Implanting 1.1B4 human β-cell pseudoislets improves glycaemic control in diabetic severe combined immune deficient mice

AIM: To investigate the potential of implanting pseudoislets formed from human insulin-releasing β-cell lines as an alternative to islet transplantation. METHODS: In this study, the anti-diabetic potential of novel human insulin releasing 1.1B4 β-cells was evaluated by implanting the cells, either as free cell suspensions, or as three-dimensional pseudoislets, into the subscapular region of severe combined immune deficient mice rendered diabetic by single high-dose administration of streptozotocin. Metabolic parameters including food and fluid intake, bodyweight and blood glucose were monitored throughout the study. At the end of the study animals were given an intraperitoneal glucose tolerance test. Animals were then culled and blood and tissues were collected for analysis. Insulin and glucagon contents of plasma and tissues were measured by insulin radioimmunoassay and chemiluminescent enzyme-linked immunosorbance assay respectively. Histological analyses of pancreatic islets were carried out by quantitative fluorescence immunohistochemistry staining. RESULTS: Both pseudoislet and cell suspension implants yielded well vascularised β-cell masses of similar insulin content. This was associated with progressive amelioration of hyperphagia (P < 0.05), polydipsia (P < 0.05), body weight loss (P < 0.05), hypoinsulinaemia (P < 0.05), hyperglycaemia (P < 0.05 - P < 0.001) and glucose tolerance (P < 0.01). Islet morphology was also significantly improved in both groups of transplanted mice, with increased β-cell (P < 0.05 - P < 0.001) and decreased alpha cell (P < 0.05 - P < 0.001) areas. Whereas mice receiving 1.1B4 cell suspensions eventually exhibited hypoglycaemic complications, pseudoislet recipients displayed a more gradual amelioration of diabetes, and achieved stable blood glucose control similar to non-diabetic mice at the end of the study. CONCLUSION: Although further work is needed to address safety issues, these results provide proof of concept for possible therapeutic applicability of human β-cell line pseudoislets in diabetes

Differential Acute and Long Term Actions of Succinic Acid Monomethyl Ester Exposure on Insulin-Secreting BRIN-BD11 Cells

Esters of succinic acid are potent insulin secretagogues, and have been proposed as novel antidiabetic agents for type 2 diabetes. This study examines the effects of acute and chronic exposure to succinic acid monomethyl ester (SAM) on insulin secretion, glucose metabolism and pancreatic beta cell function using the BRIN-BD11 cell line. SAM stimulated insulin release in a dose-dependent manner at both non-stimulatory (1.1mM) and stimulatory (16.7mM) glucose. The depolarizing actions of arginine also stimulated a significant increase in SAM-induced insulin release but 2-ketoisocaproic acid (KIC) inhibited SAM induced insulin secretion indicating a possible competition between the preferential oxidative metabolism of these two agents. Prolonged (18hour) exposure to SAM revealed decreases in the insulin-secretory responses to glucose, KIC, glyceraldehyde and alanine. Furthermore, SAM diminished the effects of nonmetabolized secretagogues arginine and 3-isobutyl-1-methylxanthine (IBMX). While the ability of BRIN-BD11 cells to oxidise glucose was unaffected by SAM culture, glucose utilization was substantially reduced. Collectively, these data suggest that while SAM may enhance the secretory potential of non-metabolized secretagogues, it may also serve as a preferential metabolic fuel in preference to other important physiological nutrients and compromise pancreatic beta cell function following prolonged exposure

How Australian Vice-Chancellors Do Their Jobs: A Role-Theory Analysis

Despite universities occupying an important role in Australian society since 1851, very little research has been devoted to the key role of Vice-Chancellor. Significant research activity has been undertaken in other national higher education systems, particularly in the United States of America and recently with groundbreaking studies in the United Kingdom. The existing literature on higher education leadership in Australia is both scarce and dominated by normative designs. The literature tends to focus on governance and leadership from traditional normative paradigms and perspectives. In effect, the extant literature has been able to encapsulate "what" Vice-Chancellors do in their roles and "why" they do it. The current research seeks to extend the understanding of the Vice-Chancellor role by examining the "how" of roleperformance. This is a critical area that has been largely neglected in the managerial role literature, not the least in the research on higher education management. This research examines two Vice-Chancellors in the context of their daily activities. Viewed within the context of a changing higher education system, characterised by shifts in policy, funding, and international landscapes, the role of the Vice-Chancellors is examined through the lens of the role-theory model of Katz and Kahn. This model seeks to provide a framework by which role-sending and role-enactment can be explained along the lines of three critical dimensions

Cyclical Reviews in Selected Western Sydney Government Schools (2006-2009): The Influence on Participating Principals

Over the period 2006 to 2009, the then Western Sydney Region of the New South Wales Department of Education and Training developed a Framework for School Cyclical Reviews and piloted these reviews in nine regional government schools. The study examined the influence the Cyclical Review process had on participating school principals. Insight was sought into the use made over time of both the evaluation processes and evaluation results by the participating principals, including impressions from the principals of the factors that had influenced them in the course of the review. From the insights gained it was expected to make recommendations about the appropriate selection and preparation of principals for reviews and review teams, and the future conduct of reviews, as well as comment on the usefulness of current research into evaluation influence

Photolariats: synthesis, metal ion complexation and photochromism

International audiencePhotolariat development, as an extension to the family of synthetic photochromic crown ether receptors, or photocrowns, is reported. Incorporated additional chelating groups, namely two anisoles or thioanisoles, contribute in completing the metal ion coordination sphere with different affinities and selectivities for a range of ions. Single-crystal X-ray diffraction analysis suggests that the thermally stable trans-form of the receptor is unsuitable for ion binding, consistent with spectrophotometric and NMR titration results, which is largely improved in the cis-form as the basis for the photocontrolled ion coordination/ejection. In terms of the azobenzene-containing receptor photochemistry, a photostationary state highly enriched in the cis-form (94:6, cis-/trans-) is reached, with slow thermal return (1.1-1.4 × 10− 5 s− 1) in the dark, which can undergo multiple cycles without discernable photodegradation

Vasoactive agents in acute mesenteric ischaemia in critical care. A systematic review

Acknowledgements With thanks to Helen Fulbright, PhD, MA, PGDip LIS, BA (Hons), MCLIP, Information Specialist, Royal College of Surgeons of England Library and Archives Team, for conducting the literature searchesPeer reviewedPublisher PD

L-Arginine Is Essential for Pancreatic b-Cell Functional Integrity, Metabolism and Defense From Inflammatory Challenge

In this work, our aim was to determine whether L-arginine (a known insulinotropic amino acid) can promote a shift of b-cell intermediary metabolism favoring glutathione (GSH) and glutathione disulfide (GSSG) antioxidant responses, stimulus–secretion coupling and functional integrity. Clonal BRIN-BD11 b-cells and mouse islets were cultured for 24 h at various L-arginine concentrations (0–1.15 mmol/l) in the absence or presence of a proinflammatory cytokine cocktail (interleukin 1b, tumour necrosis factor a and interferon g). Cells were assessed for viability, insulin secretion, GSH, GSSG, glutamate, nitric oxide (NO), superoxide, urea, lactate and for the consumption of glucose and glutamine. Protein levels of NO synthase-2, AMP-activated protein kinase (AMPK) and the heat shock protein 72 (HSP72) were also evaluated. We found that L-arginine at 1.15 mmol/l attenuated the loss of b-cell viability observed in the presence of proinflammatory cytokines. L-Arginine increased total cellular GSH and glutamate levels but reduced the GSSG/GSH ratio and glutamate release. The amino acid stimulated glucose consumption in the presence of cytokines while also stimulating AMPK phosphorylation and HSP72 expression. Proinflammatory cytokines reduced, by at least 50%, chronic (24 h) insulin secretion, an effect partially attenuated by L-arginine. Acute insulin secretion was robustly stimulated by L-arginine but this effect was abolished in the presence of cytokines. We conclude that L-arginine can stimulate b-cell insulin secretion, antioxidant and protective responses, enabling increased functional integrity of b-cells and islets in the presence of proinflammatory cytokines. Glucose consumption and intermediary metabolism were increased by L-arginine. These results highlight the importance of L-arginine availability for b-cells during inflammatory challeng