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Diabetes. 2020 Mar 5. pii: db191106. doi: 10.2337/db19-1106. [Epub ahead of print]

Role of Proinsulin Self-Association in Mutant INS gene-induced Diabetes of Youth.

Author information

1
Division of Metabolism, Endocrinology & Diabetes, the University of Michigan Medical School, Ann Arbor, MI 48105 USA.
2
Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin 300052, China.
3
Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
4
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037 USA.
5
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis IN 46202 USA.
6
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093 USA.
7
Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037 USA.
8
Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610 USA.
9
Division of Metabolism, Endocrinology & Diabetes, the University of Michigan Medical School, Ann Arbor, MI 48105 USA mingliu@tmu.edu.cn parvan@umich.edu.

Abstract

Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin in the endoplasmic reticulum (ER) drive the molecular pathogenesis of Mutant-INS-gene induced Diabetes of Youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, proinsulin-WT dimerizes in the ER. Here, we suggest that the normal proinsulin-proinsulin contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that proinsulin Tyr-B16, which is a key residue in normal proinsulin dimerization, helps confer dominant-negative behavior of MIDY mutant proinsulin-C(A7)Y. Substitutions of Tyr-B16 with ether Ala, Asp, or Pro in proinsulin-C(A7)Y each decrease the abnormal interactions between the MIDY mutant and proinsulin-WT, rescuing proinsulin-WT export, limiting ER stress, and increasing insulin production in β-cells and human islets. This study reveals the first evidence indicating that noncovalent proinsulin-proinsulin contact initiates dominant-negative behavior of misfolded proinsulin, pointing to a novel therapeutic target to enhance proinsulin-WT export and increase insulin production.

PMID:
32139596
DOI:
10.2337/db19-1106

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