CONTEXT:Intestinal glucose absorption is mediated by sodium-dependent glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2), which are linked to sweet taste receptor (STR) signaling and incretin responses.OBJECTIVE:This study aimed to examine intestinal glucose absorption in morbidly obese humans and its relationship to the expression of STR and glucose transporters, glycemia, and incretin responses.DESIGN/SETTING/PARTICIPANTS:Seventeen nondiabetic, morbidly obese subjects (body mass index [BMI], 48 ± 4 kg/m(2)) and 11 lean controls (BMI, 25 ± 1 kg/m(2)) underwent endoscopic duodenal biopsies before and after a 30-minute intraduodenal glucose infusion (30 g glucose and 3 g 3-O-methylglucose [3-OMG]).MAIN OUTCOME MEASURES:Blood glucose and plasma concentrations of 3-OMG, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), insulin, and glucagon were measured over 270 minutes. Expression of duodenal SGLT-1, GLUT2, and STR (T1R2) was quantified by PCR.RESULTS:The increase in plasma 3-OMG (P < .001) and blood glucose (P < .0001) were greater in obese than lean subjects. Plasma 3-OMG correlated directly with blood glucose (r = 0.78, P < .01). In response to intraduodenal glucose, plasma GIP (P < .001), glucagon (P < .001), and insulin (P < .001) were higher, but GLP-1 (P < .001) was less in the obese compared with lean. Expression of SGLT-1 (P = .035), but not GLUT2 or T1R2, was higher in the obese, and related to peak plasma 3-OMG (r = 0.60, P = .01), GIP (r = 0.67, P = .003), and insulin (r = 0.58, P = .02).CONCLUSIONS:In morbid obesity, proximal intestine glucose absorption is accelerated and related to increased SGLT-1 expression, leading to an incretin-glucagon profile promoting hyperinsulinemia and hyperglycemia. These findings are consistent with the concept that accelerated glucose absorption in the proximal gut underlies the foregut theory of obesity and type 2 diabetes.

A S L D A b st ra ct s score / year; p=0.42) and NAS score (1.71 vs 1.88 score / year; p=0.88) were higher among NASH recipients without significance while fibrosis score was significantly higher (0.43 vs 1 stage / year; p=0.0045) in ALD recipients. The incremental increase in the rate of fibrosis was faster in the first year compared to 4-5 years (0.8 vs 0.04 stage / year) following LT. This decreased in the rate of fibrosis progression at 4-5 years was significant among NASH recipients compared to ALD recipients (0.04 vs 0.33 stage /year; p=0.015) [Figure 1]. No single factor was associated with rate of fibrosis progression among NASH patients on multivariate analysis. Conclusion: NASH recurs following LT. The rate of fibrosis progression is slower among NASH recipients compared to ALD recipients despite increased steatosis and NASH features. This fibrosis progression is reduced in the subsequent years of LT nearing the pre-transplant rate of fibrosis progression with favorable outcome in NASH patients following LT.

182 Background: Current methods of pre-operative predicting outcome of pancreatic cancer and related pancreatectomy are limited. While several prognostic biomarkers, including S100A2 and S100A4, are associated with poor outcomes, these currently can only be assessed in operatively resected specimens. The amount of tissue from EUS guided fine needle aspirations is often insufficient for biomarker assessment. Procore needles aim to acquire larger volumes of tissue that may be suitable. We aim to (i) evaluate the feasibility of S100A2 and S100A4 assessment in EUS guided biopsy specimens using the Procore needle, and (ii) evaluate the relationship of these biomarkers with outcome. Methods: Clinico-pathological data from 79 patients (70 ± 2yrs; 44M:35F) with pancreatic ductal adenocarcinoma (PDAC) were prospectively acquired. All subjects had EUS guided biopsy with a 22G Procore needle and cell-block preparation was performed. Sections of cell-block material were assessed for S100A2 and S100A4 protein expression using immunohistochemistry. Results: Pre-operative biomarker assessments from EUS acquired specimens were possible in 90% (72/79) of patients, 14 of which then had pancreatectomy. Thirty-five (49%) of patients expressed S100A2 and S100A4, which were co-expressed in 97% of cases. Patients with S100A2/A4 tumours on EUS had a significantly shorter median survival (10.0 vs. 17.5 months, p=0.03). Among patients with S100A2/A4 expressing tumors, pancreatectomy (n=8) didn't lead to a survival benefit compared with those managed non-surgically (n=27) (12.5 vs. 10.0 months, p=0.70). Of patients who had pancreatectomy, those with S100A2/A4 expressing tumors (n=8) had shorter survival than those with S100A2/A4-negative tumors (n=6) (12.5 vs. 20.5 months; p = 0.04). Conclusions: Biomarker assessment from EUS guided biopsy specimens is feasible and successful in 90% of cases. The presence of S100A2 and S100A4 expression predicts both survival and response to pancreatectomy in patients with pancreatic cancer. These findings demonstrate a “proof-of-concept”, that pre-operative EUS guided biopsy could inform clinical decision-making, particularly with regard to selection for operative resection of PDAC.

Glucose absorption in the small intestine is mediated by sodium dependent glucose cotransporter 1 (SGLT-1) and glucose transporter-2 (GLUT2), and is potentially linked to sweet taste receptor (STR) signaling and incretin hormone secretion. Both glucose absorption and expression of SGLT-1 are increased in obese rats, but human data is lacking. This study aimed to examine intestinal glucose absorption inmorbidly obese humans, and its relationship to glycemia, incretin responses, SGLT-1, GLUT2, and STR expression. Methods: 17 nondiabetic, morbidly obese subjects (5M:12F; 45 ± 3yrs, BMI: 48 ± 4kg/m2) and 11 lean controls (10M:1F; 44 ± 6yrs, BMI: 25 ± 1kg/m2) underwent endoscopic duodenal biopsies prior to intraduodenal glucose infusion (30g glucose over 30 min, with 3g 3-O-methylglucose (3-OMG) to estimate glucose absorption). Blood glucose and plasma concentrations of 3OMG, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP1), insulin, and glucagon were measured over 240 min. Absolute expression of SGLT-1, GLUT2 and STR (T1R2) transcripts was quantified by PCR. Results: Both the rate of glucose absorption, as assessed by the rise in plasma 3-OMG concentrations (P<0.001) and blood glucose concentrations (P<0.0001) were substantially greater in obese than lean subjects (Fig AB Fig C), but not GLUT2 or T1R2, was higher in the obese than lean subjects, and was related to peaked plasma 3OMG (r=0.61, P=0.01). CONCLUSIONS: Glucose absorption in the proximal intestine is (i) accelerated in morbid obesity, (ii) associated with an incretin profile that potentially promotes both hyperinsulinemia and hyperglycemia, and (iii) associated with increased expression of SGLT-1. These novel findings suggest that accelerated glucose absorption in the proximal gutmay be the X-factor accounting for the foregut theory of obesity and diabetes.

OBJECTIVE:To determine the effect of Roux-en-Y gastric bypass (RYGB) on the expression of intestinal sweet taste receptors (STRs), glucose transporters (GTs), glucose absorption, and glycemia. METHODS:Intestinal biopsies were collected for mRNA expression of STR (T1R2) and GTs (SGLT-1 and GLUT2) from 11 non-diabetic RYGB, 13 non-diabetic obese, and 11 healthy subjects, at baseline and following a 30 min small intestinal (SI) glucose infusion (30 g/150 ml water with 3 g 3-O-methyl-d-glucopyranose (3-OMG)). Blood glucose, plasma 3-OMG, and insulin were measured for 270 min. RESULTS:In RYGB patients, expression of both GTs was ∼2-fold higher at baseline and after glucose infusion than those of morbidly obese or healthy subjects (P < 0.001). STR expressions were comparable amongst the groups. Peak plasma 3-OMG in both RYGB (r = 0.69, P = 0.01) and obese (r = 0.72, P = 0.005) correlated with baseline expression of SGLT-1, as was the case with peak blood glucose in RYGB subjects (r = 0.69, P = 0.02). CONCLUSIONS:The upregulated intestinal GTs in RYGB patients are associated with increased glucose absorption when glucose is delivered at a physiological rate, suggesting a molecular adaptation to prevent carbohydrate malabsorption from rapid intestinal transit after RYGB.

ObjectiveTo evaluate the effect of modulating pouch emptying (PE) and SI transit of glucose after Roux‐en‐Y gastric bypass (RYGB) on blood glucose, incretin hormones, glucose absorption and gastrointestinal (GI) symptoms.MethodsTen RYGB patients were studied twice in random order, receiving either a 150 ml glucose drink (200 kcal) or the same solution infused into the proximal Roux‐limb at 4 kcal/min. Data were compared with 10 healthy volunteers who received a 4 kcal/min duodenal infusion. PE, cecal arrival time (CAT), blood glucose, plasma 3‐O‐methylglucose (3‐OMG), insulin, glucose‐dependent insulinotropic polypeptide (GIP), and glucagon‐like peptide‐1 (GLP‐1), and GI symptoms were measured.ResultsIn RYGB subjects, the glucose drink emptied very rapidly (PE t50 = 3 ± 1 min) and intestinal glucose infusion was associated with higher blood glucose and plasma 3‐OMG, but lower plasma GLP‐1, GIP, insulin, and GI symptoms than oral glucose (all P < 0.001), and comparable to volunteers. In RYGB subjects, CAT correlated inversely with peak GLP‐1 (r = −0.73, P = 0.01), and plasma 3‐OMG correlated tightly blood glucose (r = 0.94, P < 0.0001).ConclusionsAfter RYGB, reducing intestinal glucose delivery to 4 kcal/min is associated with higher blood glucose, greater glucose absorption, lower incretin responses, and less GI symptoms, supporting rapid transit contribution to the exaggerated incretin responses and “dumping symptoms”.

to assessment of esophageal function was 8±7 years. None of the patients had a history of dysphagia or esophageal function testing prior to surgery. The bariatric procedures commonly found in patients with symptoms were Roux-en-Y Gastric Bypass (RYGB) [10 patients], LAGB [5 patients], and sleeve gastrectomy [3 patients]. Common complaints at presentation were dysphagia (8), GERD (6), chest pain (3) and abdominal pain (1). Results of HRM are provided in table 1. The most frequently seen abnormality was Ineffective Esophageal Motility (IEM) and hypertensive LES. Of the 18 patients, two patients had opioid induced esophageal dysmotility. LAGB had the most variable esophageal motor findings, which resolved with deflation of the balloon. Patients with RYGB and sleeve gastrectomy responded to medical management, except for one sleeve gastrectomy patient that underwent revision to RYGB for symptom control. Conclusion: Bariatric surgery has implications not only on the distal, but proximal gut transit and motility. The skewed male prominence in this study is not clearly understood. Our data is limited by the lack of pre-surgical HRM studies to compare post surgical findings. These results have important implications for clinical care, and support the use of HRM in the care management plan of bariatric surgical patients. Table 1: Results of HRM (description) and response to therapy

We showed that glucose absorption is accelerated in the proximal intestine of morbidly obese humans, associated with increased expression of sodium dependent glucose co-transporter 1 (SGLT1), an altered incretin profile, hyperinsulinemia and hyperglycemia.This study aimed to examine the effects of energy restriction on glucose absorption, expression of intestinal glucose transporters and sweet taste receptors (STR), incretin hormone responses and glycemia in the morbidly obese.Methods: 10 non-diabetic, morbidly obese subjects (2M:8F; 45±3yrs, BMI: 46±3kg/m2) were studied before and after a 2-week VLCD (750kcal/day).On each occasion, endoscopic duodenal biopsies were collected before and after intraduodenal glucose infusion (30g glucose over 30 min, with 3g 3-O-methylglucose (3-OMG) to estimate glucose absorption).Blood glucose and plasma concentrations of 3-OMG, glucosedependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and insulin were measured over 240 min.Absolute expression of SGLT-1, GLUT2 and STR (T1R2) transcripts was quantified by PCR.Results After 2 weeks of VLCD, body weight (-5.6±0.5kg,P<0.001), HbA1c (-0.32±0.08%,P=0.001), fasting blood glucose (-0.5±0.1mmol/L,P=0.02) and fasting expression of T1R2 (-54±22%, P=0.03), SGLT1 (-30±7%, P=0.004) and GLUT2 (-50±15%, P=0.008) were lower than at baseline.Prior to VLCD, intra-duodenal glucose had no impact onT1R2, SGLT-1 and GLUT2 expression, but after VLCD, intra-duodenal glucose stimulated increased expression of T1R2 (45±30%, P=0.03) and GLUT2 (57±14%, P=0.003).The blood glucose (P=0.002),plasma GIP (P=0.03) and plasma insulin (P=0.002)responses to intra-duodenal glucose were all reduced after VLCD, while plasma 3-OMG and GLP-1 concentrations were unchanged.CONCLUSIONS: The improvement in glycemic control after short-term VLCD in morbid obesity is most likely mediated by reduced insulin resistance from weight loss, but not via a reduction in intestinal glucose absorption or an increased incretin response.Although VCLD reduces the fasting expression of both STR and glucose transporters, these increase rapidly on exposure to glucose.Further studies with inhibitors of STR and/or glucose transporters are warranted to determine whether the changes in receptor expressional dynamics are responsible for the observed incretin responses.