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Ann N Y Acad Sci. 2018 Apr;1418(1):5-19. doi: 10.1111/nyas.13531. Epub 2018 Jan 28.

Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes.

Author information

1
Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan.
2
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan.
3
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
4
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan.
5
Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.

Abstract

The endoplasmic reticulum (ER) is broadly distributed throughout the cytoplasm of pancreatic beta cells, and this is where all proinsulin is initially made. Healthy beta cells can synthesize 6000 proinsulin molecules per second. Ordinarily, nascent proinsulin entering the ER rapidly folds via the formation of three evolutionarily conserved disulfide bonds (B7-A7, B19-A20, and A6-A11). A modest amount of proinsulin misfolding, including both intramolecular disulfide mispairing and intermolecular disulfide-linked protein complexes, is a natural by-product of proinsulin biosynthesis, as is the case for many proteins. The steady-state level of misfolded proinsulin-a potential ER stressor-is linked to (1) production rate, (2) ER environment, (3) presence or absence of naturally occurring (mutational) defects in proinsulin, and (4) clearance of misfolded proinsulin molecules. Accumulation of misfolded proinsulin beyond a certain threshold begins to interfere with the normal intracellular transport of bystander proinsulin, leading to diminished insulin production and hyperglycemia, as well as exacerbating ER stress. This is most obvious in mutant INS gene-induced Diabetes of Youth (MIDY; an autosomal dominant disease) but also likely to occur in type 2 diabetes owing to dysregulation in proinsulin synthesis, ER folding environment, or clearance.

KEYWORDS:

ER-associated degradation; Mutant INS gene-induced Diabetes of Youth; MIDY; disulfide mispairing; endoplasmic reticulum stress; ER; protein aggregation; secretory protein synthesis

PMID:
29377149
PMCID:
PMC5934315
DOI:
10.1111/nyas.13531
[Indexed for MEDLINE]
Free PMC Article

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