title: INS-gene mutations: from genetics and beta cell biology to clinical disease.
abstract: 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.
authors.affiliation: Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, 300052, China; Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI, 48105, USA. Electronic address: mingl65@hotmail.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI, 48105, USA.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, 300052, China.
authors.forename: Jinqiu
authors.initials: J
authors.lastname: Cui
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI, 48105, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI, 48105, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Experimental Medicine, University of Tor Vergata, Rome and Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Barbetti
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI, 48105, USA. Electronic address: parvan@umich.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
mesh_terms: D003920:Diabetes Mellitus / Q000235:genetics* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D011972:Receptor, Insulin / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D007328:Insulin; D011498:Protein Precursors; C013737:preproinsulin; D011384:Proinsulin; D011972:Receptor, Insulin
keywords: Diabetes; Endoplasmic reticulum stress; Insulin biosynthesis; Insulin gene mutation; Pancreatic beta cell; Proinsulin misfolding