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In vivo misfolding of proinsulin below the threshold of frank diabetes Hodish I; Absood A; Liu L; Liu M; Haataja L; Larkin D; Al-Khafaji A; Zaki A; Arvan PDiabetes 2011[Aug]; 60 (8): 2092-101OBJECTIVE: Endoplasmic reticulum (ER) stress has been described in pancreatic beta-cells after onset of diabetes-a situation in which failing beta-cells have exhausted available compensatory mechanisms. Herein we have compared two mouse models expressing equally small amounts of transgenic proinsulin in pancreatic beta-cells. RESEARCH DESIGN AND 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 beta-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 beta-cells continue to abundantly express transgene mRNA. Remarkably, however, a subset of beta-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 beta-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 beta-cells with relatively limited accumulation of misfolded proinsulin protein and maintenance of endogenous insulin production. Generation and maintenance of such a subset of beta-cells may have implications in the avoidance of type 2 diabetes.|Animals[MESH]|Endoplasmic Reticulum/*metabolism/pathology[MESH]|Female[MESH]|Humans[MESH]|Islets of Langerhans/pathology/physiopathology/ultrastructure[MESH]|Male[MESH]|Mice[MESH]|Mice, Transgenic[MESH]|Microscopy, Electron, Transmission[MESH]|Proinsulin/biosynthesis/genetics/*metabolism[MESH]|Protein Folding[MESH]|Transgenes[MESH] |
