INS-gene mutations: From genetics and beta cell biology to clinical disease

Ming Liu, Jinhong Sun, Jinqiu Cui, Wei Chen, Huan Guo, Fabrizio Barbetti, Peter Arvan

Research output: Contribution to journalArticlepeer-review


A growing list of insulin gene mutations causing a new form of monogenic diabetes has drawn increasing attention over the past seven years. The mutations have been identified in the untranslated regions of the insulin gene as well as the coding sequence of preproinsulin including within the signal peptide, insulin B-chain, C-peptide, insulin A-chain, and the proteolytic cleavage sites both for signal peptidase and the prohormone convertases. These mutations affect a variety of different steps of insulin biosynthesis in pancreatic beta cells. Importantly, although many of these mutations cause proinsulin misfolding with early onset autosomal dominant diabetes, some of the mutant alleles appear to engage different cellular and molecular mechanisms that underlie beta cell failure and diabetes. In this article, we review the most recent advances in the field and discuss challenges as well as potential strategies to prevent/delay the development and progression of autosomal dominant diabetes caused by INS-gene mutations. It is worth noting that although diabetes caused by INS gene mutations is rare, increasing evidence suggests that defects in the pathway of insulin biosynthesis may also be involved in the progression of more common types of diabetes. Collectively, the (pre)proinsulin mutants provide insightful molecular models to better understand the pathogenesis of all forms of diabetes in which preproinsulin processing defects, proinsulin misfolding, and ER stress are involved.

Original languageEnglish
Pages (from-to)3-18
Number of pages16
JournalMolecular Aspects of Medicine
Publication statusPublished - Apr 1 2015


  • Diabetes
  • Endoplasmic reticulum stress
  • Insulin biosynthesis
  • Insulin gene mutation
  • Pancreatic beta cell
  • Proinsulin misfolding

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Clinical Biochemistry
  • Medicine(all)


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