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Aims To investigate whether the elevation in postprandial concentrations of the gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and peptide YY (PYY) accounts for the beneficial changes in food preferences, sweet taste function and eating behaviour after Roux-en-Y gastric bypass (RYGB). Materials and methods This was a secondary analysis of a randomized single-blind study in which we infused GLP-1, OXM, PYY (GOP) or 0.9% saline subcutaneously for 4 weeks in 24 subjects with obesity and prediabetes/diabetes, to replicate their peak postprandial concentrations, as measured at 1 month in a matched RYGB cohort (ClinicalTrials.gov NCT01945840). A 4-day food diary and validated eating behaviour questionnaires were completed. Sweet taste detection was measured using the method of constant stimuli. Correct sucrose identification (corrected hit rates) was recorded, and sweet taste detection thresholds (EC50s: half maximum effective concencration values) were derived from concentration curves. The intensity and consummatory reward value of sweet taste were assessed using the generalized Labelled Magnitude Scale. Results Mean daily energy intake was reduced by 27% with GOP but no significant changes in food preferences were observed, whereas a reduction in fat and increase in protein intake were seen post-RYGB. There was no change in corrected hit rates or detection thresholds for sucrose detection following GOP infusion. Additionally, GOP did not alter the intensity or consummatory reward value of sweet taste. A significant reduction in restraint eating, comparable to the RYGB group was observed with GOP. Conclusion The elevation in plasma GOP concentrations after RYGB is unlikely to mediate changes in food preferences and sweet taste function after surgery but may promote restraint eating.

Dexamethasone significantly reduces mortality1 and is now standard treatment for patients with COVID-19 who require supplemental oxygen and/or mechanical ventilation. However, supraphysiological doses of glucocorticoids may exacerbate dysglycaemia and precipitate hyperglycaemic complications, particularly in those with or at risk of Type 2 diabetes2. The RECOVERY trial1 reported a low incidence of hyperglycaemic complications (2/1996, 0.1%), although the real-world incidence is likely to be much higher3. Type 2 diabetes itself increases the risk of severe COVID-194, and hyperglycaemia independently predicts poor outcomes5. We investigated the possibility that patients with diabetes may derive less survival benefit from steroid therapy in the setting of severe COVID-19 infection

Background: Type 2 diabetes (T2D) is characterised by the loss of pulsatile insulin secretion. We studied mice with β-cell specific loss of the glucagon receptor (GCGRflox/flox X Ins-1 cre) , to investigate the role of intra-islet glucagon signalling on pan-islet calcium oscillations and islet pulsatility. Methods: Frequently sampled intravenous glucose tolerance tests were conducted on GCGRKOβ-cells-/-and littermate controls. Crossing with GCaMP6f (STOP flox) animals allowed for β-cell specific expression of a fluorescent calcium indicator. These islets were functionally imaged in vitro and in vivo. Wild-type mice were transplanted with islets expressing GCaMP6f in β-cells into the anterior eye chamber and placed on a high fat diet. Half of the cohort received a glucagon analogue (GCG-analogue) for 40 days and the control group were fed to achieve weight matching. Calcium imaging was performed regularly during the development of hyperglycaemia and in response to GCG-analogue treatment. Results: GCGRKOβ-cells-/- mice had poorer glucose tolerance in an intraperitoneal glucose tolerance test (control 12.7mmol/L ±0.6 vs. GCGRKOβ-cells-/- 15.4mmol/L ±0.0 at 15 min, p=0.002) ; fasting glycaemia was not different to controls. In vitro, GCGRKOβ-cells-/- islets showed profound loss of synchronised calcium waves in response to glucose which is only partially rescued in vivo. First-phase insulin pulsatility on peripheral blood sampling (n=5) was significantly disordered in GCGRKOβ-cells-/- mice (burst mass GCGRKOβ-cells-/- 0.30 ±0.03 versus 0.84 ±0.23 for controls p=0.04) . Diet induced obesity and hyperglycaemia resulted in a loss of co-ordinated calcium waves in transplanted islets. This was reversed with GCG-analogue treatment, independently of weight-loss (n=8) . Conclusion: These data provide novel evidence for the role of intra-islet glucagon in sustaining synchronised calcium oscillations and support a possible therapeutic role for glucagonergic agents to restore the insulin pulsatility lost in T2D. Disclosure K.Suba: n/a. B.Jones: None. T.M.Tan: Consultant; Zihipp Ltd. B.Owen: None. D.J.Drucker: Consultant; Kallyope, Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Other Relationship; Eli Lilly and Company. S.Bloom: None. K.Murphy: None. V.Salem: None. Y.S.Patel: Employee; PerkinElmer. A.Roberts: None. J.V.Shrewsbury: None. S.Chen: None. R.Kwok: None. V.Kalogianni: None. X.Liu: None. G.A.Rutter: Advisory Panel; Sun Pharmaceutical Industries Ltd., Research Support; Sun Pharmaceutical Industries Ltd.

Objective Using a systematic review and meta-analysis, we aimed to estimate the mean effect of acute glucagon administration on components of energy balance and glucose homoeostasis in adults without diabetes. Methods CENTRAL, CINAHL, Embase, MEDLINE, PubMed, and Scopus databases were searched from inception to May 2021. To be included, papers had to be a randomised, crossover, single- or double-blind study, measuring ad libitum meal energy intake, energy expenditure, subjective appetite, glucose, and/or insulin following acute administration of glucagon and an appropriate comparator in adults without diabetes. Risk of bias was assessed using the Revised Cochrane Risk of Bias Tool for Randomized trials with additional considerations for cross-over trials. Certainty of evidence was assessed using the GRADE approach. Random-effect meta-analyses were performed for outcomes with at least five studies. This study is registered on PROSPERO (CRD42021269623). Results In total, 13 papers (15 studies) were considered eligible: energy intake (5 studies, 77 participants); energy expenditure (5 studies, 59 participants); subjective appetite (3 studies, 39 participants); glucose (13 studies, 159 participants); insulin (12 studies, 147 participants). All studies had some concerns with regards to risk of bias. Mean intervention effect of acute glucagon administration on energy intake was small (standardised mean difference [SMD]: –0.19; 95% CI, –0.59 to 0.21; P = 0.345). Mean intervention effect of acute glucagon administration on energy expenditure (SMD: 0.72; 95% CI, 0.37–1.08; P P P Conclusions Acute glucagon administration produces substantial increases in energy expenditure, and in circulating insulin and glucose concentrations. However, the effect of acute glucagon administration on energy intake is unclear. Insufficient evidence was available to evaluate the acute effect of glucagon on subjective appetite.