The transCampus Metabolic Training Programme Explores the Link of SARS-CoV-2 Virus to Metabolic Disease.

Currently, we are experiencing a true pandemic of a communicable disease by the virus SARS-CoV-2 holding the whole world firmly in its grasp. Amazingly and unfortunately, this virus uses a metabolic and endocrine pathway via ACE2 to enter our cells causing damage and disease. Our international research training programme funded by the German Research Foundation has a clear mission to train the best students wherever they may come from to learn to tackle the enormous challenges of diabetes and its complications for our society. A modern training programme in diabetes and metabolism does not only involve a thorough understanding of classical physiology, biology and clinical diabetology but has to bring together an interdisciplinary team. With the arrival of the coronavirus pandemic, this prestigious and unique metabolic training programme is facing new challenges but also new opportunities. The consortium of the training programme has recognized early on the need for a guidance and for practical recommendations to cope with the COVID-19 pandemic for the community of patients with metabolic disease, obesity and diabetes. This involves the optimal management from surgical obesity programmes to medications and insulin replacement. We also established a global registry analyzing the dimension and role of metabolic disease including new onset diabetes potentially triggered by the virus. We have involved experts of infectious disease and virology to our faculty with this metabolic training programme to offer the full breadth and scope of expertise needed to meet these scientific challenges. We have all learned that this pandemic does not respect or heed any national borders and that we have to work together as a global community. We believe that this transCampus metabolic training programme provides a prime example how an international team of established experts in the field of metabolism can work together with students from all over the world to address a new pandemic.

The crossed-leg position increases the dimensions within the acoustic target window for neuraxial needle placement in term pregnancy: a prospective observational study.

INTRODUCTION: Neuraxial anesthesia in obstetric patients may be difficult to achieve due to anatomical changes in pregnancy. The crossed-leg position may help in optimizing patient position. We prospectively evaluated the utility of the crossed-leg position compared with a standard position using ultrasound measurements. METHODS: Thirty women with term singleton pregnancy admitted for vaginal delivery were recruited. Women with a history of spinal trauma or surgery, congenital spinal abnormality, advanced first stage of labor or a language barrier were excluded. Two anesthesiologists, blinded to each other's measurements, scanned each subject in the crossed-leg position and standard position. Measurements of the lengths of the posterior longitudinal ligament, ligamentum flavum and interlaminar distance were recorded at the L3-L4 interspace. Comfort level in each position was scored on a Likert Scale. RESULTS: Twenty-nine women completed the study (complete data n=28). Significant increases were observed in the lengths of the posterior longitudinal ligament (mean difference 2.2 mm, 95% CI 1.3 to 3.2; P <0.001), ligamentum flavum (mean difference 1.4 mm, 95% CI 0.7 to 2.1; P <0.001) and interlaminar distance (mean difference 1.4 mm, 95% CI 0.4 to 2.5; P=0.006) in the crossed-leg position. No significant differences in comfort were observed. CONCLUSION: We demonstrated a significant increase in the sonographically measured lengths of the posterior longitudinal ligament, ligamentum flavum and interlaminar distance in the crossed-leg position when compared with the standard position. Both positions were comfortable. Further studies should explore whether these findings translate clinically into easier needle placement in the crossed-leg position.

Efficacy of the Epidural Positioning Device® in optimizing the acoustic target window for neuraxial needle placement in term pregnancy.

BACKGROUND: Neuraxial anesthesia can be challenging in obstetric patients due to the gravid uterus interfering with patient positioning. Ultrasound is commonly used in obstetric anesthesia to facilitate neuraxial needle placement. Some positioning maneuvers facilitate the ultrasound visualization of structures and the placement of neuraxial needles, but the Epidural Positioning Device (EPD) has yet to be evaluated. OBJECTIVES: Our goal was to evaluate whether the use of the EPD increased the acoustic target window in the lumbar area of pregnant patients. We hypothesized that the application of the EPD would increase the measured lengths of the paravertebral longitudinal ligament (PLL), the interlaminar distance (ILD) and the ligamentum flavum (LF). METHODS: Lumbar ultrasonography was performed on 29 pregnant women having an elective cesarean delivery. Two anesthesiologists independently scanned the L3-4 right paramedian space, using a curvilinear ultrasound transducer, in two positions for each patient: traditional sitting with lumbar flexion and sitting with use of the EPD for lumbar flexion. The PLL, ILD and LF lengths were measured using the ultrasound caliper software and recorded, with the anesthesiologists blinded to the results. Patients were asked to rate their comfort in both positions. RESULTS: There were no significant differences between the measured lengths of the PLL, ILD and LF in the two positions. Patient comfort was significantly higher with use of the EPD (OR 10, 95% CI 2.4 to 88). CONCLUSION: Although the application of an EPD did not improve the paramedian acoustic target area in term parturients, greater patient comfort might facilitate needle placement.

Identifying barriers to the use of ultrasound in the perioperative period: a survey of southwestern Ontario anesthesiologists.

BACKGROUND: Ultrasound (US) can be used for many perioperative procedures, but evidence is lacking as to its frequency of use and barrier of application. The objectives of this survey were to determine i) how often US guidance was used perioperatively for vascular access placement, nerve blocks, and heart and lung assessment, and ii) to identify the barriers and the limitations of using US amongst anesthesiologists in southwestern Ontario. METHODS: We conducted a web-based survey in over 40 academic or community hospitals at southwestern Ontario. RESULTS: Of 266 surveys sent, 66 complete surveys were obtained (response rate of 25%). Most respondents (> 80%) reported that US was commonly used for central venous catheter (CVC) insertion, followed by regional blocks; the uses were less frequent for neuraxial blockade and cardiopulmonary assessment. Most respondents wanted to use US more frequently as part of their practice and felt that they already had adequate US training. However, most respondents (59%) reported limited access to US machines in their working institutes as being the major barrier to incorporating US in their daily practice. CONCLUSION: The most common uses of US in anesthesia practice in southwestern Ontario were for CVC insertion and regional blocks. Most anesthesiologists in southwestern Ontario are interested to incorporate US in their daily practice but most were limited by the lack of US resources. Apparently, only providing knowledge and skills teaching may not be sufficient to further improve the US utilization in our region; a matched administrative effort appears to be the next challenge.

Educating anesthesia residents to obtain and document informed consent for epidural labor analgesia: does simulation play a role?

BACKGROUND: Informed consent is required before placing an epidural. At our hospital, teaching of residents about this is done informally at the bedside. This study aimed to assess the ability of anesthesia residents to acquire and retain knowledge required when seeking informed consent for epidural labor analgesia. It assessed how well this knowledge was translated to clinical ability, by assessing the verbal consent process during an interaction with a standardized patient. METHODS: Twenty anesthesia residents were randomized to a 'didactic group' or a 'simulation group'. Each resident was presented with a written scenario and asked to document the informed consent process, as they normally would do (pre-test). The didactic group then had a presentation about informed consent, while the simulation group members interviewed a simulated patient, the scenarios focusing on different aspects of consent. All residents then read a scenario and documented their informed consent process (post-test). Six weeks later all residents interviewed a standardized patient in labor and documented the consent from this interaction (six-week test). RESULTS: There was no significant difference in the baseline performance of the two groups. Both groups showed significant improvement in their written consent documentation at the immediate time point, the improvement in the didactic group being greater. The didactic group performed better at both the immediate time point and the six-week time point. CONCLUSIONS: In this small study, a didactic teaching method proved better than simulation-based teaching in helping residents to gain knowledge needed to obtain informed consent for epidural labor analgesia.

Onset of labour epidural analgesia with low-dose bupivacaine and different doses of fentanyl.

This study investigated the effects of different doses of epidural fentanyl on the time to onset of epidural analgesia in women in early labour. We hypothesised that onset of epidural labour analgesia (the primary outcome defined as time in minutes from completion of epidural bolus to the first uterine contraction with a numeric pain rating scale [NPRS] score ≤ 3) would be faster with 100 µg of fentanyl epidural bolus compared with 20 µg or 50 µg. Epidural labour analgesia was initiated with 20 µg of fentanyl (F20 group), 50 µg (F50 group) or 100 µg (F100 group) along with 10 ml bupivacaine 0.08% as the loading dose. We randomly allocated 105 patients, with 35 patients in each group. Median (IQR [range]) time to achieve NPRS ≤ 3 was 18 (11-30 [6-20]) min in F20, 10 (8-19 [4-30]) min in F50 and 10 (6-16 [3-30]) min in F100 groups. There was a significant difference in onset times comparing F100 with F20 (p < 0.001) and F50 with F20 (p = 0.007), but not significantly different comparing F100 with F50 (p = 0.19). The median (IQR [range]) time from the epidural loading dose to first patient controlled epidural analgesia bolus was 61 min (20-165 [20-420]) in F20, 118 min (66-176 [20-396]) in F50 and 150 min (66-214 [30-764]) in F100 groups. This was not statistically significant (p = 0.16) comparing the F20 with the F100 group. There were no significant differences in maternal side-effects, mode of delivery, patient satisfaction scores or neonatal Apgar scores between all groups. We conclude that the 50 µg and 100 µg fentanyl doses were associated with reduced onset times to effective analgesia compared with the 20 µg dose.

Evaluation of cardiovascular risk-lowering health benefits accruing from laboratory-based, community-based and exercise-referral exercise programmes.

BACKGROUND: To evaluate the ability of community-based exercise programmes to facilitate public participation in exercise and hence improved cardiovascular health, we assessed the respective impacts of: a continuously monitored exercise programme based within our university (study 1); a Valleys Regional Park-facilitated community-based outdoor exercise programme (study 2); a Wales National Exercise Referral Scheme-delivered exercise-referral programme (study 3). METHODS: Biomolecular (monocytic PPARγ target gene expression), vascular haemodynamic (central/peripheral blood pressure, arterial stiffness), clinical (insulin sensitivity, blood lipids) and anthropometric (body mass index, waist circumference, heart rate) parameters were investigated using RT-PCR, applanation tonometry, chemical analysis and standard anthropometric techniques. RESULTS: In studies 1-3, 22/28, 32/65 and 11/14 participants adhered to their respective exercise programmes, and underwent significant increases in physical activity levels. Importantly, beneficial effects similar to those seen in our previous studies (eg, modulations in expression of monocytic PPARγ target genes, decreases in blood pressure/arterial stiffness, improvements in blood lipids/insulin sensitivity) were observed (albeit to slightly differing extents) only in participants who adhered to their respective exercise programmes. While study 1 achieved more intense exercise and more pronounced beneficial effects, significant cardiovascular risk-lowering health benefits related to biomolecular markers, blood pressure, arterial stiffness and blood lipids were achieved via community/referral-based delivery modes in studies 2 and 3. CONCLUSIONS: Because cardiovascular health benefits were observed in all 3 studies, we conclude that the majority of benefits previously reported in laboratory-based studies can also be achieved in community-based/exercise-referral settings. These findings may be of use in guiding policymakers with regard to introduction and/or continued implementation of community/referral-based exercise programmes.

Lessons from aviation - the role of checklists in minimally invasive cardiac surgery.

We describe an adverse event during minimally invasive cardiac surgery that resulted in a multi-disciplinary review of intra-operative errors and the creation of a procedural checklist. This checklist aims to prevent errors of omission and communication failures that result in increased morbidity and mortality. We discuss the application of the aviation - led "threats and errors model" to medical practice and the role of checklists and other strategies aimed at reducing medical errors.

Equilibrative nucleoside transporter 3 depletion in ß-cells impairs mitochondrial function and promotes apoptosis: Relationship to pigmented hypertrichotic dermatosis with insulin-dependent diabetes.

Loss of function recessive mutations in the SLC29A3 gene that encodes human equilibrative nucleoside transporter 3 (ENT3) have been identified in patients with pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID). ENT3 is a member of the equilibrative nucleoside transporter (ENT) family whose primary function is mediating transport of nucleosides and nucleobases. The aims of this study were to characterise ENT3 expression in islet ß-cells and identify the effects of its depletion on ß-cell mitochondrial activity and apoptosis. RT-PCR amplification identified ENT3 expression in human and mouse islets and exocrine pancreas, and in MIN6 ß-cells. Immunohistochemistry using human and mouse pancreas sections exhibited extensive ENT3 immunostaining of ß-cells, which was confirmed by co-staining with an anti-insulin antibody. In addition, exposure of dispersed human islet cells and MIN6 ß-cells to MitoTracker and an ENT3 antibody showed co-localisation of ENT3 to ß-cell mitochondria. Consistent with this, Western blot analysis confirmed enhanced ENT3 immunoreactivity in ß-cell mitochondria-enriched fractions. Furthermore, ENT3 depletion in ß-cells increased mitochondrial DNA content and promoted an energy crisis characterised by enhanced ATP-linked respiration and proton leak. Finally, inhibition of ENT3 activity by dypridamole and depletion of ENT3 by siRNA-induced knockdown resulted in increased caspase 3/7 activities in ß-cells. These observations demonstrate that ENT3 is predominantly expressed by islet ß-cells where it co-localises with mitochondria. Depletion of ENT3 causes mitochondrial dysfunction which is associated with enhanced ß-cell apoptosis. Thus, apoptotic loss of islet ß-cells may contribute to the occurrence of autoantibody-negative insulin-dependent diabetes in individuals with non-functional ENT3 mutations.

The gene expression signature of anagrelide provides an insight into its mechanism of action and uncovers new regulators of megakaryopoiesis.

BACKGROUND: Anagrelide is a cytoreductive agent used to lower platelet counts in essential thrombocythemia. Although the drug has been known to selectively inhibit megakaryopoiesis for many years, the molecular mechanism accounting for this activity is still unclear. OBJECTIVES AND METHODS: To address this issue we have compared the global gene expression profiles of human hematopoietic cells treated ex-vivo with and without anagrelide while growing under megakaryocyte differentiation conditions, using high-density oligonucleotide microarrays. Gene expression data were validated by the quantitative polymerase chain reaction and mined to identify functional subsets and regulatory pathways. RESULTS: We identified 328 annotated genes differentially regulated by anagrelide, including many genes associated with platelet functions and with the control of gene transcription. Prominent among the latter was TRIB3, whose expression increased in the presence of anagrelide. Pathway analysis revealed that anagrelide up-regulated genes that are under the control of the transcription factor ATF4, a known TRIB3 inducer. Notably, immunoblot analysis demonstrated that anagrelide induced the phosphorylation of eIF2α, which is an upstream regulator of ATF4, and increased ATF4 protein levels. Furthermore, salubrinal, an inhibitor of eIF2α dephosphorylation, increased the expression of ATF4-regulated genes and blocked megakaryocyte growth. CONCLUSIONS: These findings link signaling through eIF2α/ATF4 to the anti-megakaryopoietic activity of anagrelide and identify new potential modulators of megakaryopoiesis.

Reduced nuclear protein 1 expression improves insulin sensitivity and protects against diet-induced glucose intolerance through up-regulation of heat shock protein 70.

We recently reported that deletion of the stress-regulated nuclear protein 1 (Nupr1) protected against obesity-associated metabolic alterations due to increased beta cell mass, but complete Nupr1 ablation was not advantageous since it led to insulin resistance on a normal diet. The current study used Nupr1 haplodeficient mice to investigate whether a partial reduction in Nupr1 expression conferred beneficial effects on glucose homeostasis. Islet number, morphology and area, assessed by immunofluorescence and morphometric analyses, were not altered in Nupr1 haplodeficient mice under normal diet conditions and nor was beta cell BrdU incorporation. Glucose and insulin tolerance tests indicated that there were no significant changes in in vivo insulin secretion and glucose clearance in Nupr1 haplodeficient mice, and beta cell function in vitro was normal. However, reduced Nupr1 expression decreased visceral fat deposition and significantly increased insulin sensitivity in vivo. In contrast to wild type animals, high fat diet-fed Nupr1 haplodeficient mice were not hyperinsulinaemic or glucose intolerant, and their sustained insulin sensitivity was demonstrated by appropriate insulin-induced Akt phosphorylation, as determined by Western blotting. At the molecular level, measurements of gene expression levels and promoter activities identified Nupr1-dependent inhibition of heat shock factor-1-induced heat shock protein 70 (Hsp70) expression as a mechanism through which Nupr1 regulates insulin sensitivity. We have shown for the first time that Nupr1 plays a central role in inhibiting Hsp70 expression in tissues regulating glucose homeostasis, and reductions in Nupr1 expression could be used to protect against the metabolic defects associated with obesity-induced insulin resistance.

Development of our TAVI protocol for emergency initiation of cardiopulmonary bypass.

All transcatheter aortic valve implantation (TAVI) cases are done in our hybrid operating room with a multidisciplinary team and a primed cardiopulmonary bypass (CPB) circuit on pump stand-by. We decided that we would resuscitate all patients undergoing a TAVI procedure via a transfemoral, transapical or transaortic approach, if required. Perfusion plays an essential role in providing rescue CPB for patient salvage when catastrophic complications occur. To coordinate the multidisciplinary effort, we have developed a written safety checklist that assigns a pre-determined role for team members for the rapid sequence initiation of CPB. Although many TAVI patients are not candidates for conventional aortic valve replacements, we feel strongly that rescue CPB should be offered to all TAVI patients to allow the correction of potentially reversible complications. This protocol is included in every surgical "Time Out" involving a TAVI procedure (Figure 1). The protocol has led to rapid and safe CPB initiation in less than five minutes of cardiac arrest. It has also led to a coordinated and consistent team, with pre-specified roles and improved communication. We discuss a case series of four TAVI patients who required emergent use of CPB. The first few cases did not have a written protocol. The experience from these cases led to the development of our protocol. We identified a lack of coordination, wasted movements, unnecessary delayed resuscitation and overall chaos, each of which was targeted for correction with the protocol. We will discuss the merits of the protocol in two recent TAVI cases which required emergent CPB.

The role of non-placental signals in the adaptation of islets to pregnancy.

It is well established that the maternal ß-cell mass increases during pregnancy in both humans and rodents to compensate insulin resistance and increased metabolic demand, and rapidly returns to normal levels post-partum. However, the mechanisms underlying this adaptation are not well understood. It is established that this process is driven partly by placental signals, but the contribution of non-placental signals is still unclear. This study aimed to differentiate between the role of placental and non-placental signals in regulating the ß-cell mass and glucose homeostasis during and after pregnancy. Pseudopregnant, pregnant and lactating mice were used to study the effects of maternal hormones on ß-cell function during early pregnancy, mid-to-late pregnancy and post-partum, respectively. Pseudopregnant mice, with circulating hormone levels mirroring those during pregnancy but lacking placental signals, had significantly increased ß-cell proliferation compared to non-pregnant controls but no change in glucose homeostasis, suggesting a role for non-placental hormones in increasing ß-cell mass. The rate of ß-cell proliferation rate dropped immediately after parturition, but lactating mice still had a significantly higher rate of ß-cell proliferation compared to non-lactating post-partum mice, suggesting that lactation-related hormones play a role in the controlled involution of ß-cell mass post-partum. These results implicate a role for both non-placental and placental signals in regulating ß-cell mass during and after pregnancy.

ALK5 inhibition maintains islet endothelial cell survival but does not enhance islet graft revascularisation or function.

Islet transplantation is a potential treatment for Type 1 diabetes but long term graft function is suboptimal. The rich supply of intraislet endothelial cells diminishes rapidly after islet isolation and culture, which affects the revascularisation rate of islets after transplantation. The ALK5 pathway inhibits endothelial cell proliferation and thus inhibiting ALK5 is a potential target for improving endothelial cell survival. The aim of the study was to establish whether ALK5 inhibition prevents the loss of intraislet endothelial cells during islet culture and thus improves the functional survival of transplanted islets by enhancing their subsequent revascularisation after implantation. Islets were cultured for 48 h in the absence or presence of 2 different ALK inhibitors: SB-431542 or A-83-01. Their vascular density after culture was analysed using immunohistochemistry. Islets pre-cultured with the ALK5 inhibitors were implanted into streptozotocin-diabetic mice for either 3 or 7 days and blood glucose concentrations were monitored and vascular densities of the grafts were analysed. Islets cultured with ALK5 inhibitors had higher vascular densities than control-cultured islets. Three days after implantation, endothelial cell numbers in islet grafts were minimal, irrespective of treatment during culture. Seven days after implantation, endothelial cells were evident within the islet grafts but there was no difference between control-cultured islets and islets pre-treated with an ALK5 inhibitor. Blood glucose concentrations were no different between the treatment groups. In conclusion, inhibition of ALK5 improved intraislet endothelial cell numbers after islet culture, but this effect was lost in the early post-transplantation period.

Effect of hyperglycaemia on muscarinic M3 receptor expression and secretory sensitivity to cholinergic receptor activation in islets.

AIMS: Islets are innervated by parasympathetic nerves which release acetylcholine (ACh) to amplify glucose-induced insulin secretion, primarily via muscarinic M3 receptors (M3R). Here we investigate the consequence of chronic hyperglycaemia on islet M3R expression and secretory sensitivity of mouse islets to cholinergic receptor activation. METHODS: The impact of hyperglycaemia was studied in (i) islets isolated from ob/ob mice, (ii) alginate-encapsulated mouse islets transplanted intraperitoneally into streptozotocin-induced diabetic mice and (iii) mouse and human islets maintained in vitro at 5.5 or 16 mmol/l glucose. Blood glucose levels were assessed by a commercial glucose meter, insulin content by RIA and M3R expression by qPCR and immunohistochemistry. RESULTS: M3R mRNA expression was reduced in both ob/ob islets and islets maintained at 16 mmol/l glucose for 3 days (68 and 50% control, respectively). In all three models of hyperglycaemia the secretory sensitivity to the cholinergic receptor agonist, carbachol, was reduced by 60-70% compared to control islets. Treatment for 72 h with the irreversible PKC activator, PMA, or the PKC inhibitor, Gö6983, did not alter islet M3R mRNA expression nor did incubation with the PI3K-inhibitor, LY294002, although enhancement of glucose-induced insulin secretion by LY294002 was reduced in islets maintained at 16 mmol/l glucose, as was mRNA expression of the PI3K regulatory subunit, p85α. CONCLUSIONS: Cholinergic regulation of insulin release is impaired in three experimental islet models of hyperglycaemia consistent with reduced expression of M3 receptors. Our data suggest that the receptor downregulation is a PKC- and PI3K-independent consequence of the hyperglycaemic environment, and they imply that M3 receptors could be potential targets in the treatment of type 2 diabetes.

Blurring the boundaries: decays of multiparticle isomers at the proton drip line.

A multiparticle spin-trap isomer has been discovered in the proton-unbound nucleus (73)(158)Ta85 . The isomer mainly decays by γ-ray emission with a half-life of 6.1(1) µs. Analysis of the γ-ray data shows that the isomer lies 2668 keV above the known 9+ state and has a spin 10ℏ higher and negative parity. This 19- isomer also has an 8644(11) keV, 1.4(2)% α-decay branch that populates the 9+ state in (154)Lu. No proton-decay branch from the isomer was identified, despite the isomer being unbound to proton emission by 3261(14) keV. This remarkable stability against proton emission is compared with theoretical predictions, and the implications for the extent of observable nuclides are considered.

The permissive effects of glucose on receptor-operated potentiation of insulin secretion from mouse islets: a role for ERK1/2 activation and cytoskeletal remodelling.

AIMS/HYPOTHESIS: Glucose plays two distinct roles in regulating insulin secretion from beta cells--an initiatory role, and a permissive role enabling receptor-operated secretagogues to potentiate glucose-induced insulin secretion. The molecular mechanisms underlying the permissive effects of glucose on receptor-operated insulin secretion remain uncertain. We have investigated the role of extracellular signal-regulated kinase 1/2 (ERK1/2) activation and consequent cytoskeletal remodelling in this process. METHODS: Insulin release was measured from groups of isolated mouse islets using static incubation experiments and subsequent radioimmunoassay of samples. ERK1/2 activation was measured by western blotting of islet protein samples for both phosphorylated and total ERK1/2. Rhodamine-phalloidin staining was used to measure filamentous actin in dispersed primary beta cells. RESULTS: Inhibition of ERK1/2 blocked potentiation of glucose-induced insulin release by the receptor-operated secretagogues kisspeptin, A568, exendin-4 and JWH015, although the agonists alone had minimal effects on ERK1/2 activation, suggesting a permissive rather than causal role for ERK1/2 activation in receptor-operated insulin release. Following pharmacological activation of ERK1/2 all agonists caused a significant increase in insulin release from islets incubated with sub-stimulatory levels of glucose. ERK1/2 inhibition significantly reduced the glucose-dependent decreases in filamentous actin observed in primary beta cells, while pharmacological dissociation of actin filaments enabled all receptor-operated secretagogues tested to significantly stimulate insulin release from islets at a sub-stimulatory glucose concentration. CONCLUSIONS/INTERPRETATION: Glucose-induced ERK1/2 activation in beta cells mediates the permissive effects of stimulatory glucose concentrations on receptor-operated insulin secretagogues, at least in part through effects on actin depolymerisation and cytoskeletal remodelling.