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

• Published in: Annals of the New York Academy of Sciences 2018-04, Vol.1418 (1), p.5-19
• Main Authors: Arunagiri, Anoop, Haataja, Leena, Cunningham, Corey N., Shrestha, Neha, Tsai, Billy, Qi, Ling, Liu, Ming, Arvan, Peter
• Format: Article
• Language: English
• Subjects: Animals; B7 antigen; Beta cells; Biosynthesis; Chemical synthesis; Cytoplasm; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus - metabolism; Diabetes Mellitus - pathology; Disulfide bonds; disulfide mispairing; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress; endoplasmic reticulum stress; ER; ER‐associated degradation; Humans; Hyperglycemia; INS gene; Insulin; Insulin-Secreting Cells - pathology; Molecular chains; Mutant INS gene–induced Diabetes of Youth; MIDY; Mutation; Pancreas; Proinsulin - biosynthesis; Proinsulin - chemistry; Proinsulin - genetics; Proinsulin - metabolism; protein aggregation; Protein Folding; Protein Transport; Proteins; secretory protein synthesis; Youth
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/nyas.13531

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.