Role of Proinsulin Self-Association in Mutant INS Gene-Induced Diabetes of Youth

Diabetes. 2020 May;69(5):954-964. doi: 10.2337/db19-1106. Epub 2020 Mar 5.


Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin (PI) 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, PI-WT dimerizes in the ER. Here, we suggest that the normal PI-PI contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that PI B-chain tyrosine-16 (Tyr-B16), which is a key residue in normal PI dimerization, helps confer dominant-negative behavior of MIDY mutant PI-C(A7)Y. Substitutions of Tyr-B16 with either Ala, Asp, or Pro in PI-C(A7)Y decrease the abnormal interactions between the MIDY mutant and PI-WT, rescuing PI-WT export, limiting ER stress, and increasing insulin production in β-cells and human islets. This study reveals the first evidence indicating that noncovalent PI-PI contact initiates dominant-negative behavior of misfolded PI, pointing to a novel therapeutic target to enhance PI-WT export and increase insulin production.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Humans
  • Insulin / chemical synthesis*
  • Insulin / chemistry
  • Insulin / genetics
  • Insulin / metabolism*
  • Islets of Langerhans
  • Mice
  • Models, Molecular
  • Mutation
  • Proinsulin / chemistry*
  • Proinsulin / genetics
  • Proinsulin / metabolism*
  • Protein Conformation


  • Insulin
  • Proinsulin