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Browsing by Person "Irwin, N."

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    Beneficial effects of parenteral GLP-1 delivery by cell therapy in insulin-deficient streptozotocin diabetic mice
    (Springer Nature, 2013-11) Vasu, S.; Moffett, R. C.; McCluskey, Jane T.; Hamid, M. H.; Irwin, N.; Flatt, P. R.
    Parenteral delivery of long-acting glucagon-like peptide-1 (GLP-1) mimetics has received much attention as a therapeutic option for diabetes. However, cell therapy-based GLP-1 treatments may provide a more physiological regulation of blood glucose. The present study assessed the effects of chronic GLP-1 delivery by cell therapy, using the GLP-1-secreting GLUTag cell line, in normoglycemic and streptozotocin-induced diabetic mice. GLUTag cell aggregates were transplanted into the subscapular region of mice. Over 30 days, cellular transplantation gave rise to encapsulated and well-vascularized growths, which contained immunoreactive GLP-1. Cell implantation was well tolerated and had no appreciable metabolic effects in normal mice. However, transplantation significantly (P<0.001) countered excessive food and fluid intake in diabetic mice and maintained normal body weight. Circulating glucose (P<0.01) and glucagon (P<0.05) were significantly reduced and plasma insulin and GLP-1 dramatically increased. This was associated with significantly (P<0.01) improved glucose tolerance in diabetic mice. Histological examination of the pancreata of these mice revealed elevations (P<0.001) in islet and _-cell area, with reduced (P<0.001) -cell area. Increased _-cell mass reflected the enhanced proliferation relative to apoptosis. These studies emphasize the potential of chronic GLP-1 delivery by cell therapy as a potential therapeutic option for diabetes.
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    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.