Remission of diabetes by beta-cell regeneration in diabetic mice treated with a recombinant adenovirus expressing betacellulin.
Type 1 diabetes results from destruction of the majority of the pancreatic beta cells by beta cell-specific autoimmune responses; therefore, expansion of the beta-cell mass in vivo is a possible approach to its treatment. Betacellulin (BTC) is known to promote beta-cell growth and differentiation. We investigated whether transient, constitutive expression, and secretion of BTC would regenerate sufficient numbers of pancreatic beta cells to restore normoglycemia in diabetic animals. We constructed a recombinant adenoviral vector (rAd-BTC) containing the cytomegalovirus promoter/enhancer, beta-globin chimeric intron, and albumin leader sequence to facilitate secretion, followed by BTC (1-80) complementary DNA (cDNA) encoding mature BTC. A single intravenous (i.v.) administration of rAd-BTC resulted in complete remission of streptozotocin (STZ)-induced diabetes within 2 weeks in mice. The mice remained normoglycemic for >100 days; glucose tolerance tests showed kinetics similar to normal, nondiabetic mice. Pancreatic insulin content, beta-cell mass, and serum insulin levels in rAd-BTC-treated mice were significantly higher than in the controls. Treatment of autoimmune diabetic mice with rAd-BTC in combination with an immune suppressor resulted in remission of diabetes. We conclude that transient expression of BTC by rAd-BTC administration results in prolonged remission of diabetes in mice, by the regeneration of sufficient numbers of beta cells in the pancreas.
Shin
Seungjin
S
Rosalind Franklin Comprehensive Diabetes Center, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North, Chicago, Illinois, USA.
Li
Na
N
Kobayashi
Naoya
N
Yoon
Ji-Won
JW
Jun
Hee-Sook
HS
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001327:Autoimmune Diseases; D066259:Betacellulin; D002454:Cell Differentiation; D049109:Cell Proliferation; D003920:Diabetes Mellitus / Q000235:genetics / Q000628:therapy*; D003921:Diabetes Mellitus, Experimental / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods*; D005951:Glucose Tolerance Test; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D016513:Mice, SCID; D013311:Streptozocin / Q000494:pharmacology
C587851:BTC protein, human; D066259:Betacellulin; C587852:Btc protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D013311:Streptozocin