The vagus nerve mediates the physiological but not pharmacological effects of PYY3-36 on food intake.

Peptide YY (PYY3-36) is a post-prandially released gut hormone with potent appetite-reducing activity, the mechanism of action of which is not fully understood. Unravelling how this system physiologically regulates food intake may help unlock its therapeutic potential, whilst minimising unwanted effects. Here we demonstrate that germline and post-natal targeted knockdown of the PYY3-36 preferring receptor (neuropeptide Y (NPY) Y2 receptor (Y2R)) in the afferent vagus nerve is required for the appetite inhibitory effects of physiologically-released PYY3-36, but not peripherally administered pharmacological doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is not evident in the germline model. Loss of vagal Y2R signalling also results in altered meal patterning associated with accelerated gastric emptying. These results are important for the design of PYY-based anti-obesity agents.

What can functional brain imaging teach us about remission of type 2 diabetes?

AIMS: With a paradigm shift in attitudes towards type 2 diabetes (T2D), 'weight loss responsive' diabetes is now thought of as a curable disease state. As a result, national programmes are being orchestrated to induce T2D remission soon after diagnosis with aggressive dietary interventions-such as very low-calorie diets (VLCD). However, dietary interventions to achieve weight loss and diabetes remission lack the same long-term sustainability and cardiovascular risk reduction evidence as bariatric surgery. This review aims to explore how brain imaging has contributed to our understanding of human eating behaviours and how neural correlates are affected by T2D. METHODS: We summarise functional MRI (fMRI) studies looking at human eating behaviour and obesity. We explore how these neural correlates are affected by insulin resistance and T2D itself as well as its different treatment approaches. Finally, we comment on the need for more personalised approaches to maintaining metabolic health and how fMRI studies may inform this. CONCLUSION: fMRI studies have helped to fashion our understanding of the neurobiology of human appetite and obesity. Improving our understanding of the neural implications of T2D that promote disadvantageous eating behaviours will enable prevention of disease as well as mitigation against a vicious cycle of metabolic dysfunction and associated cognitive complications.

Newly detected diabetes during the COVID-19 pandemic: What have we learnt?

The SARS-CoV-2 pandemic has had an unprecedented effect on global health, mortality and healthcare provision. Diabetes has emerged as a key disease entity over the pandemic period, influencing outcomes from COVID-19 but also a tantalising hypothesis that the virus itself may be inducing diabetes. An uptick in diabetes cases over the pandemic has been noted for both type 1 diabetes (in children) and type 2 diabetes but understanding how this increase in incidence relates to the pandemic is challenging. It remains unclear whether indirect effects of the pandemic on behaviour, lifestyle and health have contributed to the increase; whether the virus itself has somehow mediated new-onset diabetes or whether other factors such as stress hyperglycaemic of steroid treatment during COVID-19 infection have played a roll. Within the myriad possibilities are some real challenges in interpreting epidemiological data, assigning diabetes type and understanding what in vitro data are telling us. In this review article we address the issue of newly-diagnosed diabetes during the pandemic, reviewing both epidemiological and basic science data and bringing together both strands of this emerging story.

Highly specific and non-invasive imaging of Piezo1-dependent activity across scales using GenEPi.

Mechanosensing is a ubiquitous process to translate external mechanical stimuli into biological responses. Piezo1 ion channels are directly gated by mechanical forces and play an essential role in cellular mechanotransduction. However, readouts of Piezo1 activity are mainly examined by invasive or indirect techniques, such as electrophysiological analyses and cytosolic calcium imaging. Here, we introduce GenEPi, a genetically-encoded fluorescent reporter for non-invasive optical monitoring of Piezo1-dependent activity. We demonstrate that GenEPi has high spatiotemporal resolution for Piezo1-dependent stimuli from the single-cell level to that of the entire organism. GenEPi reveals transient, local mechanical stimuli in the plasma membrane of single cells, resolves repetitive contraction-triggered stimulation of beating cardiomyocytes within microtissues, and allows for robust and reliable monitoring of Piezo1-dependent activity in vivo. GenEPi will enable non-invasive optical monitoring of Piezo1 activity in mechanochemical feedback loops during development, homeostatic regulation, and disease.

Divergent acute versus prolonged pharmacological GLP-1R responses in adult ß cell-specific ß-arrestin 2 knockout mice.

The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by ß-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 in adult ß cell-specific ß-arrestin 2 knockout (KO) mice. KOs displayed a sex-dimorphic phenotype consisting of weaker acute responses that improved 6 hours after agonist injection. Similar effects were observed for semaglutide and tirzepatide but not with biased agonist exendin-phe1. Acute cyclic adenosine 5'-monophosphate increases were impaired, but desensitization reduced in KO islets. The former defect was attributed to enhanced ß-arrestin 1 and phosphodiesterase 4 activities, while reduced desensitization co-occurred with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. This study has unveiled fundamental aspects of GLP-1R response regulation with direct application to the rational design of GLP-1R-targeting therapeutics.

The Arab COVID-19 Anxiety Syndrome Scale (C-19ASS): COVID-19 anxiety syndrome and psychological symptoms in the Saudi Arabian population.

INTRODUCTION: The COVID-19 Anxiety Syndrome Scale (C-19ASS) is a reliable scale assessing dysfunctional coping strategies activated in response to COVID-19 fear and threat. The present study aimed to provide a validation of the Arabic version of the C-19ASS and to explore the association between the C-19ASS and psychological symptoms syndrome. METHOD: In Study 1, a community sample of 404 participants completed the Arabic version of the C-19ASS and results were subjected to an exploratory factor analysis. In Study 2, a community sample of 903 participants completed the Arabic version of the C-19ASS and a series of measures assessing depressed mood and anhedonia, generalized anxiety and health anxiety. Internal consistency, construct validity and incremental validity were assessed. Associations between C-19ASS and psychological symptoms were assessed. RESULTS: Factor analysis identified a two-factor solution (i.e., C-19ASS-Perseveration and C-19ASS-Avoidance), and confirmatory factor analysis suggested a two-factor model best fits the data. The Arabic version of the C-19ASS showed good internal consistency, good construct and incremental validity. COVID-19 anxiety syndrome was associated with more severe anxiety symptoms, depressive symptoms and health anxiety. Females had higher levels of COVID-19 anxiety syndrome than males. Participants diagnosed with COVID-19, and those who had experienced loss as a consequence of COVID-19, had higher levels of COVID-19 anxiety syndrome (Perseveration). CONCLUSIONS: The Arabic version of the C-19ASS appears to be a reliable and valid measure of the COVID-19 anxiety syndrome. The COVID-19 anxiety syndrome could be a suitable therapeutic target to improve psychological recovery during the COVID-19 pandemic among Arabs.

The acute effect of glucagon on components of energy balance and glucose homoeostasis in adults without diabetes: a systematic review and meta-analysis.

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 < 0.001), glucose (SMD: 1.11; 95% CI, 0.60-1.62; P < 0.001), and insulin (SMD: 1.33; 95% CI, 0.88-1.77; P < 0.001) was moderate to large. 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.

Diabetes self-management during the COVID-19 pandemic and its associations with COVID-19 anxiety syndrome, depression and health anxiety.

INTRODUCTION: The effects of the COVID-19 pandemic on mental health have been profound. Mental health and diabetes self-care are inter-related. We examined whether COVID-19 anxiety, depressive symptoms and health anxiety were associated with domains of diabetes self-management and investigated whether greater COVID-19 anxiety syndrome would independently contribute to suboptimal diabetes self-care. RESEARCH DESIGN AND METHODS: Surveys were sent to people attending diabetes clinics of three London hospitals. Participants completed the Diabetes Self-Management Questionnaire (DSMQ), the COVID-19 Anxiety Syndrome Scale (C-19 ASS), which measures perseveration and avoidant maladaptive coping behaviour, assessed with measures of co-existent depressive symptoms and anxiety, controlling for age, gender and social deprivation. Clinical data, including pre- and post-lockdown HbA1c measures, were obtained from hospital records for 369 respondents, a response rate of 12.8%. RESULTS: Depressive symptom scores were high. Both pre-existing health anxiety and depressive symptoms were independently linked to improvable measures of diabetes care, as was lower socio-economic rank. However, avoidant COVID-19 anxiety responses were independently associated with higher diabetes self-care scores. HbA1c levels improved modestly over the year of UK lockdown in this cohort. CONCLUSION: During the height of lockdown, avoidant coping behaviours characteristic of the COVID-19 anxiety syndrome may in fact work to improve diabetes self-care, at least in the short term. We recommend screening for depressive symptoms and being aware of the significant minority of people with COVID-19 anxiety syndrome who may now find it difficult to re-engage with face-to-face clinic opportunities.

Why are women still leaving academic medicine? A qualitative study within a London Medical School.

OBJECTIVES: To identify factors that influenced women who chose to leave academic medicine. DESIGN AND MAIN OUTCOME MEASURES: Independent consultants led a focus group of women in medicine who had left academia after completion of their postgraduate research degree at Imperial College London Faculty of Medicine. Thematic analysis was performed on the transcribed conversations. PARTICIPANTS AND SETTING: Nine women physicians who completed a postgraduate degree (MD or PhD) at a large London Medical School and Academic Health Sciences Centre, Imperial College London, but did not go on to pursue a career in academic medicine. RESULTS: Influences to leave clinical academia were summarised under eight themes-career intentions, supervisor support, institutional human resources support, inclusivity, work-life balance, expectations, mentors and role models, and pregnancy and maternity leave. CONCLUSION: The women in our focus group reported several factors contributing to their decision to leave clinical academia, which included lack of mentoring tailored to specific needs, low levels of acceptance for flexible working to help meet parental responsibilities and perceived explicit gender biases. We summarise the multiple targeted strategies that Imperial College London has implemented to promote retention of women in academic medicine, although more research needs to be done to ascertain the most effective interventions.

Low-Frequency Oscillations of In Vivo Ambient Extracellular Brain Serotonin.

Serotonin is an important neurotransmitter that plays a major role in many aspects of neuroscience. Fast-scan cyclic voltammetry measures fast in vivo serotonin dynamics using carbon fiber microelectrodes. More recently, fast-scan controlled-adsorption voltammetry (FSCAV) has been developed to measure slower, minute-to-minute changes in ambient extracellular serotonin. We have previously demonstrated that FSCAV measurements of basal serotonin levels give critical information regarding brain physiology and disease. In this work, we revealed the presence of low-periodicity fluctuations in serotonin levels in mouse hippocampi, measured in vivo with FSCAV. Using correlation analyses, we found robust evidence of oscillations in the basal serotonin levels, which had a period of 10 min and were not present in vitro. Under control conditions, the oscillations did not differ between male and female mice, nor do they differ between mice that underwent a chronic stress paradigm and those in the control group. After the acute administration of a selective serotonin reuptake inhibitor, we observed a shift in the frequency of the oscillations, leading us to hypothesize that the newly observed fluctuations were transporter regulated. Finally, we optimized the experimental parameters of the FSCAV to measure at a higher temporal resolution and found more pronounced shifts in the oscillation frequency, along with a decreased oscillation amplitude. We postulate that this work may serve as a potential bridge for studying serotonin/endocrine interactions that occur on the same time scale.

Understanding concepts of generalism and specialism amongst medical students at a research-intensive London medical school.

BACKGROUND: Many prominent UK medical organisations have identified a need for more generalist clinicians to address the complex requirements of an aging society. We sought to clarify attitudes towards "Specialists" and "Generalists" amongst medical students and junior doctors at Imperial College School of Medicine. METHODS: A survey exploring medical students' beliefs was followed up by qualitative analysis of focus groups of medical students and Imperial-graduate foundation year doctors. RESULTS: First year medical students associated specialists with academia and higher income, and generalists with ease of training and job availability. Senior (Years 5/6) medical students associated specialists even more firmly with broader influence and academic work, whilst generalists were assigned lower prestige but the same workload as specialists. The medical student focus group discussed concepts of Generalism pertaining only to Primary Care. In contrast, the foundation year doctor focus group revealed that Generalism was now seen to include some hospital care, and the perception that generalists sat lower in a knowledge hierarchy had been challenged. CONCLUSION: Perceptions that Generalism is associated with lower prestige in the medical profession are already present at the very start of medical school and seem to be reinforced during undergraduate training. In early postgraduate clinical practice, the perceived knowledge and prestige hierarchy lessens. These findings can help inform curriculum redesign and the promotion of Generalism as a rewarding career aspiration.

Prevalence, risk factors, and interventions for obesity in Saudi Arabia: A systematic review.

Saudi Arabia (SA) has a reported obesity prevalence greater than the global average. Here, we systematically review firstly the prevalence and associated factors (59 studies) and secondly the pharmacological, lifestyle, and surgical interventions for obesity (body mass index, >30 kg/m2 ) in SA (29 studies) between December 2020 and March 2021 in PubMed, Medline, Embase, PsycINFO, and Cochrane. Peer-reviewed articles in Arabic and English on human adults (aged >18 years) were searched. Among the eight largest studies with sample sizes over 10,000 people, the maximum-reported obesity prevalence was 35.6%, with notable variations in gender and geographic region. Diet, specifically the move towards Western diet and heavy consumption of sugary beverages, and high levels of inactivity are major contributing factors to obesity. The reported obesity-risk polymorphisms are not specific. Bariatric surgery is underrepresented, and in general, there is a lack of nationally coordinated studies on weight loss interventions. In particular, the systematic review did not find a body of research on psychological interventions. There is no trial data for the use of GLP-1 analogs in SA, despite their widespread use. These findings can help policymakers, and practitioners prioritize future research efforts to reduce obesity prevalence in SA.

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes.

Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.

Intravital imaging of islet Ca2+ dynamics reveals enhanced ß cell connectivity after bariatric surgery in mice.

Bariatric surgery improves both insulin sensitivity and secretion and can induce diabetes remission. However, the mechanisms and time courses of these changes, particularly the impact on ß cell function, are difficult to monitor directly. In this study, we investigated the effect of Vertical Sleeve Gastrectomy (VSG) on ß cell function in vivo by imaging Ca2+ dynamics in islets engrafted into the anterior eye chamber. Mirroring its clinical utility, VSG in mice results in significantly improved glucose tolerance, and enhanced insulin secretion. We reveal that these benefits are underpinned by augmented ß cell function and coordinated activity across the islet. These effects involve changes in circulating GLP-1 levels which may act both directly and indirectly on the ß cell, in the latter case through changes in body weight. Thus, bariatric surgery leads to time-dependent increases in ß cell function and intra-islet connectivity which are likely to contribute to diabetes remission.

Weight Loss by Low-Calorie Diet Versus Gastric Bypass Surgery in People With Diabetes Results in Divergent Brain Activation Patterns: A Functional MRI Study.

OBJECTIVE: Weight loss achieved with very-low-calorie diets (VLCDs) can produce remission of type 2 diabetes (T2D), but weight regain very often occurs with reintroduction of higher calorie intakes. In contrast, bariatric surgery produces clinically significant and durable weight loss, with diabetes remission that translates into reductions in mortality. We hypothesized that in patients living with obesity and prediabetes/T2D, longitudinal changes in brain activity in response to food cues as measured using functional MRI would explain this difference. RESEARCH DESIGN AND METHODS: Sixteen participants underwent gastric bypass surgery, and 19 matched participants undertook a VLCD (meal replacement) for 4 weeks. Brain responses to food cues and resting-state functional connectivity were assessed with functional MRI pre- and postintervention and compared across groups. RESULTS: We show that Roux-en-Y gastric bypass surgery (RYGB) results in three divergent brain responses compared with VLCD-induced weight loss: 1) VLCD resulted in increased brain reward center food cue responsiveness, whereas in RYGB, this was reduced; 2) VLCD resulted in higher neural activation of cognitive control regions in response to food cues associated with exercising increased cognitive restraint over eating, whereas RYGB did not; and 3) a homeostatic appetitive system (centered on the hypothalamus) is better engaged following RYGB-induced weight loss than VLCD. CONCLUSIONS: Taken together, these findings point to divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast to enduring weight loss after RYGB.