Hypothalamic arcuate nucleus glucokinase regulates insulin secretion and glucose homeostasis

Aims Glucokinase (GK) serves as a glucose sensor in several tissues including glucose‐sensitive neurons of the arcuate nucleus within the hypothalamus. We have previously demonstrated a role for arcuate GK in the regulation of food and glucose intake. However, its role in the regulation of glucose homeostasis is less clear. We therefore sought to investigate the role of arcuate GK in the regulation of glucose homeostasis. Materials and Methods Recombinant adeno‐associated virus expressing either GK or an antisense GK construct was used to alter GK activity specifically in the hypothalamic arcuate nucleus. GK activity in this nucleus was also increased by stereotactic injection of the GK activator, compound A. The effect of altered arcuate nucleus GK activity on glucose homeostasis was subsequently investigated using glucose and insulin tolerance tests. Results Increased GK activity specifically within the arcuate nucleus increased insulin secretion and improved glucose tolerance in rats during oral glucose tolerance tests. Decreased GK activity in this nucleus reduced insulin secretion and increased glucose levels during the same tests. Insulin sensitivity was not affected in either case. The effect of arcuate nucleus glucokinase was maintained in a model of type 2 diabetes. Conclusions These results demonstrate a role for arcuate nucleus GK in systemic glucose homeostasis

Glucose in the hypothalamic paraventricular nucleus regulates GLP-1 release.

Glucokinase (GK) is highly expressed in the hypothalamic paraventricular nucleus (PVN); however, its role is currently unknown. We found that GK in the PVN acts as part of a glucose-sensing mechanism within the PVN that regulates glucose homeostasis by controlling glucagon-like peptide 1 (GLP-1) release. GLP-1 is released from enteroendocrine L cells in response to oral glucose. Here we identify a brain mechanism critical to the release of GLP-1 in response to oral glucose. We show that increasing expression of GK or injection of glucose into the PVN increases GLP-1 release in response to oral glucose. On the contrary, decreasing expression of GK or injection of nonmetabolizable glucose into the PVN prevents GLP-1 release. Our results demonstrate that gluco-sensitive GK neurons in the PVN are critical to the response to oral glucose and subsequent release of GLP-1

Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats

Background Obesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing’s Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoid levels have been implicated in the development of the metabolic phenotype of obesity. Tissue glucocorticoid levels are regulated by 11β-hydroxysteroid dehydrogenase type1 (11βHSD1), which increases the local concentration of active glucocorticoids by production of corticosterone from 11-dehydrocorticosterone. 11βHSD1 is expressed in the hypothalamic arcuate nucleus (ARC), a major weight and appetite-regulating centre, and therefore represents a target for novel anti-obesity therapeutic agents. Objectives To investigate the effect of chronic alterations of ARC corticosterone levels (mediated by 11βHSD1) on food intake and body weight in adult male rats. Methods Recombinant adeno-associated virus bearing sense 11βHSD1 (rAAV-S11βHSD1) and small interfering 11βHSD1 (rAAV-si11βHSD1) respectively were stereotactically injected into the ARC (bilaterally) of adult male Wistar rats. rAAV-GFP was injected into control groups of male Wistar rats. Food intake and body weight were measured three times a week for 70 days. Terminal brain, plasma and intrascapular brown adipose tissue (iBAT) samples were taken for measurement of mRNA expression and hormone levels. Results Compared to controls, rAAV-S11βHSD1 injection resulted in higher ARC corticosterone levels, hyperphagia and increased weight gain. Conversely, rAAV-si11βHSD1 injection (compared to controls) resulted in lower ARC corticosterone levels, higher iBAT uncoupling protein-1 mRNA expression and less weight gain despite similar food intake. Conclusions Therefore, ARC corticosterone, regulated by 11βHSD1, may play a role in food intake and body weight regulation. These data have important implications for the development of centrally-acting 11βHSD1 inhibitors, which are currently being developed for the treatment of obesity, metabolic disorders and other conditions

The effects of kisspeptin on β-cell function, serum metabolites and appetite in humans

Aims: To investigate the effect of kisspeptin on glucose-stimulated insulin secretion and appetite in humans. Materials and methods: In 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose-stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose-stimulated insulin secretion in vitro in human pancreatic islets and a human β-cell line (EndoC-βH1 cells). Results: Kisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose-stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men. Conclusions: Collectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin-based therapies for reproductive and potentially metabolic conditions

Usability and feasibility of PreventS-MD webapp for stroke prevention

Background: Most strokes and cardiovascular diseases (CVDs) are potentially preventable if their risk factors are identified and well controlled. Digital platforms, such as the PreventS-MD webapp (PreventS-MD) may aid health care professionals (HCPs) in assessing and managing risk factors and promoting lifestyle changes for their patients.Methods: This is a mixed methods cross-sectional 2-phase survey using a largely positivist (quantitative and qualitative) framework. During phase 1, a prototype of PreventS-MD was tested internationally by 59 of 69 consenting HCPs of different backgrounds, age, sex, working experience and specialities using hypothetical data. Collected comments/suggestions from the study HCPs in phase 1 were reviewed and implemented. In phase 2, a near-final version of PreventS-MD was developed and tested by 58 of 72 consenting HCPs using both hypothetical and real patient (n=10) data. Qualitative semi-structured interviews with real patients (n=10) were conducted, and 1-month adherence to the preventative recommendations was assessed by self-reporting. The four System Usability Scale (SUS) groups of scores (0-50 unacceptable; 51-68 poor, 68-80.3 good; >80.3 excellent) were used to determine usability of PreventS-MD.Findings: 99 HCPs from 27 countries (45% from low- to middle-income countries) participated in the study, out of whom 10 HCPs were involved in the development of PreventS before the study, and therefore were not involved in the survey. Of the remaining 89 HCPs 69 consented to the first phase of the survey, out of whom 59 completed the first phase of the survey (response rate 86%) and 58 HCPs completed the second phase of the survey (response rate 84%). The SUS scores supported good usability of the prototype (mean score=80.2; 95% CI [77.0-84.0]) and excellent usability of the final version of PreventS-MD (mean score=81.7; 95%CI [79.1-84.3]) in the field. Scores were not affected by the age, sex, working experience or speciality of the HCPs. One month follow-up of the patients confirmed the high level of satisfaction/acceptability of PreventS-MD and (100%) adherence to the recommendations. Interpretation: The PreventS-MD webapp has a high level of usability, feasibility and satisfaction by HCPs and individuals at risk of stroke/CVD. Individuals at risk of stroke/CVD demonstrated a high level of confidence and motivation in following and adhering to preventative recommendations generated by PreventS-MD

Nuclear Factor 90(NF90) targeted to TAR RNA inhibits transcriptional activation of HIV-1

<p>Abstract</p> <p>Background</p> <p>Examination of host cell-based inhibitors of HIV-1 transcription may be important for attenuating viral replication. We describe properties of a cellular double-stranded RNA binding protein with intrinsic affinity for HIV-1 TAR RNA that interferes with Tat/TAR interaction and inhibits viral gene expression.</p> <p>Results</p> <p>Utilizing TAR affinity fractionation, North-Western blotting, and mobility-shift assays, we show that the C-terminal variant of nuclear factor 90 (NF90ctv) with strong affinity for the TAR RNA, competes with Tat/TAR interaction <it>in vitro</it>. Analysis of the effect of NF90ctv-TAR RNA interaction <it>in vivo </it>showed significant inhibition of Tat-transactivation of HIV-1 LTR in cells expressing NF90ctv, as well as changes in histone H3 lysine-4 and lysine-9 methylation of HIV chromatin that are consistent with the epigenetic changes in transcriptionally repressed gene.</p> <p>Conclusion</p> <p>Structural integrity of the TAR element is crucial in HIV-1 gene expression. Our results show that perturbation Tat/TAR RNA interaction by the dsRNA binding protein is sufficient to inhibit transcriptional activation of HIV-1.</p

INFLUENCE OF CLIENTS’ REQUIREMENTS ON PROCUREMENT SELECTION IN CONSTRUCTION INDUSTRY

Use of appropriate procurement system is a key factor which contributes to the successful outcome of a project. The wrong selection of construction procurement approach usually leads to project failure or general client’s dissatisfaction. Selection of suitable procurement system is influenced by several factors based on their significance. Therefore, investigation of factors influencing the selection is essential to assist the clients in initial decision making on appropriate procurement selection. In this context, the aim of this paper is to examine the significant factors influencing the selection of procurement systems in construction. This paper presents a set of multiple selection factors influencing the selection of construction procurement in terms of clients’ requirements. Four rounds of Delphi survey were conducted with the aim of investigating the most significant factors and their level of influence on various construction procurement systems in Sri Lanka.  In addition, few interviews were conducted with selected industry experts in view of interpreting the results derived from Delphi survey. It was found that clients’ requirements significantly influence the selection of procurement system for any kind of projects. A statistically significant consensus on the weighting of the utility values for each procurement system was obtained from 35 industrial experts. Based on the Delphi survey results, a set of exclusive selection criteria for nine factor categories of clients’ requirements was established.  The selection criteria established by this study provides a solid base for clients in initial decision making on the selection of suitable procurement system for any kind of building projects.   Keywords: Clients’ Requirements, Construction Procurement, Procurement Selection For full paper: [email protected]

A review of smart technology usage in construction and demolition waste management

The management of construction and demolition (C&D) waste, a major part of solid waste, is increasingly become a critical challenge in the quest of social, environmental, and economic sustainability. Innovative and smart technologies are emerging to provide inevitable benefits because of their capacity to enable digitisation, automation, and integration of Solid Waste Management (SWM) processes. Nevertheless, the application of such technologies in Construction and Demolition Waste Management (CDWM) has not gained the appropriate attention. This study aims to draw insights into the current and potential use of smart technologies in CDWM. A literature review-based approach surveyed both academic and applied publications to analyse the current and potential use of smart technologies in both SWM and CDWM. Altogether, 75 peer-reviewed articles and technical white papers were analysed. It was found that the usage of smart technologies is much advanced in SWM and the adoption is still at the prototype stage in CDWM. The results emphasise that the integration of smart technologies into multiple processes of CDWM would overcome many issues related to waste minimisation and management including waste estimation, waste reporting, and data management and waste diversion. The framework developed in this study contributes to the understanding of the potential role of each category of technologies in improving the waste management processes in the C&D sector. This review is useful to waste management practitioners, regulatory bodies and the government to understand the benefits of emerging technologies and to the development of effective strategies and future training programmes.

Direct comparison of the effects of intravenous kisspeptin-10, kisspeptin-54 and GnRH on gonadotrophin secretion in healthy men

STUDY QUESTION: How potently does the novel hypothalamic stimulator of reproduction, kisspeptin, increase gonadotrophin secretion when compared with GnRH in healthy men? SUMMARY ANSWER: At the doses tested, intravenous administration of either of two major kisspeptin isoforms, kisspeptin-10 and -54, was associated with similar levels of gonadotrophin secretion in healthy men; however, GnRH was more potent when compared with either kisspeptin isoform. WHAT IS KNOWN ALREADY: Kisspeptin-10 and -54 are naturally occurring hormones in the kisspeptin peptide family which potently stimulates endogenous GnRH secretion from the hypothalamus, so have the potential to treat patients with reproductive disorders. Rodent studies suggest that kisspeptin-54 is more potent when compared with kisspepitn-10; however, their effects have not previously been directly compared in humans, or compared with direct pituitary stimulation of gonadotrophin secretion using GnRH. STUDY DESIGN, SIZE AND DURATION: A single-blinded placebo controlled physiological study was performed from January to December 2013. Local ethical approval was granted, and five participants were recruited to each dosing group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthy men were administered vehicle, kisspeptin-10, kisspeptin-54 and GnRH intravenously for 3 h on different study days. Each hormone was administered at 0.1, 0.3 and 1.0 nmol/kg/h doses (n = 5 subjects per group). Regular blood sampling was conducted throughout the study to measure LH and FSH. Study visits were conducted at least a week apart. MAIN RESULTS AND THE ROLE OF CHANCE: Serum LH and FSH levels were ∼3-fold higher during GnRH infusion when compared with kisspeptin-10 and ∼2-fold higher when compared with kisspeptin-54 [mean area under the curve serum LH during infusion (in hours times international units per litre, h.IU/l): 10.81 ± 1.73, 1.0 nmol/kg/h kisspeptin-10; 14.43 ± 1.27, 1.0 nmol/kg/h kisspeptin-54; 34.06 ± 5.18, 1.0 nmol/kg/h GnRH, P < 0.001 versus kisspeptin-10, P < 0.01 versus kisspeptin-54]. LIMITATIONS, REASONS FOR CAUTION: This study had a small sample size. WIDER IMPLICATIONS OF THE FINDINGS: Kisspeptin offers a novel means of stimulating the reproductive axis. Our data suggest that kisspeptin stimulates gonadotrophin secretion less potently when compared with GnRH; however, kisspeptin may stimulate gonadotrophins in a more physiological manner when compared with current therapies. Kisspeptin is emerging as a future therapeutic agent, so it is important to establish which kisspeptin hormones could be used to treat patients with infertility. Results of this study suggest that either isoform has similar effects on reproductive hormone secretion in healthy men when administered intravenously. STUDY FUNDING/COMPETING INTERESTS: This work is funded by grants from the MRC and NIHR and is supported by the NIHR Imperial Biomedical Research Centre Funding Scheme. C.N.J. is supported by an NIHR Clinical Lectureship. A.A. is supported by Wellcome Trust Research Training Fellowships. A.N.C. is supported by Wellcome Trust Translational Medicine Training Fellowship. W.S.D. is supported by an NIHR Career Development Fellowship