RNA sequencing unravels novel L cell constituents and mechanisms of GLP-1 secretion in human gastric bypass-operated intestine.

AIMS/HYPOTHESIS: Roux-en-Y gastric bypass surgery (RYGB) frequently results in remission of type 2 diabetes as well as exaggerated secretion of glucagon-like peptide-1 (GLP-1). Here, we assessed RYGB-induced transcriptomic alterations in the small intestine and investigated how they were related to the regulation of GLP-1 production and secretion in vitro and in vivo. METHODS: Human jejunal samples taken perisurgically and 1 year post RYGB (n=13) were analysed by RNA-seq. Guided by bioinformatics analysis we targeted four genes involved in cholesterol biosynthesis, which we confirmed to be expressed in human L cells, for potential involvement in GLP-1 regulation using siRNAs in GLUTag and STC-1 cells. Gene expression analyses, GLP-1 secretion measurements, intracellular calcium imaging and RNA-seq were performed in vitro. OGTTs were performed in C57BL/6j and iScd1-/- mice and immunohistochemistry and gene expression analyses were performed ex vivo. RESULTS: Gene Ontology (GO) analysis identified cholesterol biosynthesis as being most affected by RYGB. Silencing or chemical inhibition of stearoyl-CoA desaturase 1 (SCD1), a key enzyme in the synthesis of monounsaturated fatty acids, was found to reduce Gcg expression and secretion of GLP-1 by GLUTag and STC-1 cells. Scd1 knockdown also reduced intracellular Ca2+ signalling and membrane depolarisation. Furthermore, Scd1 mRNA expression was found to be regulated by NEFAs but not glucose. RNA-seq of SCD1 inhibitor-treated GLUTag cells identified altered expression of genes implicated in ATP generation and glycolysis. Finally, gene expression and immunohistochemical analysis of the jejunum of the intestine-specific Scd1 knockout mouse model, iScd1-/-, revealed a twofold higher L cell density and a twofold increase in Gcg mRNA expression. CONCLUSIONS/INTERPRETATION: RYGB caused robust alterations in the jejunal transcriptome, with genes involved in cholesterol biosynthesis being most affected. Our data highlight SCD as an RYGB-regulated L cell constituent that regulates the production and secretion of GLP-1.

Failed Roux-en-Y Gastric Bypass-Long-Term Results of Distalization with Total Alimentary Limb Length of 250 or 300 cm.

BACKGROUND: Weight loss failure or weight regain may occur after Roux-en-Y gastric bypass (RYGB). Revisional surgery includes distalization. However, few studies have looked at the associations between the total alimentary limb length (TALL) and weight loss outcomes, none with long-term results. OBJECTIVES: Peri- and postoperative outcomes were assessed after employing TALL of either 250 cm or 300 cm in the failed RYGB. METHODS: This study is a retrospective cohort analysis of 90 patients that underwent laparoscopic distalization between January 2006 and January 2016 due to failed RYBG. The index RYGB was modified to TALL of 250 cm (n = 48) or of 300 cm (n = 42) which entailed elongating the bilio-pancreatic limb (BPL) and transposing the Roux limb (RL) to a common limb (CL) of 100 cm and 150 cm, respectively. Long-term weight loss outcomes along with nutritional and vitamin status were analyzed. RESULTS: Preoperative BMI at distalization was 38.6 kg/m2. After 8 years, excess weight loss (EWL) was 61.8%. No differences between the two groups were seen in weight loss outcomes or early surgical complication rates (6.7%). However, more vitamin and nutritional deficiencies were present in the TALL 250-cm group (50.0% and 35.4%, respectively) versus the TALL 300-cm group (33.3% and 14.3% respectively), which led to laparoscopic revision in 27 patients by lengthening the TALL with 100 cm. Patients with weight regain after index RYGB had in average 59.9% higher EWL than patients with EWL failure. CONCLUSION: Distalization of the failed RYGBP is safe and effective, but TALL should not be shorter than 300 cm (and CL 150 cm) due to high rates of malnutrition. Adequate supplementation and long-term follow-up are mandatory to prevent serious malnutrition.

Distal gastric bypass: 2-m biliopancreatic limb construction with varying lengths of common channel.

BACKGROUND: Long-term durability after Roux-en-Y gastric bypass is challenging in the super-obese population. Although lengthening of biliopancreatic limb (BPL) is associated with higher rates of weight loss, shortening of common limb (CL) is related to higher risk of malabsorption. OBJECTIVES: In this study, we aimed at evaluating the importance of the total alimentary limb length by creating a 2-m BPL diversion with varying CL lengths. SETTING: High-volume bariatric center, Norway. METHODS: Three groups of patients (N = 187) with different limb lengths were included in this retrospective cohort-analysis as follows: group 1 (n = 69; Roux limb = 150 cm, BPL = 60 cm), group 2 (n = 88; BPL = 200 cm, CL = 150 cm), and group 3 (n = 30; BPL = 200 cm, CL = 200 cm). Weight loss, regain, and failure were analyzed along with malabsorption issues. RESULTS: Preoperative body mass index (BMI) was higher in group 2 (58.5, P < .001) and 3 (57.4) versus group 1 (54.6, P = .011). No other clinically significant differences between the groups were noted. Follow-up rate was 95% at year 2, 74% at year 5, and 52% at year 10. At 10-year follow-up, excess weight loss and total weight loss was higher in group 2 (70.4%; 40.3%) and 3 (64.0%; 35.9%) compared with group 1 (55.9%; 29.2%). Excess weight loss failure was higher in group 1 versus 2 (30% versus 8.3%, P < .001). No difference in short- or long-term complications was seen except higher occurrence of internal hernia in distal Roux-en-Y gastric bypass groups (11.4%, 6.7%). Vitamin and mineral deficiencies occurred more frequently the shorter the CL was. CONCLUSION: Sustainable weight loss in a long-term follow-up is achieved by shortening the total alimentary limb length with a 2-m BPL diversion that should not be attached <200 cm from the ileocecal junction owing to higher rates of internal hernia and vitamin and mineral deficiencies.

Limb Length in Gastric Bypass in Super-Obese Patients-Importance of Length of Total Alimentary Small Bowel Tract.

BACKGROUND: In super-obese patients, rates of weight loss failure and weight regain are high after RYGB. In order to improve weight loss, lengthening of the biliopancreatic limb is vital. In this study, efficacy and safety of two types of RYGB with 2-m BP-limb were assessed in improving weight loss and in the resolution of comorbidities compared with standard RYGB in a long-term follow-up. METHODS: This is a retrospective cohort analysis on 671 super-obese patients operated in a 10-year period. Patients were classified into three groups: (1) 155 patients; roux limb 150 cm, BP-limb 60 cm; (2) 230 patients; roux limb 60 cm, BP-limb 200 cm; and (3) 286 patients; roux limb 150 cm, BP-limb 200 cm. EWL, TWL, BMI, failure, weight regain, comorbidity resolution, nutritional status, and complications were assessed. RESULTS: Total alimentary limb length was shortened with 60 cm in group 1 and with 200 cm in groups 2 and 3. EWL, BMI change, and TWL were higher in the 2-m BP-limb groups vs group 1. No differences in complication rates were found, except higher frequency of marginal ulcers in patients with a shorter roux limb. EWL failure was higher in group 1 (10.3%) vs the other groups (4.3%; 5.2%). Group 3 had significantly less weight regain (26.6%). Remission of comorbidities was higher in the 2-m BP-limb groups at expense of nutritional and vitamin deficiencies (3.9%; 5.9%). No difference in hypoalbuminemia was noted. CONCLUSION: Lengthening of the BP-limb gives significantly higher weight loss, lower rate of EWL failure, and lesser weight regain along with better resolution of obesity-associated comorbidities.