Insulin gene transfer enhances the function of human islet grafts.
OBJECTIVE
Recent success in islet transplantation renews the hope for the complete cure of patients afflicted with Type 1 diabetes. However, in the Edmonton series, two to four pancreas donors were required to obtain a sufficient islet mass to reverse the diabetes of each patient. In view of the donor shortage, this represents a major obstacle preventing greater application of islet transplantation to diabetic patients. We hypothesised that increasing the expression of the insulin gene in transplanted islets would augment their capacity for insulin production, thereby allowing reversal of diabetes with a reduced islet mass.


METHODS
We used a replication defective adenovirus to deliver the human proinsulin gene (Ad-Ins) to isolated human islets. The function of Ad-Ins-transduced human islets was compared to islets transduced with a control vector (Ad-lacz).


RESULTS
Ad-Ins-transduced islets produced two to three times more insulin than normal islets or those infected with Ad-lacz, as assessed by in vitro perifusion tests of glucose stimulated insulin release. When transplanted, Ad-Ins-transduced islets normalised the blood glucose of diabetic immunodeficient NOD-Scid mice, and less than half as many Ad-Ins islets were required for reversal of diabetes than when normal islets were transplanted.


CONCLUSIONS
Our results suggest a simple and effective approach that could enhance the efficiency of islet transplantation for treatment of diabetes in humans.
Deng
S
S
The Harrison Department of Surgical Research, Hospital of the University of Pennsylvania, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA.
Vatamaniuk
M
M
Lian
M-M
MM
Doliba
N
N
Wang
J
J
Bell
E
E
Wolf
B
B
Raper
S
S
Matschinsky
F M
FM
Markmann
J F
JF
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D018014:Gene Transfer Techniques; D005934:Glucagon / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics*; D007515:Islets of Langerhans / Q000502:physiology* / Q000648:ultrastructure; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D007763:Lac Operon / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008854:Microscopy, Electron; D011384:Proinsulin / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D014183:Transplantation, Heterologous / Q000502:physiology
D001786:Blood Glucose; D007328:Insulin; D005934:Glucagon; D011384:Proinsulin