BACKGROUND AND PURPOSEThe glucagon-like peptides GLP-1 and GLP-2 are secreted from enteroendocrine L-cells following nutrient ingestion. Drugs that increase activity of the GLP-1 axis are highly successful therapies for type 2 diabetes, and boosting L-cell secretion is a potential strategy for future diabetes treatment. The aim of the present study was to further our understanding of the bile acid receptor GPBA (TGR5), an L-cell target currently under therapeutic exploration. EXPERIMENTAL APPROACHGLUTag cells and mixed primary murine intestinal cultures were exposed to bile acids and a specific agonist, GPBAR-A. Secretion was measured using hormone assays and intracellular calcium and cAMP responses were monitored using real-time imaging techniques. KEY RESULTSBile acid-triggered GLP-1 secretion from GLUTag cells was GPBA-dependent, as demonstrated by its abolition following tgr5 siRNA transfection. Bile acids and GPBAR-A increased GLP-1 secretion from intestinal cultures, with evidence for synergy between the effects of glucose and GPBA activation. Elevation of cAMP was observed following GPBA activation in individual GLUTag cells. Direct calcium responses to GPBAR-A were small, but in the presence of the agonist, a subpopulation of cells that was previously poorly glucose-responsive exhibited robust glucose responses. In vivo, increased delivery of bile to more distal regions of the ileum augmented L-cell stimulation. CONCLUSIONS AND IMPLICATIONSGPBA signalling in L-cells involves rapid elevation of cAMP, and enhanced calcium and secretory responses to glucose. Modulation of this receptor therapeutically may be an attractive strategy to enhance GLP-1 secretion and achieve better glycaemic control in diabetic patients. AbbreviationsCDCA, chenodeoxycholic acid; CFP, cyan fluorescent protein; DCA, deoxycholic acid; Epac, cAMP-guanine nucleotide exchange factors; fsk/IBMX, forskolin plus 3-isobutyl-1-methylxanthine; GLP-1, -2, glucagon-like peptide-1, -2; KATP, ATP-sensitive potassium channel; LCA, lithocholic acid; PYY, peptide YY; TLCA, taurolithocholic acid; YFP, yellow fluorescent protein BJP British Journal of Pharmacology

RYGB leads to increased GLP-2 and mucosal crypt cell proliferation. Other gut hormones from l-cells remain elevated for at least 2 years in humans. These findings may account for the restoration of the absorptive surface area of the gut, which limits malabsorption and contributes to the long-term weight loss after RYGB.

Plasma citrulline concentration is a simple and reliable surrogate for small bowel absorptive capacity and is not influenced by intestinal inflammation.

SUMMARY BackgroundGlucagon-like peptide 2 (GLP-2) is an important peptide growth factor secreted from the human intestine. The trophic properties of GLP-2 are very specific to the gut where it is pivotal in the regulation of mucosal morphology, function and integrity.

GLP-2 therapy holds promise as an adjuvant treatment modality for short bowel syndrome and other gastrointestinal disorders.

Introduction:Current medical management of short bowel syndrome (SBS) involves the use of lifelong parenteral nutrition (PN). Glucagon-like peptide-2 (GLP-2), an important intestinotrophic growth factor has been shown to increase intestinal absorption in SBS through augmentation of post-resection intestinal adaptation. This may lead to the reduction of PN dependence in patients with SBS.Areas covered in review:Advancing research of GLP-2 physiology has spurred the growing understanding of the diverse effects of GLP-2. The development of the degradation resistant GLP-2 analog, teduglutide (GattexTM, NPS Pharmaceuticals, Bedminster, NJ), has allowed its exploration as a therapeutic agent in a variety of clinical settings. Recent multicenter, placebo-controlled studies of GLP-2 in SBS patients demonstrate meaningful reductions in PN requirements with good safety profiles. The reparative and immunomodulatory effects of teduglutide may also be beneficial in patients with inflammatory bowel disease (IBD). Safety concerns about possible carcinogenic properties during long-term use require ongoing evaluation.Summary:GLP-2 appears to offer a novel adjuvant treatment modality for SBS. Promise for its use in other clinical settings like IBD has been shown in small pilot studies.

Intestinal adaptation is the process by which the intestine responds to loss of surface area in order to maximize functional capacity. Recent studies suggest that the process can be accelerated and augmented by a combination of nutritional and non-nutritional interventions.

Although RLH NST routine data collection was insufficient for direct comparison with all details of the NCEPOD report and yielded a small data set, RLH patients were younger (mean 53 vs. 65 years) and PN use appeared more appropriate (inappropriate 6 % vs. 10 %). Duration of PN was similar between the groups. RLH is a specialist centre for hepatobiliary surgery and therefore treats complex patients, which explains the high number of PN patients in this speciality (36 %) and the high percentage of patients started on PN as a result of Intestinal Failure secondary to pancreatitis (17 %). The main indication for PN in both data sets was post-operative ileus.Some shortfalls in practice including inadequate communication between referring team and NST, the availability of 'off-the-shelf' bags containing no vitamins or trace elements and inconsistent documentation in medical notes was identified. As a result of the comparison of RLH PN practice versus NCEPOD the following changes have been implemented: 1. A database has been developed to collect all PN-relevant information for ongoing service evaluation and improvement. 2. PN referrals must be made by a doctor from the referring team with a clear explanation of the indication for and likely duration of PN. 3. The NST attend some surgical ward rounds, xray and surgical meetings to enhance the channels of communication. 4. Emergency 'off-the-shelf' PN bags (without vitamins/trace elements) are no longer available except on the Intensive Care Unit at weekends. 5. Documentation in the medical notes has been standardised through the use of a NST template which ensures all appropriate assessment and monitoring is documented.Comparison with NCEPOD found PN provision at RLH to be a high quality service but highlighted some areas for improvement including better prospective data collection for further service evaluation and improvement.1. NCEPOD. A Mixed Bag: The