Long-Term Follow-up and Risk of Recurrence of Internal Herniation after Roux-en-Y Gastric Bypass.

PURPOSE: Internal herniation (IH) is the most common complication after Roux-en-Y gastric bypass surgery (RYGB). Although primary closure has reduced the incidence, recurrences are a continued problem. This study aimed to investigate long-term follow-up and recurrence risk of IH surgery. METHODS: A retrospective cohort study of laparoscopic RYGB operated patients operated for a first IH between April 2012 and April 2015 at Skåne University Hospital in Malmö, Sweden. Status of primary closure of mesenteric gaps, time since RYGB, and findings at IH surgery were retrieved from medical records. Follow-up until December 31st, 2019, included recurrences of IH, number of computed tomography (CT) scans, emergency visits, readmissions, and other acute surgeries. RESULTS: IH (n = 44) occurred almost equally in Petersen's space (n = 24) and beneath the jejunojejunostomy (n = 20). Long-term follow-up (median 75 months) of 43 patients registered an IH recurrence rate of 14% (n = 6). All recurrences occurred in the other mesenteric gap. One patient suffered a third IH, and one patient had four IH events. During follow-up, 56% (n = 24) had ER visits for abdominal pain, 47% (n = 20) had ≥ 1 abdominal CT scan, and 40% (n = 17) were readmitted. A third of readmitted (6/17) patients suffered a recurrence of internal herniation. Two other patients were readmitted ≥ 10 times for chronic abdominal pain. CONCLUSION: Surgery for IH had a low risk of recurrence at the treated mesenteric gap, but a 14% recurrence risk at the other mesenteric gap, emphasizing the importance of carefully investigating weaknesses or gaps at the other mesenteric defect during surgery for IH.

Visuospatial ability is associated to 2D laparoscopic simulator performance amongst surgical residents.

Background: The technical skills of a surgeon influence surgical outcome. Testing technical aptitude at point of recruitment of surgical residents is only conducted in a few countries. This study investigated the impact of visuospatial ability (VSA), background factors, and manual dexterity on performance in two different laparoscopic surgical simulators amongst applicants and 1st year surgical residents. Method: Applicants from general surgery, pediatric surgery, and urology were included from seven hospitals in Sweden between 2017 and 2021. Some 73 applicants were invited and 50 completed. Participants filled out a background form, and were tested for manual dexterity, and visuospatial ability. Two laparoscopic simulators were used, one 2D video box trainer and one 3D Virtual Reality Simulator. Results: A significant association was found between the visuospatial ability test and 2D video box laparoscopic performance (95 % CI: 1.028-1.2, p-value <0.01). For every point on the visuospatial test the odds of accomplishing the task increased by 11 %. No association was found between VSA and performance in a laparoscopic VR simulator using 3D vision. No other background factors were associated with performance in the two laparoscopic simulators. Conclusion: Visuospatial ability in applicants to surgical residency positions is associated to performance in a 2D video box trainer. Knowledge of a resident's visuospatial ability can be used to tailor individualized laparoscopic training programs, and in the future might function as a selection tool concerning laparoscopic ability. Key message: Visuospatial ability differs greatly amongst applicants for surgical residency and is associated to laparoscopic simulator performance. Testing applicants' visuospatial ability could possibly be used to tailor individualized laparoscopic training programs or in the future as a selection tool concerning laparoscopic ability.

Intussusception After Roux-en-Y Gastric Bypass: Correlation Between Radiological and Operative Findings.

INTRODUCTION: Intussusceptions diagnosed on computed tomography (CT) scans in Roux-en-Y gastric bypass (RYGB) patients could cause serious small bowel obstruction (SBO) or be an incidental finding. The objective of this study was to correlate radiological findings with clinical outcomes to differentiate intussusceptions requiring emergent surgery for SBO. METHODS: A search for acute abdominal CT scans reporting intussusceptions in RYGB patients between 2012 and 2019 at Skåne University Hospital, Malmö, Sweden, retrieved 35 scans. These were independently reevaluated by two radiologists for the length and location of the intussusception, whether oral contrast passed through, proximal bowel dilatation, and signs of internal herniation. Clinical outcome in terms of emergency surgery and the diagnosis was determined through chart review. RESULTS: Out of 35 acute patients, 9 patients required emergency surgery within 24 h. Intussusception caused SBO in five patients, and one patient had an internal herniation, while three patients had unremarkable findings. Eight patients were evaluated for intermittent pain with five unremarkable laparoscopies, while 18 patients had intussusceptions as incidental findings. Intussusception length on CT as measured by radiologists O.E. and D.L. predicted acute bowel obstruction (p = .014 and p < .001). A 100 mm threshold predicted bowel obstruction with a sensitivity of 80% and 100% and a specificity of 93% and 86% by radiologists O.E. and D.L., respectively. Proximal bowel dilatation predicted SBOs of any cause as well as SBO caused by an intussusception (all p < .05). CONCLUSION: Intussusception length > 100 mm on CT in RYGB patients is an easy and valuable sign indicating SBO that may require emergent surgery.

The role of citrulline, intestinal fatty acid-binding protein, and D-dimer as potential biomarkers in the diagnosis of internal herniation after Roux-en-Y gastric bypass.

BACKGROUND: Diagnosing internal herniation (IH) in Roux-en-Y gastric bypass (RYGB) patients with acute abdominal pain poses a diagnostic challenge. Diagnostic laparoscopy is often required for a definitive diagnosis. We hypothesized that intestinal ischemia biomarkers would aid in the diagnosing of IH. OBJECTIVES: To explore intestinal ischemia biomarkers in diagnosing IH. SETTING: University Hospital, Sweden. METHODS: Prospective inclusion of 46 RYGB patients admitted for acute abdominal pain between June 2015 and December 2017. Blood samples for analysis of citrulline, intestinal fatty acid-binding protein (I-FABP), and D-dimer were drawn <72 hours from admission and compared between patients with IH (n = 8), small bowel obstruction (SBO) (n = 5), other specified diagnoses (n = 12), or unspecified abdominal pain (n = 21). Levels of white blood cell count (WBC), C-reactive protein (CRP), and lactate at admission were compared. A prospective pain questionnaire for time of pain onset and level of pain at onset and at admission was analyzed. RESULTS: None of the investigated biomarkers differed significantly between diagnosis categories. Most patients with IH had normal CRP, WBC, and D-dimer levels while their lactate levels were significantly lower (P = .029) compared with the rest of the cohort. Neither pain level nor pain duration differed between the groups. CONCLUSION: This study shows that citrulline, I-FABP, and D-dimer cannot be used to diagnose IH and indicates that CRP, D-dimer, and lactate are rarely elevated by an IH. Furthermore, pain intensity and duration cannot differentiate patients with IH. A diagnostic laparoscopy remains the gold standard to diagnose and rule out an IH.

Differences in Health-Related Quality of Life After Gastric Bypass Surgery: a Cross-Sectional Study.

BACKGROUND: Gastric bypass (GBP) is a surgical method with good evidence of sustainable weight loss, reduced obesity-related comorbidities, and improved health-related quality of life (HRQoL). However, long-term data post-GBP is scarce on HRQoL related to other factors than weight loss, such as impact of socio-economic, age, and gender. AIM: To investigate long-term HRQoL in GBP patients. METHODS: The study was conducted as a cross-sectional study covering 3 to 9 years post-GBP measuring HRQoL using RAND-36. Association to weight loss, time since surgery, gender, educational level, occupation, and age was analyzed. The participants were included on the basis that they had received a GBP that was performed by Region Skåne, the southernmost administrative healthcare region in Sweden. Recruitment to the study was by mail invitation for an online survey. RESULTS: Of the total population of 5310 persons receiving the questionnaire, 1339 of the 1372 responders fulfilled the inclusion criteria. Those with low educational level, unemployed, persons on sick leave or disability support, and those with less weight loss reported the lowest HRQoL. The longer time since surgery, the lower the HRQoL. CONCLUSION: Less weight loss, longer time since GBP, lower educational level, and lower degree of employment all affect HRQoL negatively after GBP surgery.

Abdominal pain after gastric bypass in the acute general surgical care setting.

BACKGROUND: Managing acute abdominal pain in the large and growing population of Roux-en-Y gastric bypass (RYGB)-operated patients poses a challenge to general surgeons, because of diagnostic limitations and the risk of internal herniation. OBJECTIVE: To investigate the diagnoses, management, and outcome of RYGB patients admitted for acute abdominal pain. SETTING: University Hospital, Sweden. METHODS: Prospective inclusion of 280 consecutive RYGB patients admitted for acute abdominal pain between April 2012 and June 2015. Readmissions, surgical procedures, and overall mortality were recorded until October 2018. Medical records were retrospectively reviewed for anthropometric measures, medical history, time from RYGB surgery, and previous closure of mesenteric gaps. Admissions were separated into early (≤30 d) or late (>30 d) after RYGB. Procedures performed were categorized as follows: RYGB complication, other surgery, or unremarkable laparoscopy. Patients discharged with diagnosis of unspecified abdominal pain were separately analyzed. Diagnostic investigations, bariatric competency, on call surgery, surgical complications, and length of stay were registered. RESULTS: In late admissions, the cause of the abdominal complaints remained unexplained in 127 of 262 (48%) patients despite 95 abdominal computed tomographies and 28 diagnostic laparoscopies. Emergency surgery was performed in 128 of 262 (49%) patients. RYGB complications (n = 66), mainly internal herniation (n = 42), were >2 times more frequent than other surgical procedures (n = 32), such as cholecystectomies (n = 23). Internal herniation could occur at any time interval from RYGB surgery and regardless of previously closed mesenteric gaps. CONCLUSION: Better tools for evaluation of acute abdominal pain in RYGB patients are needed to reduce the number of unremarkable laparoscopies and admissions of patients with unspecified abdominal pain.

Cholecystectomy After Previous Bariatric Surgery with Special Focus on Pregnant Patients-Results from Two Large Nationwide Registries.

BACKGROUND: Biliary complications during pregnancy is an important issue. The aim of this study was to examine if there is an increased risk to perform cholecystectomy during pregnancy in patients with previous bariatric surgery in comparison to other females subjected to cholecystectomy. METHODS: The Nationwide Swedish Registry for Gallstone Surgery (GallRiks) and the Scandinavian Obesity Surgery Registry (SOReg) were combined. Female patients 18-45 years old were included. The study group was patients with a history of bariatric surgery whom were pregnant at the time of cholecystectomy. This group was compared with pregnant patients without previous bariatric surgery and non-pregnant with and without previous bariatric surgery. RESULTS: In total, 21,314 patients were included and 292 underwent surgery during pregnancy. From 1282 patients identified in both registers, 16 patients were pregnant at the time of cholecystectomy. Acute cholecystectomy was performed in 5922 (28%) non-pregnant and 199 (68%) pregnant (p < 0.001), including 11/16 (69%) pregnant with previous bariatric surgery. When comparing all pregnant patients, those with previous bariatric surgery had longer operative time (p = 0.031) and length of stay (p = 0.043), but no differences were seen when only comparing patients with an acute indication for surgery. There was no difference in complications comparing pregnant patients with previous bariatric surgery with non-pregnant, both with and without previous bariatric surgery. CONCLUSIONS: Cholecystectomy during pregnancy in patients with previous bariatric surgery seems to be safe. The increased risk seen in the non-pregnant group after previous bariatric surgery is not seen in pregnancy, possibly due to an optimization of the circumstances at surgery.

Performance and perception of haptic feedback in a laparoscopic 3D virtual reality simulator.

Background: The benefit of haptic feedback in laparoscopic virtual reality simulators (VRS) is ambiguous. A previous study found 32% faster acquisition of skills with the combination of 3 D and haptic feedback compared to 2 D only. This study aimed to validate perception and effect on performance of haptic feedback by experienced surgeons in the previously tested VRS. Material and methods: A randomized single blinded cross-over study with laparoscopists (>100 laparoscopic procedures) was conducted in a VRS with 3 D imaging. One group started with haptic feedback, and the other group without. After performing the suturing task with haptics either enabled or disabled, the groups crossed over to the opposite setting. Face validity was assessed through questionnaires. Metrics were obtained from the VRS. Results: The haptics for 'handling the needle', 'needle through tissue' and 'tying the knot' was scored as completely realistic by 3/22, 1/22 and 2/22 respectively. Comparing the metrics for maximum stretch damage between the groups revealed a significantly lower score when a group performed with haptics enabled p = .027 (haptic first group) and p < .001(haptic last group). Conclusion: Haptic feedback in VRS has limited fidelity according to the tested laparoscopic surgeons. In spite of this, significantly less stretch damage was caused with haptics enabled.

Insulin induces Thr484 phosphorylation and stabilization of SIK2 in adipocytes.

AIMS/HYPOTHESIS: Salt-inducible kinase 2 (SIK2) is downregulated in adipose tissue from obese or insulin-resistant individuals and inhibition of SIK isoforms results in reduced glucose uptake and insulin signalling in adipocytes. However, the regulation of SIK2 itself in response to insulin in adipocytes has not been studied in detail. The aim of our work was to investigate effects of insulin on various aspects of SIK2 function in adipocytes. METHODS: Primary adipocytes were isolated from human subcutaneous and rat epididymal adipose tissue. Insulin-induced phosphorylation of SIK2 and HDAC4 was analyzed using phosphospecific antibodies and changes in the catalytic activity of SIK2 with in vitro kinase assay. SIK2 protein levels were analyzed in primary adipocytes treated with the proteasome inhibitor MG132. RESULTS: We have identified a novel regulatory pathway of SIK2 in adipocytes, which involves insulin-induced phosphorylation at Thr484. This phosphorylation is impaired in individuals with a reduced insulin action. Insulin stimulation does not affect SIK2 catalytic activity or cellular activity towards HDAC4, but is associated with increased SIK2 protein levels in adipocytes. CONCLUSION/INTERPRETATION: Our data suggest that downregulation of SIK2 in the adipose tissue of insulin-resistant individuals can partially be caused by impaired insulin signalling, which might result in defects in SIK2 expression and function.

AMPK activation by A-769662 and 991 does not affect catecholamine-induced lipolysis in human adipocytes.

Activation of AMP-activated protein kinase (AMPK) is considered an attractive strategy for the treatment of type 2 diabetes. Favorable metabolic effects of AMPK activation are mainly observed in skeletal muscle and liver tissue, whereas the effects in human adipose tissue are only poorly understood. Previous studies, which largely employed the AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranoside (AICAR), suggest an antilipolytic role of AMPK in adipocytes. The aim of this work was to reinvestigate the role of AMPK in the regulation of lipolysis, using the novel allosteric small-molecule AMPK activators A-769662 and 991, with a focus on human adipocytes. For this purpose, human primary subcutaneous adipocytes were treated with A-769662, 991, or AICAR, as a control, before being stimulated with isoproterenol. AMPK activity status, glycerol release, and the phosphorylation of hormone-sensitive lipase (HSL), a key regulator of lipolysis, were then monitored. Our results show that both A-769662 and 991 activated AMPK to a level that was similar to, or greater than, that induced by AICAR. In contrast to AICAR, which as expected was antilipolytic, neither A-769662 nor 991 affected lipolysis in human adipocytes, although 991 treatment led to altered HSL phosphorylation. Furthermore, we suggest that HSL Ser660 is an important regulator of lipolytic activity in human adipocytes. These data suggest that the antilipolytic effect observed with AICAR in previous studies is, at least to some extent, AMPK independent.

Faster acquisition of laparoscopic skills in virtual reality with haptic feedback and 3D vision.

BACKGROUND: The study investigated whether 3D vision and haptic feedback in combination in a virtual reality environment leads to more efficient learning of laparoscopic skills in novices. MATERIAL AND METHODS: Twenty novices were allocated to two groups. All completed a training course in the LapSim® virtual reality trainer consisting of four tasks: 'instrument navigation', 'grasping', 'fine dissection' and 'suturing'. The study group performed with haptic feedback and 3D vision and the control group without. Before and after the LapSim® course, the participants' metrics were recorded when tying a laparoscopic knot in the 2D video box trainer Simball® Box. RESULTS: The study group completed the training course in 146 (100-291) minutes compared to 215 (175-489) minutes in the control group (p = .002). The number of attempts to reach proficiency was significantly lower. The study group had significantly faster learning of skills in three out of four individual tasks; instrument navigation, grasping and suturing. Using the Simball® Box, no difference in laparoscopic knot tying after the LapSim® course was noted when comparing the groups. CONCLUSIONS: Laparoscopic training in virtual reality with 3D vision and haptic feedback made training more time efficient and did not negatively affect later video box-performance in 2D. [Formula: see text].

Gastric bypass in the pig increases GIP levels and decreases active GLP-1 levels.

Gastric bypass surgery results in remission of type 2 diabetes in the majority of patients. The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been implicated in the observed remission. Most knowledge so far has been generated in obese subjects. To isolate the surgical effects of gastric bypass on metabolism and hormone responses from the confounding influence of obesity, T2D, or food intake, we performed gastric bypass in lean pigs, using sham-operated and pair-fed pigs as controls. Thus, pigs were subjected to Roux-en-Y gastric bypass (RYGB) or sham surgery and oral glucose tolerance tests (OGTT). RYGB pigs and sham pigs exhibited similar basal and 120-min glucose levels in response to the OGTT. However, RYGB pigs had approximately 1.6-fold higher 30-min glucose (p<0.01). Early insulin release (EIR) was enhanced approximately 3.5-fold in the RYGB pigs (p<0.01). Furthermore, GIP release, both acute and sustained release (p<0.001 and p<0.01, respectively), was increased approximately 2.5-fold and 1.4-fold, respectively, in RYGB pigs. Although total GLP-1 release increased approximately 2.1-fold after RYGB (p<0.001), active GLP-1 was 33% lower (p<0.01). Interestingly basal DPP4-activity was approximately 3.2-fold higher in RYGB pigs (p<0.001). In conclusion, RYGB in lean pigs increases the response of GIP, total GLP-1, and insulin, but reduces levels of active GLP-1 in response to an oral glucose load. These data challenge the role of active GLP-1 as a contributor to remission from diabetes after RYGB.

The impact of Roux-en-Y gastric bypass surgery on normal metabolism in a porcine model.

BACKGROUND: A growing body of literature on Roux-en-Y gastric bypass surgery (RYGB) has generated inconclusive results on the mechanism underlying the beneficial effects on weight loss and glycaemia, partially due to the problems of designing clinical studies with the appropriate controls. Moreover, RYGB is only performed in obese individuals, in whom metabolism is perturbed and not completely understood. METHODS: In an attempt to isolate the effects of RYGB and its effects on normal metabolism, we investigated the effect of RYGB in lean pigs, using sham-operated pair-fed pigs as controls. Two weeks post-surgery, pigs were subjected to an intravenous glucose tolerance test (IVGTT) and circulating metabolites, hormones and lipids measured. Bile acid composition was profiled after extraction from blood, faeces and the gallbladder. RESULTS: A similar weight development in both groups of pigs validated our experimental model. Despite similar changes in fasting insulin, RYGB-pigs had lower fasting glucose levels. During an IVGTT RYGB-pigs had higher insulin and lower glucose levels. VLDL and IDL were lower in RYGB- than in sham-pigs. RYGB-pigs had increased levels of most amino acids, including branched-chain amino acids, but these were more efficiently suppressed by glucose. Levels of bile acids in the gallbladder were higher, whereas plasma and faecal bile acid levels were lower in RYGB- than in sham-pigs. CONCLUSION: In a lean model RYGB caused lower plasma lipid and bile acid levels, which were compensated for by increased plasma amino acids, suggesting a switch from lipid to protein metabolism during fasting in the immediate postoperative period.

Salt-inducible kinase 2 and -3 are downregulated in adipose tissue from obese or insulin-resistant individuals: implications for insulin signalling and glucose uptake in human adipocytes.

AIMS/HYPOTHESIS: Salt-inducible kinases (SIKs) are related to the metabolic regulator AMP-activated protein kinase (AMPK). SIK2 is abundant in adipose tissue. The aims of this study were to investigate the expression of SIKs in relation to human obesity and insulin resistance, and to evaluate whether changes in the expression of SIKs might play a causal role in the development of disturbed glucose uptake in human adipocytes. METHODS: SIK mRNA and protein was determined in human adipose tissue or adipocytes, and correlated to clinical variables. SIK2 and SIK3 expression and phosphorylation were analysed in adipocytes treated with TNF-α. Glucose uptake, GLUT protein levels and localisation, phosphorylation of protein kinase B (PKB/Akt) and the SIK substrate histone deacetylase 4 (HDAC4) were analysed after the SIKs had been silenced using small interfering RNA (siRNA) or inhibited using a pan-SIK-inhibitor (HG-9-91-01). RESULTS: We demonstrate that SIK2 and SIK3 mRNA are downregulated in adipose tissue from obese individuals and that the expression is regulated by weight change. SIK2 is also negatively associated with in vivo insulin resistance (HOMA-IR), independently of BMI and age. Moreover, SIK2 protein levels and specific kinase activity display a negative correlation to BMI in human adipocytes. Furthermore, SIK2 and SIK3 are downregulated by TNF-α in adipocytes. Silencing or inhibiting SIK1-3 in adipocytes results in reduced phosphorylation of HDAC4 and PKB/Akt, less GLUT4 at the plasma membrane, and lower basal and insulin-stimulated glucose uptake in adipocytes. CONCLUSION/INTERPRETATION: This is the first study to describe the expression and function of SIKs in human adipocytes. Our data suggest that SIKs might be protective in the development of obesity-induced insulin resistance, with implications for future treatment strategies.

Simball Box for Laparoscopic Training With Advanced 4D Motion Analysis of Skills.

Background Laparoscopic skills training and evaluation outside the operating room is important for all surgeons learning new skills. To study feasibility, a video box trainer tracking 4-dimensional (4D) metrics was evaluated as a laparoscopic training tool. Method Simball Box is a video box trainer with authentic surgical instruments and camera with video recording, equipped with 4D motion analysis registered through trocars using machine vision technology. Residents attending a 3-day laparoscopy course were evaluated performing a laparoscopic surgical knot at start, middle, and end. Metrics were obtained. Feedback data were presented in reference to expert/tutorial performance. Results Ten right-handed residents were included. Median time (range) to finish the task was 359 (253-418), 129 (95-166), and 95 (52-156) seconds; 655%, 236%, and 174% of tutorial performance, with significance pre-/midcourse (P < .0001), pre-/postcourse (P < .0001), and mid-/postcourse (P = .0050). Combined median total instrument motion decreased pre-/midcourse from 1208 (845-1751) to 522 cm (411-810 cm); P = .042 to 405 cm (246-864 cm) postcourse; pre-/postcourse P < .0001; 673%, 291%, 225% of tutorial performance. Total angular distance in radians (range) was 150 (87-251), 65 (42-116), and 50 (33-136) with significance pre-/midcourse (P = .022) and pre-/postcourse (P = .0002). Right-handed average speed (cm/s) increased: 1.94 (1.11-2.27) pre-, 2.39 (1.56-2.83) mid-, 2.60 (1.67-3.19) postcourse with significance pre-/midcourse (P = .022) and pre-/postcourse (P = .002). Average acceleration (mm/s(2)) and motion smoothness (µm/s(3)) failed to show any difference. Conclusion For laparoscopic training and as a promising evaluation device, Simball Box obtained metrics mirroring progression well.

Mesenteric Torsion as a Cause of Late Abdominal Pain after Gastric Bypass Surgery.

Gastric bypass (GBP) has been the most common surgical way to treat obesity and its comorbidities. Late abdominal pain may occur by gastro-jejunal ulcers, gallstones, internal herniation or, rarely, intussusception. In an area with more than 1000 GBPs performed yearly, three patients with primary small bowel volvulus causing abdominal pain and requiring emergency or semi-urgent surgery were identified. Patients' histories, radiology, and surgery performed are presented. Weight loss followed by mesenteric narrowing of the root and thus relative elongation may make rotation of the small bowel mesentery possible. Such a torsion might be an overlooked differential diagnosis in obscure abdominal pain after GBP.

Mucosal glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide cell numbers in the super-obese human foregut after gastric bypass.

BACKGROUND: Super-obesity, a body mass index>50 kg/m(2), is difficult to treat. Many studies have focused on the anatomic changes of the intestines; the physiologic background is not clearly identified. It is established that Roux-en-Y gastric bypass (RYGB) augments secretion of glucagon-like peptide-1 (GLP-1), peptide tyrosine tyrosine (PYY), and insulin, but other aspects of gut hormone cell function in the alimentary limb are unknown. OBJECTIVE: To study the effects of laparoscopic RYGB on enteroendocrine cells. SETTING: University-affiliated, high-volume bariatric surgery center. METHODS: Eighteen nondiabetic patients were drawn from the present study (NCT 01514799), randomizing between biliopancreatic (BP) limbs of either 60 cm (BP60) or 200 cm (BP200). Demographic characteristics did not differ at baseline or 12 months. Pouch and jejunal biopsies were obtained intraoperatively and using endoscopy at 12 months. Mucosal height and density of hormone-producing cell populations were assessed and mRNA expression measured with real-time polymerase chain reaction. RESULTS: In perianastomotic jejunum, a 4.9-fold increase in GLP-1 cell density was evident 12 months after RYGB, most pronounced in the BP200-group. The densities of glucose-dependent insulinotropic polypeptide (GIP) cells and PYY immunoreactive cells were doubled after 12 months. GIP mRNA was unaffected, but GLP-1 and PYY mRNA were lower 12 months after RYGB. RYGB had no impact on villi length or density of ghrelin-, cholecystokinin-, neurotensin-, secretin-, or serotonin-producing cells after 12 months. Pouch mucosal height and cell densities of ghrelin-, histamine-, serotonin-, and somatostatin-producing cells remained unaffected by RYGB in both groups. CONCLUSIONS: RYGB selectively increased the density of incretin-producing cell populations in the jejunum. This may provide anatomic explanation for the observed increased plasma levels of incretins.

SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes.

Salt-inducible kinase 2 (SIK2) is an AMP-activated protein kinase (AMPK) related kinase abundantly expressed in adipose tissue. Our aim was to identify molecular targets and functions of SIK2 in adipocytes, and to address the role of PKA-mediated phosphorylation of SIK2 on Ser358. Modulation of SIK2 in adipocytes resulted in altered phosphorylation of CREB-regulated transcription co-activator 2 (CRTC2), CRTC3 and class IIa histone deacetylase 4 (HDAC4). Furthermore, CRTC2, CRTC3, HDAC4 and protein phosphatase 2A (PP2A) interacted with SIK2, and the binding of CRTCs and PP2A to wild-type but not Ser358Ala SIK2, was reduced by cAMP elevation. Silencing of SIK2 resulted in reduced GLUT4 (also known as SLC2A4) protein levels, whereas cells treated with CRTC2 or HDAC4 siRNA displayed increased levels of GLUT4. Overexpression or pharmacological inhibition of SIK2 resulted in increased and decreased glucose uptake, respectively. We also describe a SIK2­CRTC2­HDAC4 pathway and its regulation in human adipocytes, strengthening the physiological relevance of our findings. Collectively, we demonstrate that SIK2 acts directly on CRTC2, CRTC3 and HDAC4, and that the cAMP­PKA pathway reduces the interaction of SIK2 with CRTCs and PP2A. Downstream, SIK2 increases GLUT4 levels and glucose uptake in adipocytes.

Short- and long-term hormonal and metabolic consequences of reversing gastric bypass to normal anatomy in a type 2 diabetes patient.

Gastric bypass (GBP) results in rapid type 2 diabetes (T2D) remission in most cases. Consequences of GBP reversal are unknown. A GBP-operated T2D patient was given mixed-meal tests before (MMTpre), 2 months (MMT2-M) and 12 months (MMT12-M) after GBP reversal. Glucose, hormones and metabolite profiles were assessed. MMT2-M displayed slightly lower glucose levels; MMT12-M displayed higher glucose and insulin levels, indicating deteriorating glycaemia. Homeostasis model assessment (HOMA)-ß was higher at MMT2-M, but reduced at MMT12-M. Matsuda index revealed slightly reduced insulin sensitivity at MMT2-M, which deteriorated further at MMT12-M. Markers for metabolic stress and insulin resistance were elevated at MMT12-M. Gastric inhibitory polypeptide (GIP) levels were increased at MMT2-M and decreased at MMT12-M. Glucagon-like peptide-1 (GLP-1) decreased at MMT2-M and further decreased at MMT12-M. In conclusion, in this patient, GBP reversal provoked deteriorating glycaemia and long-term development of insulin resistance.