In vivo misfolding of proinsulin below the threshold of frank diabetes.
In vivo misfolding of proinsulin below the threshold of frank diabetes.
复制标题
作者：
Hodish I;Absood A;Liu L;Liu M;Haataja L;Larkin D;Al-Khafaji A;Zaki A;Arvan P
内质网（ER）应激已被描述在胰腺β细胞发病后，糖尿病-一种情况下，失败的β细胞已经用尽可用的补偿机制。在此，我们比较了在胰腺β细胞中表达同样少量的转基因胰岛素原的两种小鼠模型。在hProCpepGFP小鼠中，人胰岛素原（在连接[C]肽内用绿色荧光蛋白[GFP]标记）在ER中折叠、输出、转化为人胰岛素并分泌。在hProC（A7）Y-CpepGFP小鼠中，转基因突变胰岛素原的错误折叠导致其保留在ER中。两种转基因动物中新生胰腺的分析显示每个β细胞对内源性胰岛素和转基因蛋白染色阳性。在该转基因表达水平下，大多数雄性hProC（A7）Y-CpepGFP小鼠不发展明显的糖尿病，但错误折叠的胰岛素原干扰内源性胰岛素原的胰岛素产生并激活ER应激反应。在非糖尿病成年hProC（A7）Y-CpepGFP雄性中，所有β细胞继续大量表达转基因mRNA。然而，值得注意的是，每个胰岛中的β细胞亚群变得基本上缺乏内源性胰岛素，其中这些细胞中的一些积累了大量的错误折叠的突变体胰岛素原，而另一个β细胞亚群具有少得多的积累的错误折叠的突变体胰岛素原，其中这些细胞中的一些含有丰富的内源性胰岛素。结果表明，在由胰岛素原错误折叠和ER应激引起的糖尿病发展之前，胰腺补偿的来源，即，存在一个重要的β细胞亚群，错误折叠的胰岛素原蛋白的积累相对有限，并维持内源性胰岛素的产生。这种β细胞亚群的产生和维持可能对避免2型糖尿病有意义。
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. 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. 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. 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.
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影响因子：
8.2
作者：
Marchetti, P.;Bugliani, M.;Cnop, M.
通讯作者：
Cnop, M.
DOI：
10.1152/ajpendo.00321.2002
发表时间：
2003-01-01
影响因子：
5.1
作者：
Hara, M;Wang, XY;Bell, GI
通讯作者：
Bell, GI
影响因子：
4.8
作者：
Trajkovski, Mirko;Mziaut, Hassan;Solimena, Michele
通讯作者：
Solimena, Michele
影响因子：
15.9
作者：
Song, Benbo;Scheuner, Donalyn;Kaufman, Randal J.
通讯作者：
Kaufman, Randal J.
影响因子：
7.7
作者：
Gupta S;McGrath B;Cavener DR
通讯作者：
Cavener DR