Journal
DIABETES
Volume 68, Issue 4, Pages 747-760Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db18-0671
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Funding
- Zealand Pharma A/S
- Danish Diabetes Academy
- Department of Biomedical Sciences at the University of Copenhagen
- Augustinus Foundation
- Punjab Educational Endowment Fund, Pakistan
- Swedish Research Council
- Diabetesfonden (Sweden)
- Novo Nordisk Foundation
- National Institutes of Health [DK48280]
- Danish Council for Independent Research [DFF-4092-00066]
- Dagmar Marshall Foundation
- A.P. Moller Foundation
- Kirsten and Freddy Johansen Foundation
- Eva and Hans Carl Holm Foundation
- Family Ernfors Foundation
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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 underinvestigated. 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 -cells. We found that GRP94 coimmunoprecipitated 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 accelerated twofold, but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in -cells selectively activated protein kinase R-like endoplasmic reticulum kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from patients with type 2 diabetes. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion.
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