A mutant human proinsulin is secreted from islets of Langerhans in increased amounts via an unregulated pathway

R. J. Carroll, Robert E Hammer, S. J. Chan, H. H. Swift, A. H. Rubenstein, D. F. Steiner

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Abstract

A coding mutation in the human insulin gene (His-B10 → Asp) is associated with familial hyperproinsulinemia. To model this syndrome, we have produced transgenic mice that express high levels of the mutant prohormone in their islets of Langerhans. Strain 24-6 mice, containing about 100 copies of the mutant gene, were normoglycemic but had marked increases of serum human proinsulin immunoreactive components. Biosynthetic studies on isolated islets revealed that ≃ 65% of the proinsulin synthesized in these mice was the human mutant form. Unlike the normal endogenous mouse proinsulin, which was almost exclusively handled via a regulated secretory pathway, up to 15% of the human [Asp10]proinsulin was rapidly secreted after synthesis via an unregulated or constitutive pathway, and ≃ 20% was degraded within the islet cells. The secreted human [Asp10]proinsulin was not processed proteolytically. However, the processing of the normal mouse and human mutant proinsulins within the islets from transgenic mice was not significantly impaired. These findings suggest that the hyperproinsulinemia of the patients is the result of the continuous secretion of unprocessed mutant prohormone from the islets via this alternative unregulated pathway.

Original languageEnglish (US)
Pages (from-to)8943-8947
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume85
Issue number23
StatePublished - 1988

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Proinsulin
Islets of Langerhans
Transgenic Mice
Secretory Pathway
Genes
Insulin
Mutation
Serum

ASJC Scopus subject areas

  • General
  • Genetics

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A mutant human proinsulin is secreted from islets of Langerhans in increased amounts via an unregulated pathway. / Carroll, R. J.; Hammer, Robert E; Chan, S. J.; Swift, H. H.; Rubenstein, A. H.; Steiner, D. F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 85, No. 23, 1988, p. 8943-8947.

Research output: Contribution to journalArticle

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AU - Hammer, Robert E

AU - Chan, S. J.

AU - Swift, H. H.

AU - Rubenstein, A. H.

AU - Steiner, D. F.

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