Dietetics, Nutrition and Biological Sciences
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Item Vitamin D status and health outcomes in school children in Northern Ireland: Year one results from the D-VinCHI study(MDPI, 2022-02-14) Glatt, Dominique; McSorley, Emeir; Pourshahidi, L. Kirsty; Revuelta-Iniesta, Raquel; McCluskey, Jane T.; Beggan, Laura; Slevin, Mary; Gleeson, Nigel; Cobice, Diego F.; Dobbin, Sara; Magee, Pamela J.(1) Background: Vitamin D status has never been investigated in children in Northern Ireland (UK). (2) Methods: Children (4−11 years) (n = 47) were recruited from November 2019 to March 2020 onto the cross-sectional study. Anthropometry was assessed. Plasma 25-hydroxyvitamin D (25(OH)D) was analysed. Vitamin D intake, parental knowledge and perceptions, participant habits, physical activity and sedentary behaviour were established via questionnaire. Muscle strength was assessed via isometric grip strength dynamometry and balance via dominant single-leg and tandem stance. Parathyroid hormone, bone turnover markers (OC, CTX and P1NP), glycated haemoglobin and inflammatory markers (CRP, IFN-γ, IL-10, IL-12p70, IL-13, IL-1β, IL-2, IL-4, IL-6, IL-8 and TNF-α) were analysed. (3) Results: Mean (SD) 25(OH)D was 49.17 (17.04) nmol/L (n = 47); 44.7% of the children were vitamin D sufficient (25(OH)D >50 nmol/L), 48.9% were insufficient (25−50 nmol/L) and 6.4% were deficient (25 nmol/L). 25(OH)D was positively correlated with vitamin D intake (µg/day) (p = 0.012, r = 0.374), spring/summer outdoor hours (p = 0.006, r = 0.402) and dominant grip strength (kg) (p = 0.044, r = 0.317). Vitamin D sufficient participants had higher dietary vitamin D intake (µg/day) (p = 0.021), supplement intake (µg/day) (p = 0.028) and spring/summer outdoor hours (p = 0.015). (4) Conclusion: Over half of the children were vitamin D deficient or insufficient. Wintertime supplementation, the consumption of vitamin D rich foods and spring/summer outdoor activities should be encouraged to minimise the risk of vitamin D inadequacy.Item RT‐CGM in conjunction with CSII vs MDI in optimizing glycaemic control in T1DM: Systemic review and meta‐analysis(Wiley, 2022-02-04) William, Jimmy; McCluskey, Jane T.; Gleeson, NigelIntroduction: To determine the impact of real‐time continuous glucose monitoring (RT‐CGM) in conjunction with ‘Open loop’‐ continuous subcutaneous insulin infusion (CSII) as compared to conventional multiple daily injections (MDI) in type 1 diabetes. Methods: We explored the COCHRANE database, MEDLINE, WEB OF SCIENCE, GOOGLE SCHOLARS, PUBMED, EMBASE, and cited literature in articles retrieved (2010–2021) for all randomized controlled trials and real‐world trials of more than 6 months duration in patients with type 1 diabetes that compared RT‐CGM+CSII vs RT‐ CGM+MDI. A total of 1645 publications have been identified; however, only 3 trials fulfilled our inclusion criteria with a total number of 150 patients (72 patients using RT‐CGM+CSII and 78 patients on RT‐CGM+MDI). A Systematic Review and Meta‐analysis were carried out. Results: No statistically significant reduction in HbA1c was found on comparing RT‐CGM+CSII vs RT‐ CGM + MDI, with p‐value = .75. Likewise, impact on TIR, weight and insulin usage was found to be statistically insignificant with p‐value of 0.15, 0.75 and 0.20 respectively. There was an overall homogeneity between the 3 trials in respect to all previous variables with I2 being 0%. Conclusions: Real‐time continuous glucose monitors in conjunction with MDI open‐loop CSII had a similar impact on HbA1c, weight, insulin usage and TIR. In addition, RT‐CGM when combined with CSII was associated with higher costs and reduced quality of life, hence RT‐ CGM+MDI can be considered as a cheaper, safer yet equivalent substitute. Review Registration: This study was registered in PROSPERO (International prospective register of systematic reviews). Registration Name: RT‐CGM in conjunction with CSII vs MDI in optimizing glycaemic control in T1DM: a systematic review. Registration No: CRD42021255333. Accessible at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021255333. Amendments: Few amendments to the above‐mentioned registration were made: (1) Title (Meta‐analysis was added). (2) Prof. Gleeson was added as an author. (3) Real‐world trials were included. (4) Outcomes required in studies as per our inclusion criteria amended to include at least 1 outcome. (5) Bias risk was assessed by the CASP tool.Item Dietary sources of vitamin D in school children in Northern Ireland(The Nutrition Society, 2021-08-17) Benson, H.; Glatt, Dominique; Beggan, L.; McSorley, E. M.; Pourshahidi, L. K.; McCluskey, Jane T.; Revuelta-Iniesta, Raquel; Gleeson, Nigel; Magee, P. J.Item Effects of oat β-glucan consumption at breakfast on ad libitum eating, appetite, glycemia, insulinemia and GLP-1 concentrations in healthy subjects.(2018-06-18) Zaremba, Suzanne; Gow, Iain F.; Drummond, Sandra; McCluskey, Jane T.; Steinert, Robert E.There is evidence that oat β-glucan lowers appetite and ad libitum eating; however, not all studies are consistent, and the underpinning mechanisms are not entirely understood. We investigated the effects of 4 g high molecular weight (MW) oat β-glucan on ad libitum eating, subjective appetite, glycemia, insulinemia and plasma GLP-1 responses in 33 normal-weight subjects (22 female/11 male, mean age (y): 26.9 ± 1.0, BMI (kg/m ): 23.5 ± 0.4). The study followed a randomised double-blind, cross-over design with subjects fed two test breakfasts with and without oat β-glucan followed by an ad libitum test meal on two different days. Blood samples and ratings for subjective appetite were collected postprandially at regular time intervals. Oat β-glucan increased feelings of fullness (p = 0.048) and satiety (p = 0.034), but did not affect energy and amount eaten at the ad libitum test meal. There was a treatment by time interaction for plasma GLP-1, plasma insulin and blood glucose. GLP-1 was significantly reduced at 90 min (p = 0.021), blood glucose at 30 min (p = 0.008) and plasma insulin at 30 and 60 min (p = 0.002 and 0.017, respectively) following the oat β-glucan breakfast when compared with the control breakfast. Four grams of high MW oat β-glucan lowers appetite but not ad libitum eating and beneficially modulates postprandial glycaemia, it does however, not increase plasma GLP-1 secretion. [Abstract copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.]Item Cellular responses of novel human pancreatic _-cell line, 1.1B4 to hyperglycemia(Taylor & Francis, 2013-08-28) Vasu, Srividya; McClenaghan, Neville H.; McCluskey, Jane T.; Flatt, Peter R.The novel human-derived pancreatic _-cell line, 1.1B4 exhibits insulin secretion and _-cell enriched gene expression. Recent investigations of the cellular responses of this novel cell line to lipotoxicity and cytokine toxicity revealed similarities to primary human _ cells. The current study has investigated the responses of 1.1B4 cells to chronic 48 and 72 h exposure to hyperglycemia to probe mechanisms of human _-cell dysfunction and cell death. Exposure to 25 mM glucose significantly reduced insulin content (p < 0.05) and glucokinase activity (p < 0.01) after 72 h. Basal insulin release was unaffected but acute secretory response to 16.7 mM glucose was impaired (p < 0.05). Insulin release stimulated by alanine, GLP-1, KCl, elevated Ca2+ and forskolin was also markedly reduced after exposure to hyperglycemia (p < 0.001). In addition, PDX1 protein expression was reduced by 58% by high glucose (p < 0.05). Effects of hyperglycemia on secretory function were accompanied by decreased mRNA expression of INS, GCK, PCSK1, PCSK2, PPP3CB, GJA1, ABCC8, and KCNJ11. In contrast, exposure to hyperglycemia upregulated the transcription of GPX1, an antioxidant enzyme involved in detoxification of hydrogen peroxide and HSPA4, a molecular chaperone involved in ER stress response. Hyperglycemia-induced DNA damage was demonstrated by increased % tail DNA and olive tail moment, assessed by comet assay. Hyperglycemia-induced apoptosis was evident from increased activity of caspase 3/7 and decreased BCL2 protein. These observations reveal significant changes in cellular responses and gene expression in novel human pancreatic 1.1B4 _ cells exposed to hyperglycemia, illustrating the usefulness of this novel human-derived cell line for studying human _-cell biology and diabetes.Item Mechanisms of toxicity by proinflammatory cytokines in a novel human pancreatic beta cell line, 1.1B4.(Elsevier, 2014-01-01) Vasu, Srividya; McClenaghan, Neville H.; McCluskey, Jane T.; Flatt, Peter R.BACKGROUND Molecular mechanisms of toxicity and cell damage were investigated in the novel human beta cell line, 1.1B4, after exposure to proinflammatory cytokines - IL-1_, IFN-_, TNF-. METHODS MTT assay, insulin radioimmunoassay, glucokinase assay, real time reverse transcription PCR, western blotting, nitrite assay, caspase assay and comet assay were used to investigate mechanisms of cytokine toxicity. RESULTS Viability of 1.1B4 cells decreased after 18h cytokine exposure. Cytokines significantly reduced cellular insulin content and impaired insulin secretion induced by glucose, alanine, KCl, elevated Ca(2+), GLP-1 or forskolin. Glucokinase enzyme activity, regulation of intracellular Ca(2+) and PDX1 protein expression were significantly reduced by cytokines. mRNA expression of genes involved in secretory function - INS, GCK, PCSK2 and GJA1 was downregulated in cytokine treated 1.1B4 cells. Upregulation of transcription of genes involved in antioxidant defence - SOD2 and GPX1 was observed, suggesting involvement of oxidative stress. Cytokines also upregulated transcriptions of NFKB1 and STAT1, which was accompanied by a significant increase in NOS2 transcription and accumulation of nitrite in culture medium, implicating nitrosative stress. Oxidative and nitrosative stresses induced apoptosis was evident from increased % tail DNA, DNA fragmentation, caspase 3/7 activity, apoptotic cells and lower BCL2 protein expression. CONCLUSIONS This study delineates molecular mechanisms of cytokine toxicity in 1.1B4 cells, which agree with earlier observations using human islets and rodent beta cells. GENERAL SIGNIFICANCE This study emphasizes the potential usefulness of this cell line as a human beta cell model for research investigating autoimmune destruction of pancreatic beta cells.Item Comparison of Insulin Release From MIN6 Pseudoislets and Pancreatic Islets of Langerhans Reveals Importance of Homotypic Cell Interactions(Wolters Luwer, 2010-10) Kelly, Catriona; Guo, Hong; McCluskey, Jane T.; Flatt, Peter R.; McClenaghan, Neville H.OBJECTIVES: Cellular communication is required for normal patterns of insulin secretion from _ cells. Experiments using isolated islets of Langerhans are hampered by lack of supply and the consuming isolation process. Pseudoislets comprising clonal cells have emerged as an alternative to study islet-cell interactions and insulin secretion. The current study compared MIN6 pseudoislets and freshly isolated mouse islets. METHODS: Insulin content and release were measured by insulin radioimmunoassay. Reverse transcription polymerase chain reaction and Western blot analysis of adhesion molecule expression were performed on MIN6 monolayers and pseudoislets. MIN6 cellular proliferation and viability were measured by 5-bromo-2-deoxyuridine (BrdU) enzyme-linked immunosorbent assay, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and lactate dehydrogenase assays. RESULTS: Mouse islets were found to have greater insulin content than pseudoislets. However, insulin release was comparable between the 2 groups. With the use of MIN6 monolayers as a control, the expression of the adhesion molecule E-cadherin and connexin 36 were found to be enhanced in cells cultured as pseudoislets. Moreover, connexin 43 was shown to be absent from MIN6 cells irrespective of configuration. Finally, MIN6 pseudoislets seem able to manage their rate of proliferation with apoptosis resulting in a static size in the culture for extended periods. CONCLUSIONS: The current study found that MIN6 pseudoislets share many important functional and molecular features with islets of Langerhans.Item Daily administration of the GIP-R antagonist (Pro3)GIP in streptozotocin-induced diabetes suggests that insulin-dependent mechanisms are critical to anti-obesity-diabetes actions of (Pro3)GIP(Wiley, 2008-04) McClean, P. L.; Gault, V. A.; Irwin, N.; McCluskey, Jane T.; Flatt, P. R.AIM: Glucose-dependent insulinotropic polypeptide-receptor (GIP-R) antagonism using (Pro3)GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure and function in a commonly used model of obesity-diabetes, namely ob/ob mice. The effect of GIP-R antagonism in a streptozotocin (STZ)-induced model of insulin deficiency has not been evaluated. The present study has investigated the effects of daily administration of (Pro(3))GIP to STZ-treated mice. METHODS: Swiss TO mice received once-daily injection of (Pro3)GIP (25 nmol/kg body weight) or saline 4 days prior to and 16 days after injection of STZ, and effects on metabolic parameters and islet architecture were assessed. RESULTS: (Pro3)GIP treatment had no significant effect on hyperphagia or body weight loss. However, hyperglycaemia and glycated haemoglobin were worsened, glucose tolerance further decreased and insulin sensitivity was impaired by (Pro3)GIP. These effects were observed on an STZ-induced background characterized by severe reductions of circulating insulin, beta-cell mass and pancreatic insulin stores. CONCLUSIONS: These data indicate that the beneficial actions of the GIP-R antagonist, (Pro3)GIP, in obesity-diabetes appear to be largely mediated through insulin-dependent mechanisms that merit further investigation.Item The role of glucagon- and somatostatin-secreting cells in the regulation of insulin release and beta-cell function in heterotypic pseudoislets(Wiley, 2010-08-18) Kelly, Catriona; Parke, Hong Guo; McCluskey, Jane T.; Flatt, Peter R.; McClenaghan, Neville H.BACKGROUND: Pseudoislet studies have concentrated on single beta-cell lines or a combination of insulin and glucagon-secreting cells, overlooking the potential role of somatostatin in insulin release. This study sought to evaluate a heterotypic pseudoislet model containing insulin- (MIN6), glucagon- (TC1.9) and somatostatin (TGP52)-secreting cells of mouse origin and to compare these pseudoislets with traditional monolayer preparations. METHODS: Cellular viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase assays), proliferation (5-bromo-2-deoxyuridine ELISA), hormone content and functional insulin release in response to a variety of stimuli were measured. Differential expression of E-cadherin, connexin 36 and connexin 43 was assessed by reverse transcriptase-polymerase chain reaction and Western blot to determine a possible role for adherens in insulin release from these pseudoislets. RESULTS: All pseudoislet cells displayed reduced proliferation coupled with an increase in cell death which may contribute to their static size in culture. While MIN6 and TGP52 cells expressed E-cadherin and showed sustained or improved hormone content when configured as pseudoislets, TC1.9 lacked E-cadherin and contained less glucagon following pseudoislet formation. MIN6 and TC1.9 cells expressed connexin 36, but not connexin 43 and TGP52 cells expressed connexin 43 only. In the presence of Alanine, Arginine and glucagon-like peptide-1, heterotypic pseudoislet cultures secreted levels of insulin that were comparable to that of MIN6 pseudoislets. In addition, pseudoislets comprising all three cell lines released more insulin into the surrounding culture medium than MIN6 pseudoislets when studied over a 1-week period. CONCLUSIONS: The current model may prove useful in studying the role of islet cell interactions in the release of insulin from pancreatic islets.Item Effects of lipotoxicity on a novel insulin-secreting human pancreatic _-cell line, 1.1B4(De Gruyter, 2013-07-01) Vasu, Srividya; McClenaghan, Neville H.; McCluskey, Jane T.; Flatt, Peter R.The novel insulin-secreting human pancreatic _-cell line, 1.1B4, demonstrates stability in culture and many of the secretory functional attributes of human pancreatic _-cells. This study investigated the cellular responses of 1.1B4 cells to lipotoxicity. Chronic 18-h exposure of 1.1B4 cells to 0.5 mm palmitate resulted in decreased cell viability and insulin content. Secretory responses to classical insulinotropic agents and cellular Ca2+ handling were also impaired. Palmitate decreased glucokinase activity and mRNA expression of genes involved in secretory function but up-regulated mRNA expression of HSPA5, EIF2A, and EIF2AK3, implicating activation of the endoplasmic reticulum stress response. Palmitate also induced DNA damage and apoptosis of 1.1B4 cells. These responses were accompanied by increased gene expression of the antioxidant enzymes SOD1, SOD2, CAT and GPX1. This study details molecular mechanisms underlying lipotoxicity in 1.1B4 cells and indicates the potential value of the novel _-cell line for future research.