Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 40, Pages 15841-15846Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0702697104
Keywords
diabetes mellitus; endoplasmic reticulum storage disease; insulin secretion; proinsulin disulfide isomers
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Funding
- NIDDK NIH HHS [R01 DK050610, R01 DK048280, P60 DK020572, DK20572, R01 DK048280-14, P30 DK020572, DK48280] Funding Source: Medline
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As a tool to explore proinsulin (PI) trafficking, a human PI cDNA has been constructed with GFP fused within the C peptide. In regulated secretory cells containing appropriate prohormone convertases, the hProCpepGFP construct undergoes endoproteolytic processing to CpepGFP and native human insulin, which are specifically detected and cosecreted in parallel with endogenous insulin. Expression of C(A7)Y mutant PI results in autosomal dominant diabetes in Akita mice. We directly identify the misfolded PI in Akita islets and also showthatC(A7)Y mutant Pl, either in the context of the hProCpepGFP chimera or not, engages directly in protein complexes with nonmutant PI, impairing the trafficking and recovery of nonmutant Pl. This trapping mechanism decreases insulin production in P cells. Thereafter we observe a loss of 13 cell viability. The data imply that Pl misfolding leading to impaired endoplasmic reticulum exit of nonmutant 131 may be a key early step in a chain reaction of 13 cell dysfunction and demise leading to onset and progression of diabetes.
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