Adenovirus-mediated transfer of a modified human proinsulin gene reverses hyperglycemia in diabetic mice

Daniel K. Short, Shuichi Okada, Keishi Yamauchi, Jeffrey E. Pessin

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The human proinsulin cDNA was introduced into a replication-defective adenovirus and was found to confer proinsulin expression to a hepatocyte (H4- II-E) cell line upon infection. A second virus was constructed in which the dibasic prohormone convertase recognition sequence was mutated to a tetrabasic furin cleavage site. Cells infected with this virus synthesized both proinsulin and mature insulin. Gel filtration chromatography, competition of insulin binding, and activation of the insulin receptor kinase activity demonstrated that this mature insulin was functionally identical to that of authentic processed insulin. Injection of these viral constructs into the external jugular vein of mice resulted in insulin gene expression in the liver. Expression from the mutated proinsulin virus dramatically improved the glycemic state of diabetic mice. However, the effects of the viral infection were transient, being maximal at ~5-7 days and returning to steady-state levels by 14-21 days. These data demonstrate that somatic cell insulin gene delivery by the use of recombinant adenovirus can be used to transiently reverse the diabetic state in mice.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume275
Issue number5 38-5
StatePublished - 1998
Externally publishedYes

Fingerprint

Proinsulin
Adenoviridae
Hyperglycemia
Genes
Insulin
Viruses
Proprotein Convertases
Furin
Insulin Receptor
Jugular Veins
Virus Diseases
Chromatography
Gene expression
Liver
Gel Chromatography
Hepatocytes
Phosphotransferases
Complementary DNA
Gels
Chemical activation

Keywords

  • Diabetes
  • Furin
  • Gene therapy

ASJC Scopus subject areas

  • Physiology
  • Endocrinology
  • Biochemistry

Cite this

Adenovirus-mediated transfer of a modified human proinsulin gene reverses hyperglycemia in diabetic mice. / Short, Daniel K.; Okada, Shuichi; Yamauchi, Keishi; Pessin, Jeffrey E.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 275, No. 5 38-5, 1998.

Research output: Contribution to journalArticle

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