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.

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.

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.

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.

Leader ß-cells coordinate Ca2+ dynamics across pancreatic islets in vivo.

Pancreatic ß-cells form highly connected networks within isolated islets. Whether this behaviour pertains to the situation in vivo, after innervation and during continuous perfusion with blood, is unclear. In the present study, we used the recombinant Ca2+ sensor GCaMP6 to assess glucose-regulated connectivity in living zebrafish Danio rerio, and in murine or human islets transplanted into the anterior eye chamber. In each setting, Ca2+ waves emanated from temporally defined leader ß-cells, and three-dimensional connectivity across the islet increased with glucose stimulation. Photoablation of zebrafish leader cells disrupted pan-islet signalling, identifying these as likely pacemakers. Correspondingly, in engrafted mouse islets, connectivity was sustained during prolonged glucose exposure, and super-connected 'hub' cells were identified. Granger causality analysis revealed a controlling role for temporally defined leaders, and transcriptomic analyses revealed a discrete hub cell fingerprint. We thus define a population of regulatory ß-cells within coordinated islet networks in vivo. This population may drive Ca2+ dynamics and pulsatile insulin secretion.