Adenoviral vector-mediated insulin gene transfer in the mouse pancreas corrects streptozotocin-induced hyperglycemia.
Therapy for type 1 diabetes consists of tight blood glucose (BG) control to minimize complications. Current treatment relies on multiple insulin injections or an insulin pump placement, beta-cell or whole pancreas transplantation. All approaches have significant limitations and have led to the realization that novel treatment strategies are needed. Pancreatic acinar cells have features that make them a good target for insulin gene transfer. They are not subject to autoimmune attack, a problem with pancreas or islets transplantation, they are avidly transduced by recombinant adenoviral vectors, and capable of exporting a variety of peptides into the portal circulation. Recombinant adenoviral vectors were engineered to express either wild-type or furin-modified human insulin cDNA (AdCMVhInsM). Immunodeficient mice were made diabetic with streptozotocin and injected intrapancreatically with the vectors. BG and blood insulin levels have normalized after administration of AdCMVhInsM. Immunohistochemistry and electron microscopy showed the presence of insulin in acinar cells throughout the pancreas and localization of insulin molecules to acinar cell vesicles. The data clearly establish a relationship between intrapancreatic vector administration, decreased BG and elevated blood insulin levels. The findings support the use of pancreatic acinar cells to express and secrete insulin into the blood stream.
Shifrin
A L
AL
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Auricchio
A
A
Yu
Q C
QC
Wilson
J
J
Raper
S E
SE
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007328:Insulin / Q000032:analysis / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D016253:Microscopy, Immunoelectron / Q000379:methods; D010179:Pancreas / Q000737:chemistry / Q000378:metabolism*; D011863:Radioimmunoassay / Q000379:methods
D001786:Blood Glucose; D007328:Insulin