Double-strand adeno-associated virus-mediated exendin-4 expression in salivary glands is efficient in a diabetic rat model.
OBJECTIVE
Exendin-4 (Ex-4) is an agonist of the glucagon-like peptide 1 (GLP-1) receptor, approved for the treatment of type 2 diabetes (T2DM). Several strategies have been tried to develop stable and efficacious Ex-4 expression systems. The purpose of the current study was to determine whether double-stranded adeno-associated virus (dsAAV)-mediated in vivo expression of exendin-4 in salivary glands (SG), improves pathology in the Sprague-Dawley (SD) rat model of diabetes mellitus (DM).


METHODS
The effects of Ex-4 expression by recombinant dsAAV-NT4-Ex-4 were evaluated in vitro compared with a single-strand (ss) AAV. The dsAAV was delivered into SGs and the blood glucose and insulin levels were assessed in a rat model of DM.


RESULTS
DsAAV-NT4-Ex-4 virus induces significant exendin-4 expression in vitro. Furthermore, Ex-4 expressed from dsAAV virus in SGs enhances insulins secretion in vivo and significantly controls the onset of hyperglycemia in rat model of DM.


CONCLUSIONS
Results suggest that sustained secretion of Ex-4 following dsAAV-mediated gene therapy is feasible. SGs appear to be promising targets with potential clinical applicability for the treatment of DM. This represents the example of a successful use of Ex-4 for diabetes therapy, providing support for direct AAV-mediated in vivo as an easy, safe and efficient therapeutic strategy.
Department of Endocrine, The Second Hospital, Medical College of Xi'an Jiaotong University, Xi'an 710004, China.
Junhong
J
Wang
Department of Nutrition and Food Hygiene, The Fourth Military Medical University, Xi'an 710032, China.
Feng
F
Wang
Department of Endocrine, The Second Hospital, Medical College of Xi'an Jiaotong University, Xi'an 710004, China.
Jing
J
Xu
Department of Endocrine, The Second Hospital, Medical College of Xi'an Jiaotong University, Xi'an 710004, China.
Shimei
S
Ding
Department of Infectious Disease, The Second Hospital, Medical College of Xi'an Jiaotong University, Xi'an 710004, China. Electronic address: xiaoqing9759@sina.com.
Yonghong
Y
Guo
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics / Q000628:therapy*; D004195:Disease Models, Animal; D000077270:Exenatide; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D052216:Glucagon-Like Peptide 1 / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000097:blood; D051379:Mice; D041681:NIH 3T3 Cells; D010455:Peptides / Q000235:genetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists*; D012469:Salivary Glands / Q000378:metabolism*; D014688:Venoms / Q000235:genetics / Q000627:therapeutic use*
D001786:Blood Glucose; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
Adeno-associated virus; Diabetes mellitus; Exendin-4; Salivary glands