Background Since 2014, the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) has produced an annual report of all bariatric surgery submitted to the Global Registry. We describe baseline demographics of international practice from the 4th report. Methods The IFSO Global Registry amalgamated data from 51 different countries, 14 of which provided data from their national registries. Data were available from 394,431 individual records, of which 190,177 were primary operations performed since 2014. Results Data were submitted on 72,645 Roux en Y gastric bypass operations (38.2%), 87,467 sleeve gastrectomy operations (46.0%), 14,516 one anastomosis gastric bypass procedures (7.6%) and 9534 gastric banding operations (5.0%) as the primary operation since 2014. The median patient body mass index (BMI) pre-surgery was 41.7 kg m 2 (inter-quartile range: 38.3-46.1 kg m 2). Following gastric bypass, 84.1% of patients were discharged within 2 days of surgery; and 84.5% of sleeve gastrectomy patients were discharged within 3 days. Assessing operations performed between 2012 and 2016, at one year after surgery, the mean recorded percentage weight loss was 28.9% and 66.1% of those taking medication for type 2 diabetes were recorded as not using them. The proportion of patients no longer receiving treatment for diabetes was highly dependent on weight loss achieved. There was marked variation in access and practice. Conclusions A global description of patients undergoing bariatric surgery is emerging. Future iterations of the registry have the potential to describe the operated patients comprehensively.

We have compared the ability of a number of -opioid receptor (MOPr) ligands to activate G proteins with their abilities to induce MOPr phosphorylation, to promote association of arrestin-3 and to cause MOPr internalization. For a model of G protein-coupled receptor (GPCR) activation where all agonists stabilize a single active conformation of the receptor, a close correlation between signaling outputs might be expected. Our results show that overall there is a very good correlation between efficacy for G protein activation and arrestin-3 recruitment, whereas a few agonists, in particular endomorphins 1 and 2, display apparent bias toward arrestin recruitment. The agonist-induced phosphorylation of MOPr at Ser 375 , considered a key step in MOPr regulation, and agonist-induced internalization of MOPr were each found to correlate well with arrestin-3 recruitment. These data indicate that for the majority of MOPr agonists the ability to induce receptor phosphorylation, arrestin-3 recruitment, and internalization can be predicted from their ability as agonists to activate G proteins. For the prototypic MOPr agonist morphine, its relatively weak ability to induce MOPr internalization can be explained by its low agonist efficacy.

1 The receptor for glucagon-like peptide-1 (GLP-1) can be activated by both its physiological hormone and a peptide discovered in the venom of the Gila Monster, exendin-4, which shows promise as an antidiabetic agent. 2 Exendin-4 displays receptor-binding properties not observed for GLP-1. Firstly, exendin-4 can be truncated by up to eight residues at its N-terminus without a significant loss of affinity. Secondly, exendin-4 maintains high affinity for the isolated N-terminal domain of the receptor, suggesting that exendin-4 makes additional contacts with this domain of the receptor, which nullify the requirement for ligand -receptor interactions involving the extracellular loops and/or transmembrane helices of the receptor's core domain. 3 In order to further understand the nature of the receptor -peptide interaction, a variety of full length and truncated peptide analogues were used to quantify the contribution of each distinct region of exendin-4 and GLP-1 to receptor affinity. 4 Our data show that, for both exendin-4 and GLP-1, the primary interaction is between the putative helical region of the peptide and the extracellular N-terminal domain of the receptor.5 However, we demonstrate that the contribution to receptor affinity provided by the N-terminal segment of GLP-1 is greater than that of exendin-4, while the C-terminal nine residue extension of exendin-4, absent in GLP-1, forms a compensatory interaction with the N-terminal domain of the receptor. 6 We describe a peptide -receptor binding model to account for these data.

Background and ObjectivesGlucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important regulators of insulin secretion, and their functional loss is an early characteristic of type 2 diabetes mellitus (T2DM). Pharmacological levels of GLP-1, but not GIP, can overcome this loss. GLP-1 and GIP exert their insulinotropic effects through their respective receptors expressed on pancreatic β-cells. Both the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR) are members of the secretin family of G protein-coupled receptors (GPCRs) and couple positively to adenylate cyclase. We compared the signalling properties of these two receptors to gain further insight into why GLP-1, but not GIP, remains insulinotropic in T2DM patients.MethodsGLP-1R and GIPR were transiently expressed in HEK-293 cells, and basal and ligand-induced cAMP production were investigated using a cAMP-responsive luciferase reporter gene assay. Arrestin3 (Arr3) recruitment to the two receptors was investigated using enzyme fragment complementation, confocal microscopy and fluorescence resonance energy transfer (FRET).ResultsGIPR displayed significantly higher (P<0.05) ligand-independent activity than GLP-1R. Arr3 displayed a robust translocation to agonist-stimulated GLP-1R but not to GIPR. These observations were confirmed in FRET experiments, in which GLP-1 stimulated the recruitment of both GPCR kinase 2 (GRK2) and Arr3 to GLP-1R. These interactions were not reversed upon agonist washout. In contrast, GIP did not stimulate recruitment of either GRK2 or Arr3 to its receptor. Interestingly, arrestin remained at the plasma membrane even after prolonged (30 min) stimulation with GLP-1. Although the GLP-1R/arrestin interaction could not be reversed by agonist washout, GLP-1R and arrestin did not co-internalise, suggesting that GLP-1R is a class A receptor with regard to arrestin binding.ConclusionsGIPR displays higher basal activity than GLP-1R but does not effectively recruit GRK2 or Arr3.

Type 2 diabetes (T2D) is a growing pandemic associated with metabolic dysregulation and chronic inflammation. Meteorin-like hormone (METRNL) is an adipomyokine that is linked to T2D. Our objective was to evaluate the changes in METRNL levels in T2D and obesity and assess the association of METRNL levels with irisin. Overall, 228 Arab individuals were enrolled. Plasma levels of METRNL and irisin were assessed using immunoassay. Plasma levels of METRNL and irisin were significantly higher in T2D patients than in non-diabetic patients (p < 0.05). When the population was stratified based on obesity, METRNL and irisin levels were significantly higher in obese than in non-obese individuals (p < 0.05). We found a significant positive correlation between METRNL and irisin (r = 0.233 and p = 0.001). Additionally, METRNL and irisin showed significant correlation with various metabolic biomarkers associated with T2D and Obesity. Our data shows elevated METRNL plasma levels in individuals with T2D, further exacerbated with obesity. Additionally, a strong positive association was observed between METRNL and irisin. Further studies are necessary to examine the role of these proteins in T2D and obesity, against their ethnic background and to understand the mechanistic significance of their possible interplay.

Homologous desensitization of ␤ 2 -adrenergic and other G-protein-coupled receptors is a two-step process. After phosphorylation of agonist-occupied receptors by G-protein-coupled receptor kinases, they bind ␤-arrestins, which triggers desensitization and internalization of the receptors. Because it is not known which regions of the receptor are recognized by ␤-arrestins, we have investigated ␤-arrestin interaction and internalization of a set of mutants of the human ␤ 2 -adrenergic receptor. Mutation of the four serine/threonine residues between residues 355 and 364 led to the loss of agonist-induced receptor-␤-arrestin2 interaction as revealed by fluorescence resonance energy transfer (FRET), translocation of ␤-arrestin2 to the plasma membrane, and receptor internalization. Mutation of all seven serine/threonine residues distal to residue 381 did not affect agonist-induced receptor internalization and ␤-arrestin2 translocation. A ␤ 2 -adrenergic receptor truncated distal to residue 381 interacted normally with ␤-arrestin2, whereas its ability to internalize in an agonist-dependent manner was compromised. A similar impairment of internalization was observed when only the last eight residues of the C terminus were deleted. Our experiments show that the C terminus distal to residue 381 does not affect the initial interaction between receptor and ␤-arrestin, but its last eight amino acids facilitate receptor internalization in concert with ␤-arrestin2.The interaction of ␤-arrestins with G-protein-coupled receptors is a prerequisite for at least three different processes: homologous desensitization (1), activation of tyrosine kinasemediated signaling pathways (2), and receptor internalization (3). This interaction requires the phosphorylation of the receptor by G-protein-coupled receptor kinases (GRKs) 3 and (at least for some receptors) the continuous presence of agonist (4). GRKs are unique among serine/threonine kinases in that they do not recognize a well-defined consensus sequence but instead show high specificity for agonist-activated receptors. This lack of a consensus sequence has made mapping of phosphorylated residues in G-protein-coupled receptors difficult. For example, the residues phosphorylated by GRK2 in the ␤ 2 -adrenergic receptor have been mapped to the C terminus, either between amino acids 384 and 411 (5) or between amino acids 355 and 364 (6 -10). It is now clear from a variety of studies (see Ref.11 for a review) that ␤-arrestins do not simply act as "phosphoreceptor-specific antibodies." Rather, the interaction of ␤-arrestins with GRK-phosphorylated receptors is believed to lead to a conformational change in the ␤-arrestin molecule, which enables it to bind to other parts of the receptor with higher affinity. Furthermore, it has also been demonstrated that ␤-arrestins sense the activated conformation of the receptor (4, 12). For example, ␤-arrestin mutants have been described that do not require GRK-mediated phosphorylation to bind to a receptor but still only interact with a receptor when...

The use of SEMS appears to be a safe and effective method in the treatment of post-LSG leaks, with a success rate of 76%. The time frame of intervention after surgery is critical, as earlier stent placement is associated with favorable outcomes. Finally, SEPS is often required to facilitate SEMS removal, and further modification of stents and its delivery system may improve results.

The receptor for GLP-1 [glucagon-like peptide-1-(7-36)-amide] is a member of the 'Family B' of GPCRs (G-protein-coupled receptors) comprising an extracellular N-terminal domain containing six conserved cysteine residues (the N-domain) and a core domain (or J-domain) comprising the seven transmembrane helices and interconnecting loop regions. According to the two-domain model for peptide binding, the N-domain is primarily responsible for providing most of the peptide binding energy, whereas the core domain is responsible for binding the N-terminal region of the peptide agonists and transmitting the signal to the intracellular G-protein. Two interesting differences between the binding properties of two GLP-1 receptor agonists, GLP-1 and EX-4 (exendin-4), can be observed. First, while GLP-1 requires its full length to maintain high affinity, the eight N-terminal residues of EX-4 can be removed with little reduction in affinity. Secondly, EX-4 (but not GLP-1) can bind to the fully isolated N-domain of the receptor with an affinity matching that of the full-length receptor. In order to better understand these differences, we have studied the interaction between combinations of full-length or truncated ligands with full-length or truncated receptors.