Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth

Trends Endocrinol Metab. 2010 Nov;21(11):652-9. doi: 10.1016/j.tem.2010.07.001. Epub 2010 Aug 18.


Type 1B diabetes (typically with early onset and without islet autoantibodies) has been described in patients bearing small coding sequence mutations in the INS gene. Not all mutations in the INS gene cause the autosomal dominant Mutant INS-gene Induced Diabetes of Youth (MIDY) syndrome, but most missense mutations affecting proinsulin folding produce MIDY. MIDY patients are heterozygotes, with the expressed mutant proinsulins exerting dominant-negative (toxic gain of function) behavior in pancreatic beta cells. Here we focus primarily on proinsulin folding in the endoplasmic reticulum, providing insight into perturbations of this folding pathway in MIDY. Accumulated evidence indicates that, in the molecular pathogenesis of the disease, misfolded proinsulin exerts dominant effects that initially inhibit insulin production, progressing to beta cell demise with diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / metabolism
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Models, Biological
  • Molecular Sequence Data
  • Mutation / physiology
  • Proinsulin / chemistry*
  • Proinsulin / genetics*
  • Proinsulin / metabolism
  • Proinsulin / physiology
  • Protein Folding*
  • Proteostasis Deficiencies / genetics
  • Proteostasis Deficiencies / metabolism


  • Proinsulin