Organ-on-a-Chip Research at Salem Lab
Salem Lab is at the forefront of Organ-on-a-Chip research, utilizing innovative bioengineering techniques to advance islet biology and find new treatments for type 1 diabetes. Our team is dedicated to pushing the boundaries of scientific knowledge and making groundbreaking discoveries that will shape the future of medical research.
Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homeostasis
Background Type 2 diabetes (T2D) is characterised by the loss of first-phase insulin secretion. We studied mice with β-cell selective loss of the glucagon receptor (Gcgrfl/fl X Ins-1Cre), to investigate the role of intra-islet glucagon receptor signalling on pan-islet calcium activity and insulin secretion. Methods Metabolic profiling was conducted on Gcgrβ-cell−/− and littermate controls. Crossing with GCaMP6f (STOP flox) animals further 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. Part 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 Gcgrβ-cell−/− mice exhibited higher glucose levels following intraperitoneal glucose challenge (control 12.7 mmol/L ± 0.6 vs. Gcgrβ-cell−/− 15.4 mmol/L ± 0.0 at 15 min, p = 0.002); fasting glycaemia was not different to controls. In vitro, Gcgrβ-cell−/− islets showed profound loss of pan-islet [Ca2+]I waves in response to glucose which was only partially rescued in vivo. Diet induced obesity and hyperglycaemia also resulted in a loss of co-ordinated [Ca2+]I 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 GCGR signalling in sustaining synchronised [Ca2+]I waves and support a possible therapeutic role for glucagonergic agents to restore the insulin secretory capacity lost in T2D.
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.
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.