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The Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 94 is Essential for Proinsulin Handling
Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
Univ Michigan, Div Metab Endocrinol & Diabet, Med Ctr, Ann Arbor, MI USA.
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2019 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 4, p. 747-760Article in journal (Refereed) Published
Abstract [en]

Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaperones in the handling of wild-type proinsulin is under-investigated. Here, we have explored the importance of glucose regulated protein 94 (GRP94), a prominent ER chaperone known to fold insulin-like growth factors, in proinsulin handling within β-cells. We found that GRP94 co-immunoprecipitated with proinsulin and that inhibition of GRP94 function and/or expression reduced glucose-dependent insulin secretion, shortened proinsulin half-life and lowered intracellular proinsulin and insulin levels. This phenotype was accompanied by post-ER proinsulin misprocessing and higher numbers of enlarged insulin granules that contained amorphic material with reduced immunogold staining for mature insulin. Insulin granule exocytosis was two-fold accelerated but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in β-cells selectively activated Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from T2D patients. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion.

Place, publisher, year, edition, pages
2019. Vol. 68, no 4, p. 747-760
National Category
Cell and Molecular Biology Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-378915DOI: 10.2337/db18-0671ISI: 000462053100007PubMedID: 30670477OAI: oai:DiVA.org:uu-378915DiVA, id: diva2:1295040
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Swedish Research CouncilAvailable from: 2019-03-08 Created: 2019-03-08 Last updated: 2019-05-06Bibliographically approved

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Omar-Hmeadi, MuhmmadYang, MingyuBarg, SebastianTengholm, Anders

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