PMID- 22808093
OWN - NLM
STAT- MEDLINE
DCOM- 20130326
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 7
DP  - 2012
TI  - Sustained exendin-4 secretion through gene therapy targeting salivary glands in 
      two different rodent models of obesity/type 2 diabetes.
PG  - e40074
LID - 10.1371/journal.pone.0040074 [doi]
LID - e40074
AB  - 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.
FAU - Di Pasquale, Giovanni
AU  - Di Pasquale G
AD  - Molecular Physiology and Therapeutics Branch, National Institute of Dental and 
      Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United 
      States of America.
FAU - Dicembrini, Ilaria
AU  - Dicembrini I
FAU - Raimondi, Laura
AU  - Raimondi L
FAU - Pagano, Claudio
AU  - Pagano C
FAU - Egan, Josephine M
AU  - Egan JM
FAU - Cozzi, Andrea
AU  - Cozzi A
FAU - Cinci, Lorenzo
AU  - Cinci L
FAU - Loreto, Andrea
AU  - Loreto A
FAU - Manni, Maria E
AU  - Manni ME
FAU - Berretti, Silvia
AU  - Berretti S
FAU - Morelli, Annamaria
AU  - Morelli A
FAU - Zheng, Changyu
AU  - Zheng C
FAU - Michael, Drew G
AU  - Michael DG
FAU - Maggi, Mario
AU  - Maggi M
FAU - Vettor, Roberto
AU  - Vettor R
FAU - Chiorini, John A
AU  - Chiorini JA
FAU - Mannucci, Edoardo
AU  - Mannucci E
FAU - Rotella, Carlo M
AU  - Rotella CM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120713
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Blood Glucose)
RN  - 0 (GLP1R protein, human)
RN  - 0 (Glp1r protein, mouse)
RN  - 0 (Glp1r protein, rat)
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Peptides)
RN  - 0 (Receptors, Glucagon)
RN  - 0 (Venoms)
RN  - 9P1872D4OL (Exenatide)
SB  - IM
MH  - Animals
MH  - Blood Glucose/analysis
MH  - Dependovirus/*genetics
MH  - Diabetes Mellitus, Type 2/blood/*therapy
MH  - Diet, High-Fat/adverse effects
MH  - Disease Models, Animal
MH  - Exenatide
MH  - Gene Expression
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors
MH  - Glucagon-Like Peptide-1 Receptor
MH  - Glucose Tolerance Test
MH  - Humans
MH  - Male
MH  - Mice
MH  - Obesity/blood/etiology/*therapy
MH  - Peptides/blood/*genetics/metabolism
MH  - Rats
MH  - Rats, Zucker
MH  - Receptors, Glucagon/agonists
MH  - Salivary Glands/*metabolism
MH  - Venoms/blood/*genetics/metabolism
MH  - Weight Gain
PMC - PMC3396615
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/07/19 06:00
MHDA- 2013/03/27 06:00
PMCR- 2012/07/13
CRDT- 2012/07/19 06:00
PHST- 2012/01/09 00:00 [received]
PHST- 2012/06/05 00:00 [accepted]
PHST- 2012/07/19 06:00 [entrez]
PHST- 2012/07/19 06:00 [pubmed]
PHST- 2013/03/27 06:00 [medline]
PHST- 2012/07/13 00:00 [pmc-release]
AID - PONE-D-12-00873 [pii]
AID - 10.1371/journal.pone.0040074 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(7):e40074. doi: 10.1371/journal.pone.0040074. Epub 2012 Jul 13.