Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth.
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.
Liu
Ming
M
Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, MI, USA.
Hodish
Israel
I
Haataja
Leena
L
Lara-Lemus
Roberto
R
Rajpal
Gautam
G
Wright
Jordan
J
Arvan
Peter
P
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
D011384:Proinsulin