Implantation of primary cultured adipocytes that secrete insulin modifies blood glucose levels in diabetic mice.
OBJECTIVE
In type 1 diabetic patients, basal insulin supplementation plays a central role in tight glycaemic control. Therefore, safe and steady supplementation of basal insulin is strongly desirable, despite the need for multiple injections. The aim of this study was to investigate a procedure for supplementation using genetically engineered, primary-cultured adipocytes in diabetic mice.


METHODS
Furin-cleavable human proinsulin cDNA was transferred into murine primary-cultured adipocytes using a retroviral vector. The cells were implanted subcutaneously into streptozotocin-induced diabetic mice.


RESULTS
The transfected cells secreted substantial amounts of mature insulin, as well as C-peptide, into conditioned medium. Syngeneic implantation of the cells significantly improved hyperglycaemia and blood HbA(1)c concentrations in a manner that was dependent on cell number, without causing hypoglycaemia. The plasma insulin concentration was dependent on the implanted cell number, and the systemic effect of the circulating insulin was confirmed by marked improvement of body weight reduction and liver glycogen content. Additionally, surgical resection of the implants, in which the insulin secretion was immunologically confirmed after transplantation, diminished the glucose-lowering effect, suggesting that in vivo expression could be eliminated if necessary.


CONCLUSIONS
These results indicate that the autotransplantation of functionalised adipocytes may lead to a clinical application in the treatment of diabetes.
Department of Genome Research and Clinical Application, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
M
M
Ito
H
H
Bujo
K
K
Takahashi
T
T
Arai
I
I
Tanaka
Y
Y
Saito
D017667:Adipocytes / Q000378:metabolism* / Q000637:transplantation*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000473:pathology; D012190:Retroviridae / Q000235:genetics; D023822:Tissue Engineering; D015431:Weight Loss / Q000502:physiology
D001786:Blood Glucose; D018076:DNA, Complementary; D007328:Insulin; D008112:Liver Glycogen