ICEECE2012 Poster Presentations Diabetes (248 abstracts)
Sustained Exendin-4 secretion through gene therapy targeting salivary glands in Zucker fa/fa rats and high fat diet fed mice.
I. Dicembrini 1 , G. Di Pasquale 4 , L. Raimondi 2 , C. Pagano 3 , J. Egan 4 , A. Cozzi 2 , L. Cinci 2 , E. Manni 2 , A. Loreto 2, , S. Berretti 2 , A. Morelli 2 , B. Baum 4 , M. Maggi 2 , R. Vettor 3 , J. Chiorini 4 , C. Rotella 1 & E. Mannucci 1
1Careggi Teaching Hospital, Florence, Italy; 2University of Florence, Florence, Italy; 3University of Padua, Padua, Italy; 4National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
Background: Exendin-4 (Ex-4) is a GLP-1 receptor agonist approved for the treatment of Type 2 Diabetes (T2DM). Aim of this study was to characterize the effects of Ex-4 expressed continuously from salivary glands (SG), following adeno-associated virus-mediated (AAV) gene therapy in two different model of obesity and T2DM. Several trials support an AAV good safety and little toxicity profile. Serotype 5 (AAV5) presented enhanced gene transfer activity in SG and an efficient protein secretion into the bloodstream. Materials and methods: a recombinant AAV vector was produced using a four-plasmid procedure. Following 5x1012 DRP/ml vector (encoding Ex-4 or empty) administration, efficacy and metabolic effects in high fat diet (HFD) fed mice (n=20) and Zucker fa/fa rats (n=10) were evaluated.
Results: Ex-4 levels averaged 138.9±42.3 pmol/L at day 42 in treated mice and 238.2±72 pmol/L at day 30 increasing to 3 nmol/L at day 60 in treated rats. Transduction specificity was confirmed through a qPCR amplification using specific primer in SG, liver, spleen and pancreas. Treated animals reached a significantly lower weight gain in comparison to controls at day 42 in mice (16.5±2.7 vs 19.5±1.9 g; P<0.05) and by day 35 in rats (156.8±17.5 vs 186.2±18.6 g, P<0.05) throught the study. Transient reduction on food intake was reported. Furthermore, treated mice presented: significant lower leptin circulating levels (2.24±0.39 vs 5.89±1.07 ng/ml; P<0.01) and visceral adipose mRNA expression (3.43±0.48 vs 8.28±0.72 Arbitrary Unit; P<0.01) and at day 41, a greater insulin-induced reduction in glycaemia during an intraperitoneal insulin tolerance test. A significant reduction in HbA1c (4.7±0.1 vs 4.9±0.1%; P<0.05) and glycosuria (4 cases vs 0) was reported in treated rats.
Conclusion: This study suggests an alternative approach delivering Ex-4 in the treatment of T2DM.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector
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Endocrine Abstracts
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