Redox regulation of insulin degradation by insulin-degrading enzyme

Crystal M. Cordes, Robert G Bennett, Gerri L. Siford, Frederick G Hamel

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Insulin-degrading enzyme (IDE) is a thiol sensitive peptidase that degrades insulin and amyloid β, and has been linked to type 2 diabetes mellitus and Alzheimer's disease. We examined the thiol sensitivity of IDE using S-nitrosoglutathione, reduced glutathione, and oxidized glutathione to distinguish the effects of nitric oxide from that of the redox state. The in vitro activity of IDE was studied using either partially purified cytosolic enzyme from male Sprague-Dawley rats, or purified rat recombinant enzyme. We confirm that nitric oxide inhibits the degrading activity of IDE, and that it affects proteasome activity through this interaction with IDE, but does not affect the proteasome directly. Oxidized glutathione inhibits IDE through glutathionylation, which was reversible by dithiothreitol but not by ascorbic acid. Reduced glutathione had no effect on IDE, but reacted with partially degraded insulin to disrupt its disulfide bonds and accelerate its breakdown to trichloroacetic acid soluble fragments. Our results demonstrate the sensitivity of insulin degradation by IDE to the redox environment and suggest another mechanism by which the cell's oxidation state may contribute to the development of, and the link between, type 2 diabetes and Alzheimer's disease.

Original languageEnglish (US)
Article numbere18138
JournalPloS one
Volume6
Issue number3
DOIs
StatePublished - Mar 28 2011

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Insulysin
Oxidation-Reduction
insulin
Insulin
Degradation
degradation
enzymes
glutathione
Glutathione Disulfide
Proteasome Endopeptidase Complex
Medical problems
Sulfhydryl Compounds
Type 2 Diabetes Mellitus
Glutathione
proteasome endopeptidase complex
Rats
Alzheimer disease
Alzheimer Disease
Nitric Oxide
thiols

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Redox regulation of insulin degradation by insulin-degrading enzyme. / Cordes, Crystal M.; Bennett, Robert G; Siford, Gerri L.; Hamel, Frederick G.

In: PloS one, Vol. 6, No. 3, e18138, 28.03.2011.

Research output: Contribution to journalArticle

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