Prolonged remission of diabetes by regeneration of beta cells in diabetic mice treated with recombinant adenoviral vector expressing glucagon-like peptide-1.
Type 1 diabetes results from insulin deficiency caused by destruction of pancreatic beta cells. Glucagon-like peptide (GLP)-1 stimulates beta cell growth and differentiation. To determine whether continuous expression of GLP-1 in vivo can regenerate beta cells and remit type 1 diabetes in mice for a prolonged time, we constructed an adenoviral vector containing the cytomegalovirus promoter/enhancer and albumin leader sequence followed by GLP-1 cDNA (rAd-GLP-1). A single administration of rAd-GLP-1 via the tail vein into streptozotocin (STZ)-induced diabetic non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice resulted in remission of diabetes within 10 days; normoglycemia remained until the experiment was terminated. The number of insulin-positive cells in the pancreas and insulin secretion significantly increased in rAd-GLP-1-treated mice compared with STZ-induced diabetic mice treated with rAd-beta-galactosidase. Glucose tolerance tests in mice that achieved normoglycemia after treatment with rAd-GLP-1 showed that the kinetics of glucose clearance was similar to normal NOD/SCID mice. Treatment of autoimmune diabetic mice with rAd-GLP-1 restored normoglycemia, which was maintained for 1 year when mice were also treated with an immunoregulator to halt the autoimmune response to beta cells. We suggest that regeneration of insulin-producing cells by GLP-1 gene therapy may be a potential method for prolonged control of type 1 diabetes in humans.
Liu
Meng-Ju
MJ
Rosalind Franklin Comprehensive Diabetes Center and Department of Pathology, Chicago Medical School, North Chicago, Illinois, USA.
Shin
Seungjin
S
Li
Na
N
Shigihara
Toshikatsu
T
Lee
Young-Sun
YS
Yoon
Ji-Won
JW
Jun
Hee-Sook
HS
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control*; D015870:Gene Expression / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D013311:Streptozocin / Q000494:pharmacology
D007328:Insulin; D012333:RNA, Messenger; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1