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 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.
Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
Giovanni
G
Di Pasquale
Ilaria
I
Dicembrini
Laura
L
Raimondi
Claudio
C
Pagano
Josephine M
JM
Egan
Andrea
A
Cozzi
Lorenzo
L
Cinci
Andrea
A
Loreto
Maria E
ME
Manni
Silvia
S
Berretti
Annamaria
A
Morelli
Changyu
C
Zheng
Drew G
DG
Michael
Mario
M
Maggi
Roberto
R
Vettor
John A
JA
Chiorini
Edoardo
E
Mannucci
Carlo M
CM
Rotella
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D000229:Dependovirus / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000628:therapy*; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D000077270:Exenatide; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D051379:Mice; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000628:therapy*; D010455:Peptides / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D018027:Receptors, Glucagon / Q000819:agonists; D012469:Salivary Glands / Q000378:metabolism*; D014688:Venoms / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D015430:Weight Gain
D001786:Blood Glucose; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide