Acyl-ghrelin mediated lipid retention and inflammation within in vitro and ex vivo adipose depots

The 28 amino acid hormone, ghrelin, has been found to have various effects on metabolism. This thesis focuses on the pathways integrated into ghrelin’s effect within adipocytes and adipose tissue depots of those with and without Type 2 diabetes. To determine whether acyl-ghrelin plays a role in mediating the metabolic state in an in vitro and ex vivo setting this thesis investigates cellular mechanisms via the analysis of: lipid staining, lipid retention gene expression pathway, inflammatory marker levels and determination of oxidative burden. This project confirms and translates previous murine model findings that establishes a mediatory role for acyl-ghrelin within lipid retention. Furthermore, this mechanism is influenced and magnified within the presence of hyperglycaemia, indicating that the impact of glucose metabolism on acyl-ghrelin and lipid homeostasis may result in the deterioration of dyslipidaemia. In addition to novel findings relating to lipid retention, results indicate that acyl-ghrelin also impacts the inflammatory state. Acyl-ghrelin exposure resulted in a marked decrease in pro-inflammatory marker IL-6, and ghrelin mRNA expression was associated with an increase in IL-10 and total antioxidant status. The promotion of the inflammatory state in the presence of acyl-ghrelin may yield novel therapeutic avenues for acyl-ghrelin combination treatment in the amelioration of the low-grade inflammation present within Type 2 diabetes

Interrupting prolonged sitting with frequent short bouts of light‐intensity activity in people with type 1 diabetes improves glycaemic control without increasing hypoglycaemia: The <scp>SIT‐LESS</scp> randomised controlled trial

AimTo examine the impact of interrupting prolonged sitting with frequent short bouts of light-intensity activity on glycaemic control in people with type 1 diabetes (T1D).Materials and MethodsIn total, 32 inactive adults with T1D [aged 27.9 ± 4.7 years, 15 men, diabetes duration 16.0 ± 6.9 years and glycated haemoglobin 8.4 ± 1.4% (68 ± 2.3 mmol/mol)] underwent two 7-h experimental conditions in a randomised crossover fashion with >7-day washout consisting of: uninterrupted sitting (SIT), or, interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals (SIT-LESS). Standardised mixed-macronutrient meals were administered 3.5 h apart during each condition. Blinded continuous glucose monitoring captured interstitial glucose responses during the 7-h experimental period and for a further 48-h under free-living conditions.ResultsSIT-LESS reduced total mean glucose (SIT 8.2 ± 2.6 vs. SIT-LESS 6.9 ± 1.7 mmol/L, p = .001) and increased time in range (3.9-10.0 mmol/L) by 13.7% (SIT 71.5 ± 9.5 vs. SIT-LESS 85.1 ± 7.1%, p = .002). Hyperglycaemia (>10.0 mmol/L) was reduced by 15.0% under SIT-LESS (SIT 24.2 ± 10.8 vs. SIT-LESS 9.2 ± 6.4%, p = .002), whereas hypoglycaemia exposure (<3.9 mmol/L) (SIT 4.6 ± 3.0 vs. SIT-LESS 6.0 ± 6.0%, p = .583) was comparable across conditions. SIT-LESS reduced glycaemic variability (coefficient of variation %) by 7.8% across the observation window (p = .021). These findings were consistent when assessing discrete time periods, with SIT-LESS improving experimental and free-living postprandial, whole-day and night-time glycaemic outcomes (p < .05).ConclusionsInterrupting prolonged sitting with frequent short bouts of light-intensity activity improves acute postprandial and 48-h glycaemia in adults with T1D. This pragmatic strategy is an efficacious approach to reducing sedentariness and increasing physical activity levels without increasing risk of hypoglycaemia in T1D

Assessing the Link between Individual Differences in Distress Tolerance and the use of Exposure-Based Therapies in UK based Cognitive Behavioural Therapists

Despite the demonstrated effectiveness of exposure-based therapies, studies show that therapists often avoid using exposure or do so in ways not consistent with evidence-based practice. Delivering exposure in an overly cautious, suboptimal manner, such as in combination with arousal reduction techniques, has been shown to reduce exposures effectiveness and can exacerbate clients’ symptoms. Research points to therapist characteristics, such as experiential avoidance of discomfort, as interfering with exposure use and delivery. The present study used an online survey including a therapy case vignette to evaluate the extent to which CBT therapists practicing in the UK would choose to use exposure, and to explore the links between therapists’ traits related to their ability to tolerate distress, and their use and delivery of exposure. As part of this exploration, the role of ACT training on experiential avoidance, cognitive fusion, exposure use and exposure delivery was considered. Results show most therapists chose to use exposure therapy; however, they delivered exposure in a suboptimal manner. Therapists’ traits related to distress tolerance were significantly correlated with their use and delivery of exposure. Suggesting therapists who struggle to manage their own distress, are less likely to use exposure therapy and, if used, are more likely to deliver exposure in an overly cautious, suboptimal manner. We found participants trained in ACT, in addition to CBT, used exposure more and delivered it closer to recommended guidelines. Experiential avoidance and cognitive fusion fully mediated this relationship, suggesting ACT training improves therapists use and delivery of exposure through decreasing their experiential avoidance and cognitive fusion. The findings highlight the need for further research into therapist factors impacting exposure use, particularly into the role of empathy and when it leads to distress. This research suggests training and supervision aimed at decreasing therapists’ experiential avoidance and cognitive fusion, may improve both delivery and frequency of exposure use, alongside making organisational changes to reduce therapists distress linked to burnout

Anti-carcinogenic effects of exercise-conditioned human serum: evidence, relevance and opportunities

Regular physical activity reduces the risk of several site-specific cancers in humans and suppresses tumour growth in animal models. The mechanisms through which exercise reduces tumour growth remain incompletely understood, but an intriguing and accumulating body of evidence suggests that the incubation of cancer cells with post-exercise serum can have powerful effects on key hallmarks of cancer cell behaviour in vitro. This suggests that exercise can impact tumour biology through direct changes in circulating proteins, RNA molecules and metabolites. Here, we provide a comprehensive narrative overview of what is known about the effects of exercise-conditioned sera on in vitro cancer cell behaviour. In doing so, we consider the key limitations of the current body of literature, both from the perspective of exercise physiology and cancer biology, and we discuss the potential in vivo physiological relevance of these findings. We propose key opportunities for future research in an area that has the potential to identify key anti-oncogenic protein targets and optimise physical activity recommendations for cancer prevention, treatment and survivorship

Liquid Metal-Enabled Filtering Switches and Switchplexers

The via-pad-slot (VPS) structure, as the switchable element, has been used to demonstrate a single-pole-triple-throw (SPTT) filtering switch and a switchplexer. The VPS can be flexibily switched using liquid metal (LM) or high dielectric constant materials to either cover or uncover the slot. Since the LM only moves on the surface of the VPS and the substrate-integrated waveguide (SIW), the implementation and actuation of the LM is simple and does not cause excessive loss on the device. In the switchplexer design, all channels can be switched on and off to form filters or multiplexers of various channel combinations. Additional transmission zeros (TZs) can be generated by the loaded, partially switched-off channel. The generation of the TZs was discussed and analyzed using coupling matrix approach. The demonstrated &lt;italic&gt;X&lt;/italic&gt;-band (9.56&amp;#x2013;10.44 GHz) cross-shaped SPTT fifth-order filtering switch exhibits a suppression level of better than 40 dB at 8 and 12 GHz, an insertion loss (IL) of 1.55 dB at 10 GHz, and an isolation level of 58 dB at 10 GHz. The &lt;italic&gt;X&lt;/italic&gt;-band switchplexer operates at three frequency bands, e.g., 11.08&amp;#x2013;11.55 GHz, 10.61&amp;#x2013;10.99 GHz, and 9.76&amp;#x2013;10.33 GHz. The LM-enabled VPS-based switchable element can be integrated with other multifunctional circuits and systems for channel control and reconfiguration.</p

Design and fabrication of a next generation regenerative neural interface

A Spiral Peripheral Neural Interface (SPNI) is an electrode array that has been previously presented as a regenerative neural interface capable of receiving information from, and transmitting information to nerves. The SPNI has previously been proven in concept, however, when stimulating nerves in the device, the electrodes areinsufficiently isolated from each other and stimulations can trigger unwanted neural activity in neighbouring channels of the SPNI. Along with this, neural interfaces generally, suffer from chronic viability problems, due to biological rejection. These issues were addressed in this thesis, by the addition of a PDMS silicone membrane, into the structure of the SPNI. Improvements to the understanding and performance of structural, electrical and biocompatibility aspects of the SPNI are addressed, with the addition of the PDMS film, which is used to electrically seal SPNI channels whilst not hindering conductor integrity. The inclusion ofPDMS also provides a platform which may enable drug delivery. This work dramatically improves SPNI performance whilst providing routes to improved biocompatibility. This thesis addresses the main issues previously presented in the SPNI and brings the device up to a new standard which can once again be tested for its viability in vivo

Temporal Effects of Sleeve Gastrectomy on Glucose-Insulin Homeostasis and Incretin Hormone Response at 1 and 6 Months

BackgroundBariatric surgery is an effective treatment for morbid obesity and glycaemic dysfunction.ObjectivesThe aim of the work was to examine both the static and dynamic changes of glucose-insulin homeostasis and incretin hormone response following sleeve gastrectomy (SG) in a sample of 55 participants preoperatively and 1 month and 6 months postoperatively. The focus was on a sample of patients with impaired glucose tolerance and type 2 diabetes (T2D).SettingMorriston Hospital, UK.MethodsProspective study comprising of 55 participants with impaired glucose homeostasis and T2D undergoing SG (mean body mass index [BMI] 50.4 kg/m2, mean glycated haemoglobin [A1C] 7.4%). Serial measurements of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic hormone (GIP) were performed during oral glucose tolerance testing preoperatively and 1 and 6 months postoperatively. Areas under the curve (AUC) were examined at 30, 60, and 120 min.ResultsWe observed significant improvements in measures of obesity, as well as static and dynamic measures of glucose, insulin, C-peptide and HOMA. Furthermore, significant increases in GLP-1 response as early as 6 months postoperatively were also seen.ConclusionsTo our knowledge, no study has examined the detailed dynamic changes in glucose and insulin homeostasis in this number of participants undergoing SG in relation to incretin hormones GIP and GLP-1. This current study supports the role of SG for the treatment of obesity-related glucose dysregulation