title: In vivo misfolding of proinsulin below the threshold of frank diabetes.
abstract: OBJECTIVE
  Endoplasmic reticulum (ER) stress has been described in pancreatic β-cells after onset of diabetes-a situation in which failing β-cells have exhausted available compensatory mechanisms. Herein we have compared two mouse models expressing equally small amounts of transgenic proinsulin in pancreatic β-cells.
  
  
  METHODS
  In hProCpepGFP mice, human proinsulin (tagged with green fluorescent protein [GFP] within the connecting [C]-peptide) is folded in the ER, exported, converted to human insulin, and secreted. In hProC(A7)Y-CpepGFP mice, misfolding of transgenic mutant proinsulin causes its retention in the ER. Analysis of neonatal pancreas in both transgenic animals shows each β-cell stained positively for endogenous insulin and transgenic protein.
  
  
  RESULTS
  At this transgene expression level, most male hProC(A7)Y-CpepGFP mice do not develop frank diabetes, yet the misfolded proinsulin perturbs insulin production from endogenous proinsulin and activates ER stress response. In nondiabetic adult hProC(A7)Y-CpepGFP males, all β-cells continue to abundantly express transgene mRNA. Remarkably, however, a subset of β-cells in each islet becomes largely devoid of endogenous insulin, with some of these cells accumulating large quantities of misfolded mutant proinsulin, whereas another subset of β-cells has much less accumulated misfolded mutant proinsulin, with some of these cells containing abundant endogenous insulin.
  
  
  CONCLUSIONS
  The results indicate a source of pancreatic compensation before the development of diabetes caused by proinsulin misfolding with ER stress, i.e., the existence of an important subset of β-cells with relatively limited accumulation of misfolded proinsulin protein and maintenance of endogenous insulin production. Generation and maintenance of such a subset of β-cells may have implications in the avoidance of type 2 diabetes.
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan, USA. ihodish@umich.edu
authors.forename: Israel
authors.initials: I
authors.lastname: Hodish
authors.forename: Afaf
authors.initials: A
authors.lastname: Absood
authors.forename: Leanza
authors.initials: L
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Leena
authors.initials: L
authors.lastname: Haataja
authors.forename: Dennis
authors.initials: D
authors.lastname: Larkin
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al-Khafaji
authors.forename: Anthony
authors.initials: A
authors.lastname: Zaki
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007515:Islets of Langerhans / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D011384:Proinsulin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D019076:Transgenes
chemical_list: D011384:Proinsulin