In Vivo Misfolding of Proinsulin Below the Threshold of Frank Diabetes

[摘要]：OBJECTIVE-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. Diabetes 60:2092-2101, 2011

[全文传递流程]：

一般上传文献全文的时限在1个工作日内