title: Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth.
abstract: 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.
authors: Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors: Ming
authors: M
authors: Liu
authors: Israel
authors: I
authors: Hodish
authors: Leena
authors: L
authors: Haataja
authors: Roberto
authors: R
authors: Lara-Lemus
authors: Gautam
authors: G
authors: Rajpal
authors: Jordan
authors: J
authors: Wright
authors: Peter
authors: P
authors: Arvan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D011384:Proinsulin / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism
chemical_list: D011384:Proinsulin