Remission of diabetes by beta-cell regeneration in diabetic mice treated with a recombinant adenovirus expressing betacellulin

Mol Ther. 2008 May;16(5):854-61. doi: 10.1038/mt.2008.22. Epub 2008 Mar 18.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Autoimmune Diseases
  • Betacellulin
  • Cell Differentiation
  • Cell Proliferation
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / therapy*
  • Diabetes Mellitus, Experimental / therapy
  • Genetic Therapy / methods*
  • Glucose Tolerance Test
  • Humans
  • Insulin-Secreting Cells / cytology*
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Kinetics
  • Male
  • Mice
  • Mice, SCID
  • Streptozocin / pharmacology

Substances

  • BTC protein, human
  • Betacellulin
  • Btc protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Streptozocin