Sustained exendin-4 secretion through gene therapy targeting salivary glands in two different rodent models of obesity/type 2 diabetes.
Exendin-4 (Ex-4) is a Glucagon-like peptide 1 (GLP-1) receptor agonist approved for the treatment of Type 2 Diabetes (T2DM), which requires daily subcutaneous administration. In T2DM patients, GLP-1 administration is reported to reduce glycaemia and HbA1c in association with a modest, but significan...
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2012
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oai:doaj.org-article:b5a58b6ba4de46ae91ab1ee5fd254e6b2021-11-18T07:12:35ZSustained exendin-4 secretion through gene therapy targeting salivary glands in two different rodent models of obesity/type 2 diabetes.1932-620310.1371/journal.pone.0040074https://doaj.org/article/b5a58b6ba4de46ae91ab1ee5fd254e6b2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22808093/?tool=EBIhttps://doaj.org/toc/1932-6203Exendin-4 (Ex-4) is a Glucagon-like peptide 1 (GLP-1) receptor agonist approved for the treatment of Type 2 Diabetes (T2DM), which requires daily subcutaneous administration. In T2DM patients, GLP-1 administration is reported to reduce glycaemia and HbA1c in association with a modest, but significant weight loss. The aim of present study was to characterize the site-specific profile and metabolic effects of Ex-4 levels expressed from salivary glands (SG) in vivo, following adeno-associated virus-mediated (AAV) gene therapy in two different animal models of obesity prone to impaired glucose tolerance and T2DM, specifically, Zucker fa/fa rats and high fed diet (HFD) mice. Following percutaneous injection of AAV5 into the salivary glands, biologically active Ex-4 was detected in the blood of both animal models and expression persisted in salivary gland ductal cell until the end of the study. In treated mice, Ex-4 levels averaged 138.9±42.3 pmol/L on week 6 and in treated rats, mean circulating Ex-4 levels were 238.2±72 pmol/L on week 4 and continued to increase through week 8. Expression of Ex-4 resulted in a significant decreased weight gain in both mice and rats, significant improvement in glycemic control and/or insulin sensitivity as well as visceral adipose tissue adipokine profile. In conclusion, these results suggest that sustained site-specific expression of Ex-4 following AAV5-mediated gene therapy is feasible and may be useful in the treatment of obesity as well as trigger improved metabolic profile.Giovanni Di PasqualeIlaria DicembriniLaura RaimondiClaudio PaganoJosephine M EganAndrea CozziLorenzo CinciAndrea LoretoMaria E ManniSilvia BerrettiAnnamaria MorelliChangyu ZhengDrew G MichaelMario MaggiRoberto VettorJohn A ChioriniEdoardo MannucciCarlo M RotellaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e40074 (2012) |
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Medicine R Science Q Giovanni Di Pasquale Ilaria Dicembrini Laura Raimondi Claudio Pagano Josephine M Egan Andrea Cozzi Lorenzo Cinci Andrea Loreto Maria E Manni Silvia Berretti Annamaria Morelli Changyu Zheng Drew G Michael Mario Maggi Roberto Vettor John A Chiorini Edoardo Mannucci Carlo M Rotella Sustained exendin-4 secretion through gene therapy targeting salivary glands in two different rodent models of obesity/type 2 diabetes. |
| description |
Exendin-4 (Ex-4) is a Glucagon-like peptide 1 (GLP-1) receptor agonist approved for the treatment of Type 2 Diabetes (T2DM), which requires daily subcutaneous administration. In T2DM patients, GLP-1 administration is reported to reduce glycaemia and HbA1c in association with a modest, but significant weight loss. The aim of present study was to characterize the site-specific profile and metabolic effects of Ex-4 levels expressed from salivary glands (SG) in vivo, following adeno-associated virus-mediated (AAV) gene therapy in two different animal models of obesity prone to impaired glucose tolerance and T2DM, specifically, Zucker fa/fa rats and high fed diet (HFD) mice. Following percutaneous injection of AAV5 into the salivary glands, biologically active Ex-4 was detected in the blood of both animal models and expression persisted in salivary gland ductal cell until the end of the study. In treated mice, Ex-4 levels averaged 138.9±42.3 pmol/L on week 6 and in treated rats, mean circulating Ex-4 levels were 238.2±72 pmol/L on week 4 and continued to increase through week 8. Expression of Ex-4 resulted in a significant decreased weight gain in both mice and rats, significant improvement in glycemic control and/or insulin sensitivity as well as visceral adipose tissue adipokine profile. In conclusion, these results suggest that sustained site-specific expression of Ex-4 following AAV5-mediated gene therapy is feasible and may be useful in the treatment of obesity as well as trigger improved metabolic profile. |
| format |
article |
| author |
Giovanni Di Pasquale Ilaria Dicembrini Laura Raimondi Claudio Pagano Josephine M Egan Andrea Cozzi Lorenzo Cinci Andrea Loreto Maria E Manni Silvia Berretti Annamaria Morelli Changyu Zheng Drew G Michael Mario Maggi Roberto Vettor John A Chiorini Edoardo Mannucci Carlo M Rotella |
| author_facet |
Giovanni Di Pasquale Ilaria Dicembrini Laura Raimondi Claudio Pagano Josephine M Egan Andrea Cozzi Lorenzo Cinci Andrea Loreto Maria E Manni Silvia Berretti Annamaria Morelli Changyu Zheng Drew G Michael Mario Maggi Roberto Vettor John A Chiorini Edoardo Mannucci Carlo M Rotella |
| author_sort |
Giovanni Di Pasquale |
| title |
Sustained exendin-4 secretion through gene therapy targeting salivary glands in two different rodent models of obesity/type 2 diabetes. |
| title_short |
Sustained exendin-4 secretion through gene therapy targeting salivary glands in two different rodent models of obesity/type 2 diabetes. |
| title_full |
Sustained exendin-4 secretion through gene therapy targeting salivary glands in two different rodent models of obesity/type 2 diabetes. |
| title_fullStr |
Sustained exendin-4 secretion through gene therapy targeting salivary glands in two different rodent models of obesity/type 2 diabetes. |
| title_full_unstemmed |
Sustained exendin-4 secretion through gene therapy targeting salivary glands in two different rodent models of obesity/type 2 diabetes. |
| title_sort |
sustained exendin-4 secretion through gene therapy targeting salivary glands in two different rodent models of obesity/type 2 diabetes. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/b5a58b6ba4de46ae91ab1ee5fd254e6b |
| work_keys_str_mv |
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