Functional enhancement of beta cells in transplanted pancreatic islets by secretion signal peptide-linked exendin-4 gene transduction.
This study assessed whether the newly designed exendin-4 (Ex-4) gene with highly releasable characteristics could enhance the beta cell function, thereby attenuating the essential islet mass required to cure diabetes. We constructed a lentivirus system encoding for a highly releasable secretion signal peptide, the peptide linked Ex-4 (SP-Ex-4) gene. After the transduction of lentivirus encoding for SP-Ex-4 (LV-SP-Ex-4) gene into the islets, the therapeutic effects of Ex-4 secreted were evaluated by conducting glucose-stimulated insulin secretion and cytokine- or hypoxia-induced apoptosis. Additionally, the effect of reduced islet numbers for transplantation was evaluated via in vivo models. The transduction of LV-SP-Ex-4 gene did not affect the viability of islets. In diabetic animal models, 50 islets expressing Ex-4 were transplanted to cure the diabetic nude mice, whereas at least 150 untransduced islets had to be transplanted to cure the diabetic nude mice. When the transduced islets were transplanted into diabetic immunocompetent mice, the survival rate of the mice was 18.0±4.9 days; however, when the untransduced islets were transplanted, they were rejected within 10.0±0.6 days. Therefore, the highly releasable Ex-4 could enhance the beta cell function with slightly enhanced viability of transplanted islets, presenting as a potential technology for overcoming islet shortage.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
Jee-Heon
JH
Jeong
Simmyung
S
Yook
Yoonsuk
Y
Jung
Bok-Hyeon
BH
Im
Minhyung
M
Lee
Cheol-Hee
CH
Ahn
Dong Yun
DY
Lee
Youngro
Y
Byun
D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000601:surgery*; D000077270:Exenatide; D005822:Genetic Vectors; D005947:Glucose / Q000494:pharmacology; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D021382:Protein Sorting Signals / Q000235:genetics*; D014161:Transduction, Genetic / Q000379:methods*; D014184:Transplantation, Homologous; D014688:Venoms / Q000235:genetics / Q000378:metabolism
D007328:Insulin; D010455:Peptides; D021382:Protein Sorting Signals; D014688:Venoms; D000077270:Exenatide; D005947:Glucose