Remission of Diabetes by β-Cell Regeneration in Diabetic Mice Treated With a Recombinant Adenovirus Expressing Betacellulin.
Type 1 diabetes results from destruction of the majority of the pancreatic β cells by β cell-specific autoimmune responses; therefore, expansion of the β-cell mass in vivo Is a possible approach to its treatment. Betacellulin (BTC) is known to promote β-cell growth and differentiation. We investigated whether transient, constitutive expression, and secretion of BTC would regenerate sufficient numbers of pancreatic β cells to restore normoglycemia in diabetic animals. We constructed a recombinant adenoviral vector (rAd-BTC) containing the cytomegalovirus promoter/enhancer, β-globin chimeric intron, and albumin leader sequence to facilitate secretion, followed by BTC (1-80) complementary DNA (cDNA) encoding mature BTC. A single intravenous (IV) 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, β-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 β cells in the pancreas.
Rosalind Franklin Comprehensive Diabetes Center, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North, Chicago, Illinois, USA.
Seungjin
S
Shin
Rosalind Franklin Comprehensive Diabetes Center, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North, Chicago, Illinois, USA.
Na
N
Li
Department of Surgery, Okayama University Graduate School of Medicine and Dentistry Shikata-cho, Okayama, Japan.
Naoya
N
Kobayashi
Rosalind Franklin Comprehensive Diabetes Center, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North, Chicago, Illinois, USA; Deceased.
Ji-Won
JW
Yoon
Rosalind Franklin Comprehensive Diabetes Center, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North, Chicago, Illinois, USA; Laboratory of Beta-Cell Biology and Autoimmunity, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Songdo-dong, Yeongsu-ku, Incheon, Korea. Electronic address: hsjeon@gachon.ac.kr.
Hee-Sook
HS
Jun