Gut Mucosal Gene Expression and Metabolic Changes After Roux-en-Y Gastric Bypass Surgery.

OBJECTIVE: Changes in the secretion of gut-derived peptide hormones have been associated with the metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. In this study, the effects of RYGB on anthropometrics, postprandial plasma hormone responses, and mRNA expression in small intestinal mucosa biopsy specimens before and after RYGB were evaluated. METHODS: In a cross-sectional study, 20 individuals with obesity undergoing RYGB underwent mixed meal tests and upper enteroscopy with retrieval of small intestinal mucosa biopsy specimens 3 months before and after surgery. Concentrations of circulating gut and pancreatic hormones during mixed meal tests as well as full mRNA sequencing of biopsy specimens were evaluated. RESULTS: RYGB-induced improvements of body weight and composition, insulin resistance, and circulating cholesterols were accompanied by significant changes in postprandial plasma responses of pancreatic and gut hormones. Global gene expression analysis of biopsy specimens identified 2,437 differentially expressed genes after RYGB, including changes in genes that encode prohormones and G protein-coupled receptors. CONCLUSIONS: RYGB affects the transcription of a wide range of genes, indicating that the observed beneficial metabolic effects of RYGB may rely on a changed expression of several genes in the gut. RYGB-induced changes in the expression of genes encoding signaling peptides and G protein-coupled receptors may disclose new gut-derived treatment targets against obesity and diabetes.

Investigating Intestinal Glucagon After Roux-en-Y Gastric Bypass Surgery.

CONTEXT: After Roux-en-Y gastric bypass (RYGB) surgery, postprandial plasma glucagon concentrations have been reported to increase. This occurs despite concomitant improved glucose tolerance and increased circulating plasma concentrations of insulin and the glucagon-inhibiting hormone glucagon-like peptide 1 (GLP-1). OBJECTIVE: To investigate whether RYGB-induced hyperglucagonemia may be derived from the gut. DESIGN AND SETTING: Substudy of a prospective cross-sectional study at a university hospital in Copenhagen, Denmark. PARTICIPANTS: Morbidly obese individuals undergoing RYGB (n = 8) with or without type 2 diabetes. INTERVENTIONS: Three months before and after RYGB, participants underwent upper enteroscopy with retrieval of gastrointestinal mucosal biopsy specimens. Mixed-meal tests were performed 1 week and 3 months before and after RYGB. MAIN OUTCOME MEASURES: The 29-amino acid glucagon concentrations in plasma and in mucosal gastrointestinal biopsy specimens were assessed using mass spectrometry-validated immunoassays, and a new monoclonal antibody reacting with immunoreactive glucagon was used for immunohistochemistry. RESULTS: Postprandial plasma concentrations of glucagon after RYGB were increased. Expression of the glucagon gene in the small intestine increased after surgery. Glucagon was identified in the small-intestine biopsy specimens obtained after, but not before, RYGB. Immunohistochemically, mucosal biopsy specimens from the small intestine harbored cells costained for GLP-1 and immunoreactive glucagon. CONCLUSION: Increased concentrations of glucagon were observed in small-intestine biopsy specimens and postprandially in plasma after RYGB. The small intestine harbored cells immunohistochemically costaining for GLP-1 and glucagon-like immunoreactivity after RYGB. Glucagon derived from small-intestine enteroendocrine l cells may contribute to postprandial plasma concentrations of glucagon after RYGB.

Guanylin and uroguanylin mRNA expression is increased following Roux-en-Y gastric bypass, but guanylins do not play a significant role in body weight regulation and glycemic control.

AIM: To determine whether intestinal expression of guanylate cyclase activator 2A (GUCA2A) and guanylate cyclase activator 2B (GUCA2B) genes is regulated in obese humans following Roux-en-Y gastric bypass (RYGB), and to evaluate the corresponding guanylin (GN) and uroguanylin (UGN) peptides for potentially contributing to the beneficial metabolic effects of RYGB. METHODS: Enteroendocrine cells were harvested peri- and post-RYGB, and GUCA2A/GUCA2B mRNA expression was compared. GN, UGN and their prohormones (proGN, proUGN) were administered subcutaneously in normal-weight mice to evaluate effects on food intake and glucose regulation. The effect of pro-UGN or UGN overexpression, using adeno-associated virus (AAV) vectors, was assessed in diet-induced obese (DIO) mice. Intracerebroventricular administration of GN and UGN was performed in rats for assessment of putative centrally mediated effects on food intake. GN and UGN, as well as their prohormones, were evaluated for effects on glucose-stimulated insulin secretion (GSIS) in rat pancreatic islets and perfused rat pancreas. RESULTS: GUCA2A and GUCA2B mRNA expression was significantly upregulated in enteroendocrine cells after RYGB. Peripheral administration of guanylins or prohormones did not influence food intake, oral glucose tolerance, and GSIS. Central administration of GN and UGN did not affect food intake in rats. Chronic AVV-mediated overexpression of UGN and proUGN had no effect on body weight or glucose homeostasis in DIO mice. CONCLUSION: GN and UGN, as well as their prohormones, do not seem to play a significant role in body weight regulation and glycemic control, suggesting that guanylin-family peptides do not show promise as targets for the treatment of obesity or diabetes.

The impact of EndoBarrier gastrointestinal liner in obese patients with normal glucose tolerance and in patients with type 2 diabetes.

AIMS: The duodenal-jejunal bypass sleeve ((DJBS) or EndoBarrier Gastrointestinal Liner) induces weight loss in obese subjects and may improve glucose homeostasis in patients with type 2 diabetes (T2D). To explore the underlying mechanisms, we evaluated postprandial physiology including glucose metabolism, gut hormone secretion, gallbladder emptying, appetite and food intake in patients undergoing DJBS treatment. MATERIAL AND METHODS: A total of 10 normal glucose-tolerant (NGT) obese subjects and 9 age-, body weight- and body mass index-matched metformin-treated T2D patients underwent a liquid mixed meal test and a subsequent ad libitum meal test before implantation with DJBS and 1 week (1w) and 26 weeks (26w) after implantation. RESULTS: At 26w, both groups had achieved a weight loss of 6 to 7 kg. Postprandial glucagon-like peptide-1 (GLP-1) and peptide YY responses increased at 1w and 26w, but only in T2D subjects. In contrast, glucose-dependent insulinotropic polypeptide responses were reduced only by DJBS in the NGT group. Postprandial glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin responses were unaffected by DJBS in both groups. Satiety and fullness sensations were stronger and food intake was reduced at 1w in NGT subjects; no changes in appetite measures or food intake were observed in the T2D group. No effect of DJBS on postprandial gallbladder emptying was observed, and gastric emptying was not delayed. CONCLUSIONS: DJBS-induced weight loss was associated with only marginal changes in postprandial physiology, which may explain the absence of effect on postprandial glucose metabolism.

[Cyclic vomiting and abdominal pain from prolonged cannabis use]. / Cykliska kräkningar och buksmärta av långvarig cannabisanvändning - Cannabisrelaterat hyperemesissyndrom ¼ny« diagnos som lindras av varma duschar och bad.

A 19-year old female was admitted with intractable nausea, vomiting and intermittent abdominal pain. The medical history of the patient contained nine previous, similar admissions and extensive investigations within several medical specialties at several hospitals in the vicinity of Copenhagen, as well as abroad during the patient's holidays. All of the investigations were without findings that could explain the recurring condition. The patient reported chronic morning sickness, exacerbating with vomiting and abdominal pain every month since the age of 13. Especially during these exacerbations, the patient took frequent hot baths for symptom relief. Cannabinoid hyperemesis syndrome (CHS) was suspected and the patient admitted having used cannabis daily for the past seven years. She received parenteral rehydration and counseling regarding cannabis cessation. Two months after discharge the patient was no longer using cannabis and was symptom-free. This case report intends to raise clinicians' awareness of CHS in Sweden, a country where 55 000 of the inhabitants aged 16 years and older report having used cannabis during the past 30 day period.

Effect of Roux-en-Y gastric bypass on the distribution and hormone expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes.

AIMS/HYPOTHESIS: We studied the impact of Roux-en-Y gastric bypass (RYGB) on the density and hormonal gene expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes. METHODS: Twelve patients with diabetes and 11 age- and BMI-matched controls underwent RYGB followed by enteroscopy ~10 months later. Mucosal biopsies taken during surgery and enteroscopy were immunohistochemically stained for glucagon-like peptide-1 (GLP-1), peptide YY (PYY), cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and prohormone convertase 2 (PC2) and the expression of GCG (encoding preproglucagon), PYY, CCK, GIP, GHRL (encoding ghrelin), SCT (encoding secretin), NTS (encoding neurotensin) and NR1H4 (encoding farnesoid X receptor) was evaluated. RESULTS: The density of cells immunoreactive for GLP-1, CCK and GIP increased in patients after RYGB and the density of those immunoreactive for GLP-1, PYY, CCK and PC2 increased in controls. In both groups, GHRL, SCT and GIP mRNA was reduced after RYGB while PYY, CCK, NTS and NR1H4 gene expression was unaltered. GCG mRNA was upregulated in both groups. CONCLUSIONS/INTERPRETATION: Numerous alterations in the distribution of enteroendocrine cells and their expression of hormonal genes are seen after RYGB and include increased density of GLP-1-, PYY-, CCK-, GIP- and PC2-positive cells, reduced gene expression of GHRL, SCT and GIP and increased expression of GCG.

[Duodenal-jejunal bypass sleeve - a potential alternative to bariatric surgery?].

Overweight and obesity are risk factors for several co-morbidities reducing life expectancy. Conservative treatment of obesity is generally ineffective in the long-term. Bariatric surgery has proven effective, but is associated with potential complications. Duodenal-jejunal bypass sleeve is a novel minimal invasive and fully reversible endoscopic treatment modality approved for treatment of obesity with or without concomitant type 2 diabetes. Here we review present data for the efficacy and safety of this treatment modality.

Elevated liver enzymes, anaemia and osteopaenia in a young woman.

A 23-year-old woman presented with elevated liver enzymes, anaemia and lower limb oedema. Iron-deficiency anaemia due to gynaecological problems was suspected. The patient was treated with iron supplements normalising the blood haemoglobin. Alcohol binge drinking was suspected to be the cause of elevated liver enzymes. After 7 years, the patient presented to our outpatient clinic with non-specific gastrointestinal symptoms. Blood tests revealed low levels of serum s-iron and elevated liver function tests. Abdominal ultrasound was normal. No signs of viral hepatitis or hereditary liver disease were detected. There was a marked elevation of tissue transglutaminase antibodies. A small intestine biopsy confirmed the diagnosis of coeliac disease. A bone density scan showed osteopaenia. Following a gluten-free, lactose-reduced diet, the gastrointestinal symptoms disappeared and s-transaminase activity and s-iron levels normalised.

[Diagnostic strategy in patients with clinically suspected deep vein thrombosis]. / Diagnostisk strategi hos patienter, der er henvist til skadestuen på mistanke om dyb venøs trombose.

INTRODUCTION: The standard method for diagnosing deep vein thrombosis (DVT) involves determination of D-dimer and ultrasound scanning. In an attempt to reduce the number of ultrasound examinations we have supplemented this with a clinical probability estimate for DVT (DVT-score) over one year. MATERIALS AND METHODS: A total of 508 consecutive patients presenting in the emergency room with suspected DVT had D-dimer and DVT-score performed. Patients with non-elevated D-dimer and a low or moderate DVT score received no treatment. The remainder had ultrasound scanning from the groin to the popliteal fossa. If no DVT was revealed, the patient was contacted by telephone 7-10 days later, and was offered a repeat examination if symptoms persisted. RESULTS: Three patients with chronic DVT were excluded. Normal D-dimer and low or moderate DVT-score was found in 103 patients, none had DVT. Only five patients with normal D-dimer had high DVT-scores, none had DVT, so that the benefit from determining DVT-scores was modest. Ultrasound scanning revealed DVT in 85 out of 397 patients with elevated D-dimer. A repeat examination was performed in 91 patients with persisting symptoms, and disclosed DVT in two. CONCLUSION: We recommend that ambulatory patients with clinically suspected DVT have a D-dimer test. If D-dimer is elevated, compression ultrasound should be performed in the groin and the popliteal fossa.