mortality was up until 6 months. The validated European Quality of life 5 Dimensions 3 level version (EQ-5D) questionnaire was used for health status measurements. RESULTS: The procedures were successfully completed in all patients. The median operative time was 10 min for PEG and 20 min for RIG (p < 0.001). The overall rate of adverse events was lower for PEG (22%) than for RIG (51%, p = 0.002), mostly due to less local self-limiting stoma reactions and tube problems. The 30-day mortality was lower after PEG (2% versus 14%, p = 0.020). Patient-scored health status remained low for the entire cohort, with an EQ-5D utility index of 0.164. Self-rated health was low but improved in the RIG group (52.5 from 41.1, out of 100). CONCLUSION: PEG can be recommended as the primary procedure in patients in need of a feeding gastrostomy, mainly due to a lower frequency of tube complications. However, as the two techniques complement each other, RIG is also a valid alternative method. CLINICAL TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number ISRCTN17642761. https://doi.org/10.1186/ISRCTN17642761.

Association between attention deficit hyperactivity disorder and outcomes after metabolic and bariatric surgery: a nationwide propensity-matched cohort study.

BACKGROUND: The risks and benefits of metabolic and bariatric surgery for patients with attention deficit hyperactivity disorder (ADHD) remain to be investigated. OBJECTIVE: The aim of this study was to assess short- and long-term outcomes after metabolic and bariatric surgery in patients with previous ADHD compared with matched control individuals. SETTING: Registry based. METHODS: This 2-staged matched-cohort study included all adults with a body mass index of ≥30 kg/m2 who underwent primary Roux-en-Y gastric bypass or sleeve gastrectomy from 2007 until 2017 registered in the Scandinavian Obesity Surgery Registry. Patients with prescribed medication for ADHD were matched with control individuals without ADHD with a follow-up of up to 11 years after surgery. RESULTS: Among 1431 patients with ADHD and 2862 control individuals (mean body mass index, 42 kg/m2; mean age, 35 years), no difference in weight loss or follow-up attendance over 2 years was seen. ADHD was associated with a higher risk for early postoperative complications (odds ratio [OR] = 1.31; 95% confidence interval [CI], 1.05-1.63), self-harm (hazards ratio [HR] = 1.39; 95% CI, 1.11-1.75), and substance abuse (HR = 1.34; 95% CI, 1.16-1.55), while associations with overall mortality (HR = 1.42; 95% CI, .99-2.03), major adverse cardiovascular and cerebrovascular events (HR = 1.93; 95% CI, .98-3.83), and effects on obesity-related diseases were uncertain. ADHD was associated with a lower health-related quality of life in all aspects before surgery. These differences increased for mental and obesity-related aspects but remained unchanged over time for physical aspects. CONCLUSIONS: Compared with patients without ADHD, patients treated pharmacologically for ADHD experience similar weight loss and remission of obesity-related diseases without an increased risk for serious complications but report a lower health-related quality of life and have an increased risk of substance abuse and self-harm. This further emphasizes the need for close follow-up care for this group of individuals.

Effects of gastric bypass surgery on brain connectivity responses to hypoglycemia.

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) leads to beneficial effects on glucose homeostasis, and attenuated hormonal counterregulatory responses to hypoglycemia are likely to contribute. RYGB also induces alterations in neural activity of cortical and subcortical brain regions. We aimed to characterize RYGB-induced changes in resting-state connectivity of specific brain regions of interest for energy homeostasis and behavioral control during hypoglycemia. METHOD: Ten patients with BMI > 35 kg/m2 were investigated with brain PET/MR imaging during a hyperinsulinemic normo- and hypoglycemic clamp, before and 4 months after RYGB. Hormonal levels were assessed throughout the clamp. Resting-state (RS) fMRI scans were acquired in the glucose-lowering phase of the clamp, and they were analyzed with a seed-to-voxel approach. RESULTS: RS connectivity during initiation of hypoglycemia was significantly altered after RYGB between nucleus accumbens, thalamus, caudate, hypothalamus and their crosstalk with cortical and subcortical regions. Connectivity between the nucleus accumbens and the frontal pole was increased after RYGB, and this was associated with a reduction of ACTH (r = -0.639, p = 0.047) and cortisol (r = -0.635, p = 0.048) responses. Instead, connectivity between the caudate and the frontal pole after RYGB was reduced and this was associated with less attenuation of glucagon response during the hypoglycemic clamp (r = -0.728, p = 0.017), smaller reduction in fasting glucose (r = -0.798, p = 0.007) and less excess weight loss (r = 0.753, p = 0.012). No other significant associations were found between post-RYGB changes in ROI-to-voxel regional connectivity hormonal responses and metabolic or anthropometric outcomes. CONCLUSION: RYGB alters brain connectivity during hypoglycemia of several neural pathways involved in reward, inhibitory control, and energy homeostasis. These changes are associated with altered hormonal responses to hypoglycemia and may be involved in the glucometabolic outcome of RYGB.

Impact of biliopancreatic diversion with duodenal switch on glucose homeostasis and gut hormones and their correlations with appetite.

BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD/DS) results in lifelong changes in gastrointestinal physiology with unclear associations with appetite perception. OBJECTIVE: To explore mixed meal-induced changes in glucose homeostasis and gut hormones and their correlations with appetite perception. SETTING: University hospital. METHODS: Of 28 patients studied preoperatively (age: 38.4 ± 11.3 years; body mass index [BMI]: 56.5 ± 5.1 kg/m2; 14 women), 19 (68%) returned for postoperative follow-up. Plasma was sampled for 180 minutes during a 260-kcal standardized mixed meal. Concentrations of leptin, glucose, insulin, triglycerides, active acyl-ghrelin, motilin, total glucose-dependent insulinotropic polypeptide (GIP), active glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY) were measured. Subjective appetite sensations were scored. RESULTS: BPD/DS resulted in 66.1% ± 23.3% excess BMI loss. Leptin was halved. Glucose and insulin levels were reduced, blunting a preoperative peak at 30 minutes, giving a lower homeostasis model assessment for insulin resistance (HOMA-IR; 13.9 versus 4.8). In contrast, reduced ghrelin and motilin concentrations were accompanied by pronounced peaks 20-30 minutes prior to meal responses. GIP was reduced, whereas GLP-1 and PYY responses were markedly increased, with an early postprandial peak (P < .05, for all). HOMA-IR correlated with insulin (r = .72) and GIP (r = .57). Postoperatively, satiety correlated with GLP-1 (r = .56), whereas the gastric motility index correlated with the desire to eat (r = .60), percentage excess BMI loss (r = -.55), and percentage total weight loss (r = -.49). Delta insulin, GLP-1, and leptin correlated positively with percentage total weight loss (r = .51, r = .48, and r = .58, respectively). CONCLUSIONS: BPD/DS reduces leptin, HOMA-IR, and GIP while markedly increasing GLP-1 and PYY. This study marks the magnitude change in GLP-1 with additional effects of PYY as important factors for weight loss.

Barriers to the Intestinal Absorption of Four Insulin-Loaded Arginine-Rich Nanoparticles in Human and Rat.

Peptide drugs and biologics provide opportunities for treatments of many diseases. However, due to their poor stability and permeability in the gastrointestinal tract, the oral bioavailability of peptide drugs is negligible. Nanoparticle formulations have been proposed to circumvent these hurdles, but systemic exposure of orally administered peptide drugs has remained elusive. In this study, we investigated the absorption mechanisms of four insulin-loaded arginine-rich nanoparticles displaying differing composition and surface characteristics, developed within the pan-European consortium TRANS-INT. The transport mechanisms and major barriers to nanoparticle permeability were investigated in freshly isolated human jejunal tissue. Cytokine release profiles and standard toxicity markers indicated that the nanoparticles were nontoxic. Three out of four nanoparticles displayed pronounced binding to the mucus layer and did not reach the epithelium. One nanoparticle composed of a mucus inert shell and cell-penetrating octarginine (ENCP), showed significant uptake by the intestinal epithelium corresponding to 28 ± 9% of the administered nanoparticle dose, as determined by super-resolution microscopy. Only a small fraction of nanoparticles taken up by epithelia went on to be transcytosed via a dynamin-dependent process. In situ studies in intact rat jejunal loops confirmed the results from human tissue regarding mucus binding, epithelial uptake, and negligible insulin bioavailability. In conclusion, while none of the four arginine-rich nanoparticles supported systemic insulin delivery, ENCP displayed a consistently high uptake along the intestinal villi. It is proposed that ENCP should be further investigated for local delivery of therapeutics to the intestinal mucosa.

Response of multiple hormones to glucose and arginine challenge in T2DM after gastric bypass.

Purpose: In patients with type 2 diabetes mellitus (T2DM), Roux-en-Y gastric bypass (RYGB) leads to beneficial metabolic adaptations, including enhanced incretin secretion, beta-cell function, and systemic insulin sensitivity. We explored the impact of RYGB on pituitary, pancreatic, gut hormones, and cortisol responses to parenteral and enteral nutrient stimulation in patients with obesity and T2DM with repeated sampling up to 2 years after intervention. Methods: We performed exploratory post hoc analyses in a previously reported randomized trial. Levels of adrenocorticotropic hormone (ACTH), cortisol, growth hormone (GH), glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY), ACTH, insulin, and glucagon were measured in 13 patients with T2DM and obesity at four different visits: before and 4, 24, and 104 weeks after RYGB; and in three sequential conditions on the same day: fasting, intravenous arginine challenge, and OGTT. Results: RYGB surprisingly induced a rise in ACTH, cortisol, and GH levels upon an oral glucose load, together with enhanced GLP-1 and PYY responses. Fasting and post-arginine GH levels were higher after RYGB, whereas insulin, glucagon, GLP-1, GIP, and cortisol were lower. These endocrine adaptations were seen as early as 4 weeks after surgery and were maintained for up to 2 years. Conclusion: These findings indicate adaptations of glucose sensing mechanisms and responses in multiple endocrine organs after RYGB, involving the gut, pancreatic islets, the pituitary gland, the adrenals, and the brain.

The influence of summer closure on serious postoperative complications in bariatric surgery.

INTRODUCTION: Bariatric surgery is an effective method of treating obesity, with gastric bypass and sleeve gastrectomy being the most common techniques used worldwide. Despite the technical challenges in these methods, little is known about the effects of summer closure on the incidence of serious postoperative complications in surgeries performed shortly after summer vacation. This has therefore been studied in our large cohort. MATERIALS AND METHODS: A retrospective cohort study based on data from the Scandinavian Obesity Surgery Registry was conducted. Patients who underwent a primary gastric bypass or sleeve gastrectomy operation between 2010 and 2019 were included. The rate of serious complications within 30 days after surgery for patients who underwent surgery the first month after summer closure was compared to those who underwent surgery during the rest of the year using the χ2 test and adjusted logistic regression. RESULTS: The study included 42,404 patients, 36,094 of whom underwent gastric bypass and 6310 of whom received sleeve gastrectomy. Summer closure was associated with an increased risk for serious postoperative complications in gastric bypass surgery (adjusted odds ratio (adj-OR) = 1.17; 95% confidence interval (CI): 1.01-1.36). No statistically significant association was seen for sleeve gastrectomy (adj-OR = 1.17; 95% CI: 0.72-1.91), nor in overall complication rate. CONCLUSIONS: Summer closure increases the risk of serious postoperative complications in gastric bypass surgery. No statistically significant association was found for sleeve gastrectomy surgery.