Distinct hypothalamic control of same- and opposite-sex mounting behaviour in mice.

Animal behaviours that are superficially similar can express different intents in different contexts, but how this flexibility is achieved at the level of neural circuits is not understood. For example, males of many species can exhibit mounting behaviour towards same- or opposite-sex conspecifics1, but it is unclear whether the intent and neural encoding of these behaviours are similar or different. Here we show that female- and male-directed mounting in male laboratory mice are distinguishable by the presence or absence of ultrasonic vocalizations (USVs)2-4, respectively. These and additional behavioural data suggest that most male-directed mounting is aggressive, although in rare cases it can be sexual. We investigated whether USV+ and USV- mounting use the same or distinct hypothalamic neural substrates. Micro-endoscopic imaging of neurons positive for oestrogen receptor 1 (ESR1) in either the medial preoptic area (MPOA) or the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) revealed distinct patterns of neuronal activity during USV+ and USV- mounting, and the type of mounting could be decoded from population activity in either region. Intersectional optogenetic stimulation of MPOA neurons that express ESR1 and vesicular GABA transporter (VGAT) (MPOAESR1∩VGAT neurons) robustly promoted USV+ mounting, and converted male-directed attack to mounting with USVs. By contrast, stimulation of VMHvl neurons that express ESR1 (VMHvlESR1 neurons) promoted USV- mounting, and inhibited the USVs evoked by female urine. Terminal stimulation experiments suggest that these complementary inhibitory effects are mediated by reciprocal projections between the MPOA and VMHvl. Together, these data identify a hypothalamic subpopulation that is genetically enriched for neurons that causally induce a male reproductive behavioural state, and indicate that reproductive and aggressive states are represented by distinct population codes distributed between MPOAESR1 and VMHvlESR1 neurons, respectively. Thus, similar behaviours that express different internal states are encoded by distinct hypothalamic neuronal populations.

Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models.

Point mutations and structural variants that directly disrupt the coding sequence of MEF2C have been associated with a spectrum of neurodevelopmental disorders (NDDs). However, the impact of MEF2C haploinsufficiency on neurodevelopmental pathways and synaptic processes is not well understood, nor are the complex mechanisms that govern its regulation. To explore the functional changes associated with structural variants that alter MEF2C expression and/or regulation, we generated an allelic series of 204 isogenic human induced pluripotent stem cell (hiPSC)-derived neural stem cells and glutamatergic induced neurons. These neuronal models harbored CRISPR-engineered mutations that involved direct deletion of MEF2C or deletion of the boundary points for topologically associating domains (TADs) and chromatin loops encompassing MEF2C. Systematic profiling of mutation-specific alterations, contrasted to unedited controls that were exposed to the same guide RNAs for each edit, revealed that deletion of MEF2C caused differential expression of genes associated with neurodevelopmental pathways and synaptic function. We also discovered significant reduction in synaptic activity measured by multielectrode arrays (MEAs) in neuronal cells. By contrast, we observed robust buffering against MEF2C regulatory disruption following deletion of a distal 5q14.3 TAD and loop boundary, whereas homozygous loss of a proximal loop boundary resulted in down-regulation of MEF2C expression and reduced electrophysiological activity on MEA that was comparable to direct gene disruption. Collectively, these studies highlight the considerable functional impact of MEF2C deletion in neuronal cells and systematically characterize the complex interactions that challenge a priori predictions of regulatory consequences from structural variants that disrupt three-dimensional genome organization.

Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models.

Chromosome 16p11.2 reciprocal genomic disorder, resulting from recurrent copy-number variants (CNVs), involves intellectual disability, autism spectrum disorder (ASD), and schizophrenia, but the responsible mechanisms are not known. To systemically dissect molecular effects, we performed transcriptome profiling of 350 libraries from six tissues (cortex, cerebellum, striatum, liver, brown fat, and white fat) in mouse models harboring CNVs of the syntenic 7qF3 region, as well as cellular, transcriptional, and single-cell analyses in 54 isogenic neural stem cell, induced neuron, and cerebral organoid models of CRISPR-engineered 16p11.2 CNVs. Transcriptome-wide differentially expressed genes were largely tissue-, cell-type-, and dosage-specific, although more effects were shared between deletion and duplication and across tissue than expected by chance. The broadest effects were observed in the cerebellum (2,163 differentially expressed genes), and the greatest enrichments were associated with synaptic pathways in mouse cerebellum and human induced neurons. Pathway and co-expression analyses identified energy and RNA metabolism as shared processes and enrichment for ASD-associated, loss-of-function constraint, and fragile X messenger ribonucleoprotein target gene sets. Intriguingly, reciprocal 16p11.2 dosage changes resulted in consistent decrements in neurite and electrophysiological features, and single-cell profiling of organoids showed reciprocal alterations to the proportions of excitatory and inhibitory GABAergic neurons. Changes both in neuronal ratios and in gene expression in our organoid analyses point most directly to calretinin GABAergic inhibitory neurons and the excitatory/inhibitory balance as targets of disruption that might contribute to changes in neurodevelopmental and cognitive function in 16p11.2 carriers. Collectively, our data indicate the genomic disorder involves disruption of multiple contributing biological processes and that this disruption has relative impacts that are context specific.

Is Robotic Surgery the Future for Resectable Esophageal Cancer?: A Systematic Literature Review of Oncological and Clinical Outcomes.

BACKGROUND: Radical esophagectomy for resectable esophageal cancer is a major surgical intervention, associated with considerable postoperative morbidity. The introduction of robotic surgical platforms in esophagectomy may enhance advantages of minimally invasive surgery enabled by laparoscopy and thoracoscopy, including reduced postoperative pain and pulmonary complications. This systematic review aims to assess the clinical and oncological benefits of robot-assisted esophagectomy. METHODS: A systematic literature search of the MEDLINE (PubMed), Embase and Cochrane databases was performed for studies published up to 1 August 2023. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocols and was registered in the PROSPERO database (CRD42022370983). Clinical and oncological outcomes data were extracted following full-text review of eligible studies. RESULTS: A total of 113 studies (n = 14,701 patients, n = 2455 female) were included. The majority of the studies were retrospective in nature (n = 89, 79%), and cohort studies were the most common type of study design (n = 88, 79%). The median number of patients per study was 54. Sixty-three studies reported using a robotic surgical platform for both the abdominal and thoracic phases of the procedure. The weighted mean incidence of postoperative pneumonia was 11%, anastomotic leak 10%, total length of hospitalisation 15.2 days, and a resection margin clear of the tumour was achieved in 95% of cases. CONCLUSIONS: There are numerous reported advantages of robot-assisted surgery for resectable esophageal cancer. A correlation between procedural volume and improvements in outcomes with robotic esophagectomy has also been identified. Multicentre comparative clinical studies are essential to identify the true objective benefit on outcomes compared with conventional surgical approaches before robotic surgery is accepted as standard of practice.

Introduction of day-case robotic liver surgery: a case series from a tertiary hepatobiliary and pancreatic centre.

BACKGROUND: Liver surgery is associated with a significant hospital stay regardless the type of liver resection. A large incision is essential for open liver surgery which is a major factor in the course of the patient's recovery. For patients with small parenchyma liver lesions requiring surgical resection, robotic surgery potentially offers the opportunity to transform the patient's post-operative course. A day-case robotic liver resection pathway was formulated and implemented at our institution when patients were planned for discharge within 24 h of admission for liver surgery. METHODS: Single surgeon case series of cases performed at a tertiary hepatobiliary and pancreatic centre between September 2022 and November 2023. The inclusion criteria were non-anatomical wedge resections, < 2 anatomical segmental resections, left lateral hepatectomy and minimally invasive surgery. RESULTS: This is the first series of robotic day-case minor liver resection in the United Kingdom. 20 patients were included in this case series. The mean operative time was 86.6 ± 30.9 min and mean console time was 58.6 ± 24.5 min. Thirteen patients (65%) were discharged within 24 h of surgery. The main cause of hospitalisation beyond 24 h was inadequate pain relief. There were no Clavien-Dindo grade III or above complications, no 30-day readmission and 90-day mortalities. CONCLUSION: This case series demonstrates that robotic day-case liver resection is safe and feasible. Robust follow-up pathways must be in place to allow for the safe implementation of this approach, to monitor for any complications and to allow intervention as required in a timely manner.

Safety of robotic cholecystectomy as index training procedure: the UK experience.

AIMS: To evaluate the safety profile of robotic cholecystectomy performed within the United Kingdom (UK) Robotic Hepatopancreatobiliary (HPB) training programme. METHODS: A retrospective evaluation of prospectively collected data from eleven centres participating in the UK Robotic HPB training programme was conducted. All adult patients undergoing robotic cholecystectomy for symptomatic gallstone disease or gallbladder polyp were considered. Bile duct injury, conversion to open procedure, conversion to subtotal cholecystectomy, length of hospital stay, 30-day re-admission, and post-operative complications were the evaluated outcome parameters. RESULTS: A total of 600 patients were included. The median age was 53 (IQR 65-41) years and the majority (72.7%; 436/600) were female. The main indications for robotic cholecystectomy were biliary colic (55.5%, 333/600), cholecystitis (18.8%, 113/600), gallbladder polyps (7.7%, 46/600), and pancreatitis (6.2%, 37/600). The median length of stay was 0 (IQR 0-1) days. Of the included patients, 88.5% (531/600) were discharged on the day of procedure with 30-day re-admission rate of 5.5% (33/600). There were no bile duct injuries and the rate of conversion to open was 0.8% (5/600) with subtotal cholecystectomy rate of 0.8% (5/600). CONCLUSION: The current study confirms that robotic cholecystectomy can be safely implemented to routine practice with a low risk of bile duct injury, low bile leak rate, low conversion to open surgery, and low need for subtotal cholecystectomy.

Does Sleeve Gastrectomy Expose the Distal Esophagus to Severe Reflux?: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of this study was to appraise the prevalence of gastroesophageal reflux disease (GERD), esophagitis, and Barrett's esophagus (BE) after sleeve gastrectomy (SG) through a systematic review and meta-analysis. BACKGROUND: The precise prevalence of new-onset or worsening GERD after SG is controversial. Subsequent esophagitis and BE can be a serious unintended sequalae. Their postoperative prevalence remains unclear. METHODS: A systematic literature search was performed to identify studies evaluating postoperative outcomes in primary SG for morbid obesity. The primary outcome was prevalence of GERD, esophagitis, and BE after SG. Meta-analysis was performed to calculate combined prevalence. RESULTS: A total of 46 studies totaling 10,718 patients were included. Meta-analysis found that the increase of postoperative GERD after sleeve (POGAS) was 19% and de novo reflux was 23%. The long-term prevalence of esophagitis was 28% and BE was 8%. Four percent of all patients required conversion to RYGB for severe reflux. CONCLUSIONS: The postoperative prevalence of GERD, esophagitis, and BE following SG is significant. Symptoms do not always correlate with the presence of pathology. As the surgical uptake of SG continues to increase, there is a need to ensure that surgical decision-making and the consent process for this procedure consider these long-term complications while also ensuring their postoperative surveillance through endoscopic and physiological approaches. The long-term outcomes of this commonly performed bariatric procedure should be considered alongside its weight loss and metabolic effects.

Biallelic mutation of FBXL7 suggests a novel form of Hennekam syndrome.

Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder characterized by congenital lymphedema, intestinal lymphangiectasia, facial dysmorphism, and variable intellectual disability. Known disease genes include CCBE1, FAT4, and ADAMTS3. In a patient with clinically diagnosed Hennekam syndrome but without mutations or copy-number changes in the three known disease genes, we identified a homozygous single-exon deletion affecting FBXL7. Specifically, exon 3, which encodes the F-box domain and several leucine-rich repeats of FBXL7, is eliminated. Our analyses of databases representing >100,000 control individuals failed to identify biallelic loss-of-function variants in FBXL7. Published studies in Drosophila indicate Fbxl7 interacts with Fat, of which human FAT4 is an ortholog, and mutation of either gene yields similar morphological consequences. These data suggest that FBXL7 may be the fourth gene for Hennekam syndrome, acting via a shared pathway with FAT4.

CREB SUMOylation by the E3 ligase PIAS1 enhances spatial memory.

cAMP-responsive element binding protein (CREB) phosphorylation and signaling plays an important role in long-term memory formation, but other posttranslational modifications of CREB are less known. Here, we found that CREB1Δ, the short isoform of CREB, could be sumoylated by the small ubiquitin-like modifier (SUMO) E3 ligase protein inhibitor of activated STAT1 (PIAS1) at Lys271 and Lys290 and PIAS1 SUMOylation of CREB1Δ increased the expression level of CREB1Δ. CREB1Δ could also be sumoylated by other PIAS family proteins, but not by the E3 ligases RanBP2 and Pc2 or by the E2 ligase Ubc9. Furthermore, water maze training increased the level of endogenous CREB SUMOylation in rat CA1 neurons determined by in vitro SUMOylation assay, but this effect was not observed in other brain areas. Moreover, transduction of Lenti-CREBWT to rat CA1 area facilitated, whereas transduction of Lenti-CREB double sumo-mutant (CREBK271RK290R) impaired, spatial learning and memory performance. Transduction of Lenti-CREBWT-SUMO1 fusion vector to rat CA1 area showed a more significant effect in enhancing spatial learning and memory and CREB SUMOylation. Lenti-CREBWT transduction increased, whereas Lenti-CREBK271RK290R transduction decreased, CREB DNA binding to the brain-derived neurotrophic factor (bdnf) promoter and decreased bdnf mRNA expression. Knock-down of PIAS1 expression in CA1 area by PIAS1 siRNA transfection impaired spatial learning and memory and decreased endogenous CREB SUMOylation. In addition, CREB SUMOylation was CREB phosphorylation dependent and lasted longer. Therefore, CREB phosphorylation may be responsible for signal transduction during the early phase of long-term memory formation, whereas CREB SUMOylation sustains long-term memory.

Novel role and mechanism of protein inhibitor of activated STAT1 in spatial learning.

By using differential display PCR, we have previously identified 98 cDNA fragments from rat dorsal hippocampus, which are expressed differentially between the fast learners and slow learners from water-maze learning task. One cDNA fragment, which showed a higher expression level in fast learners, encodes the rat protein inhibitor of activated STAT1 (pias1) gene. Spatial training induced a significant increase in PIAS1 expression in rat hippocampus. Transient transfection of the wild-type (WT) PIAS1 plasmid to CA1 neurons facilitated, whereas transfection of PIAS1 siRNA impaired spatial learning in rats. Meanwhile, PIAS1WT increased STAT1 sumoylation, decreased STAT1 DNA binding and decreased STAT1 phosphorylation at Tyr-701 associated with spatial learning facilitation. But PIAS1 siRNA transfection produced an opposite effect on these measures associated with spatial learning impairment. Further, transfection of STAT1 sumoylation mutant impaired spatial acquisition, whereas transfection of STAT1 phosphorylation mutant blocked the impairing effect of PIAS1 siRNA on spatial learning. In this study, we first demonstrate the role of PIAS1 in spatial learning. Both posttranslational modifications (increased sumoylation and decreased phosphorylation) mediate the effect of PIAS1 on spatial learning facilitation.

Parallelized engineering of mutational models using piggyBac transposon delivery of CRISPR libraries.

New technologies and large-cohort studies have enabled novel variant discovery and association at unprecedented scale, yet functional characterization of these variants remains paramount to deciphering disease mechanisms. Approaches that facilitate parallelized genome editing of cells of interest or induced pluripotent stem cells (iPSCs) have become critical tools toward this goal. Here, we developed an approach that incorporates libraries of CRISPR-Cas9 guide RNAs (gRNAs) together with inducible Cas9 into a piggyBac (PB) transposon system to engineer dozens to hundreds of genomic variants in parallel against isogenic cellular backgrounds. This method empowers loss-of-function (LoF) studies through the introduction of insertions or deletions (indels) and copy-number variants (CNVs), though generating specific nucleotide changes is possible with prime editing. The ability to rapidly establish high-quality mutational models at scale will facilitate the development of isogenic cellular collections and catalyze comparative functional genomic studies investigating the roles of hundreds of genes and mutations in development and disease.

Activation of the imprinted Prader-Willi Syndrome locus by CRISPR-based epigenome editing.

Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For example, Prader-Willi Syndrome (PWS) is caused by loss of paternally expressed imprinted genes on chromosome 15q11.2-q13.3, although the maternal allele is intact but epigenetically silenced. Using CRISPR repression and activation screens in human induced pluripotent stem cells (iPSCs), we identified genomic elements that control expression of the PWS gene SNRPN from the paternal and maternal chromosomes. We showed that either targeted transcriptional activation or DNA demethylation can activate the silenced maternal SNRPN and downstream PWS transcripts. However, these two approaches function at unique regions, preferentially activating different transcript variants and involving distinct epigenetic reprogramming mechanisms. Remarkably, transient expression of the targeted demethylase leads to stable, long-term maternal SNRPN expression in PWS iPSCs. This work uncovers targeted epigenetic manipulations to reprogram a disease-associated imprinted locus and suggests possible therapeutic interventions.

Complete Primary Pathological Response Following Neoadjuvant Treatment and Radical Resection for Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Neoadjuvant treatment (NAT) for borderline (BD) or locally advanced (LA) primary pancreatic cancer (PDAC) is now a widely adopted approach. We present a case series of patients who have achieved a complete pathological response of the primary tumour on final histology following neoadjuvant chemotherapy +/- chemoradiation and radical surgery. METHODS: Patients who underwent radical pancreatic resection following neoadjuvant treatment between March 2006 and March 2023 at a single institution were identified by retrospective case note review of a prospectively maintained database. RESULTS: Ten patients were identified to have a complete primary pathological response (ypT0) on postoperative histology. Before treatment, five patients were considered BD and five were LA according to National Comprehensive Cancer Network guidelines. All patients underwent staging Computed Tomography (CT) and nine underwent 18Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET/CT) imaging, with a mean maximum standardized uptake value (SUVmax) of the primary lesion at 6.14 ± 1.98 units. All patients received neoadjuvant chemotherapy, and eight received further chemoradiotherapy prior to resection. Mean pre- and post-neoadjuvant treatment serum Ca19-9 was 148.0 ± 146.3 IU/L and 18.0 ± 18.7 IU/L, respectively (p = 0.01). The mean duration of NAT was 5.6 ± 1.7 months. The mean time from completion of NAT to surgery was 13.1 ± 8.3 weeks. The mean lymph node yield was 21.1 ± 10.4 nodes, with one patient found to have 1 lymph node involved. All resections were reported to be R0. The mean length of stay was 11.8 ± 6.2 days. At the time of analysis, one death was reported at 35 months postoperatively. Two cases of recurrence were reported at 16 months (surgical bed) and 33 months (pulmonary). All other patients remain alive and under active surveillance. The current overall survival is 26.6 ± 20.7 months and counting. CONCLUSIONS: Complete primary pathological response is uncommon but possible following neoadjuvant treatment in patients with PDAC. Further work to identify the common denominator within this unique cohort may lead to advances in the therapeutic approach and offer hope for patients diagnosed with borderline or locally advanced pancreatic ductal adenocarcinoma.

Excitatory Dysfunction Drives Network and Calcium Handling Deficits in 16p11.2 Duplication Schizophrenia Induced Pluripotent Stem Cell-Derived Neurons.

BACKGROUND: Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human induced pluripotent stem cell-derived neurons (iNs) has emerged as a promising strategy. Copy number variants confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing the risk 14.5-fold. METHODS: To dissect the contribution of induced excitatory neurons (iENs) versus GABAergic (gamma-aminobutyric acidergic) neurons (iGNs) to SCZ pathophysiology, we induced iNs from CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 isogenic and SCZ patient-derived induced pluripotent stem cells and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures. RESULTS: In iEN/iGN cocultures, neuronal firing and synchrony were reduced at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for iENs. Moreover, isogenic iENs showed reduced dendrite length and deficits in calcium handling. iENs from 16p11.2 duplication-carrying patients with SCZ displayed overlapping deficits in network synchrony, dendrite outgrowth, and calcium handling. Transcriptomic analysis of both iEN cohorts revealed molecular markers of disease related to the glutamatergic synapse, neuroarchitecture, and calcium regulation. CONCLUSIONS: Our results indicate the presence of 16p11.2 duplication-dependent alterations in SCZ patient-derived iENs. Transcriptomics and cellular phenotyping reveal overlap between isogenic and patient-derived iENs, suggesting a central role of glutamatergic, morphological, and calcium dysregulation in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers. Our results support network synchrony and calcium handling as outcomes directly linked to this genetic risk variant.

Anti-Human CD9 Fab Fragment Antibody Blocks the Extracellular Vesicle-Mediated Increase in Malignancy of Colon Cancer Cells.

Intercellular communication between cancer cells themselves or with healthy cells in the tumor microenvironment and/or pre-metastatic sites plays an important role in cancer progression and metastasis. In addition to ligand-receptor signaling complexes, extracellular vesicles (EVs) are emerging as novel mediators of intercellular communication both in tissue homeostasis and in diseases such as cancer. EV-mediated transfer of molecular activities impacting morphological features and cell motility from highly metastatic SW620 cells to non-metastatic SW480 cells is a good in vitro example to illustrate the increased malignancy of colorectal cancer leading to its transformation and aggressive behavior. In an attempt to intercept the intercellular communication promoted by EVs, we recently developed a monovalent Fab fragment antibody directed against human CD9 tetraspanin and showed its effectiveness in blocking the internalization of melanoma cell-derived EVs and the nuclear transfer of their cargo proteins into recipient cells. Here, we employed the SW480/SW620 model to investigate the anti-cancer potential of the anti-CD9 Fab antibody. We first demonstrated that most EVs derived from SW620 cells contain CD9, making them potential targets. We then found that the anti-CD9 Fab antibody, but not the corresponding divalent antibody, prevented internalization of EVs from SW620 cells into SW480 cells, thereby inhibiting their phenotypic transformation, i.e., the change from a mesenchymal-like morphology to a rounded amoeboid-like shape with membrane blebbing, and thus preventing increased cell migration. Intercepting EV-mediated intercellular communication in the tumor niche with an anti-CD9 Fab antibody, combined with direct targeting of cancer cells, could lead to the development of new anti-cancer therapeutic strategies.

The impact of bariatric surgery on serum tryptophan-kynurenine pathway metabolites.

This study aims to explore the immediate effects of bariatric surgery on serum tryptophan-kynurenine pathway metabolites in individuals with type 2 diabetes and BMI > 30. With the goal of providing insight into the link between tryptophan pathway metabolites, type 2 diabetes, and chronic obesity-induced inflammation. This longitudinal study included 20 participants. Half were diagnosed with type 2 diabetes. 11 and 9 underwent RYGB and SG respectively. Blood samples were obtained at pre-operative and 3 months post-operative timepoints. Tryptophan and downstream metabolites of the kynurenine pathway were quantified with an ultrahigh-performance liquid chromatography tandem mass spectrometry with electrospray ionisation method. At 3 months post-operation, RYGB led to significant reductions in tryptophan, kynurenic acid and xanthurenic acid levels when compared to baseline. Significant reductions of the same metabolites after surgery were also observed in individuals with T2D irrespective of surgical procedure. These metabolites were significantly correlated with serum HbA1c levels and BMI. Bariatric surgery, in particular RYGB reduces serum levels of tryptophan and its downstream kynurenine metabolites. These metabolites are associated with T2D and thought to be potentially mechanistic in the systemic processes of obesity induced inflammation leading to insulin resistance. Its reduction after surgery is associated with an improvement in glycaemic control (HbA1c).