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Misfolded Proinsulin Affects Bystander Proinsulin in Neonatal Diabetes*

机译:错误折叠的胰岛素原影响新生儿糖尿病的旁观者胰岛素原*

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摘要

It has previously been shown that misfolded mutant Akita proinsulin in the endoplasmic reticulum engages directly in protein complexes either with nonmutant proinsulin or with “hProCpepGFP” (human proinsulin bearing emerald-GFP within the C-peptide), impairing the trafficking of these “bystander” proinsulin molecules (Liu, M., Hodish, I., Rhodes, C. J., and Arvan, P. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 15841–15846). Herein, we generated transgenic mice, which, in addition to expressing endogenous proinsulin, exhibit β-cell-specific expression of hProCpepGFP via the Ins1 promoter. In these mice, hProCpepGFP protein levels are physiologically regulated, and hProCpepGFP is packaged and processed to CpepGFP that is co-stored in β-secretory granules. Visualization of CpepGFP fluorescence provides a quantifiable measure of pancreatic islet insulin content that can be followed in live animals in states of health and disease. We examined loss of pancreatic insulin in hProCpepGFP transgenic mice mated to Akita mice that develop neonatal diabetes because of the expression of misfolded proinsulin. Loss of bystander insulin in Akita animals is detected initially as a block in CpepGFP/insulin production with intracellular accumulation of the precursor, followed ultimately by loss of pancreatic β-cells. The data support that misfolded proinsulin perturbs bystander proinsulin in the endoplasmic reticulum, leading to β-cell failure.
机译:先前已显示,内质网中折叠错误的突变体秋田胰岛素原直接与非突变胰岛素原或“ hProCpepGFP”(C肽中带有祖母绿GFP的人胰岛素原)直接结合在蛋白质复合物中,从而损害了这些“旁观者”的贩运胰岛素原分子(Liu,M.,Hodish,I.,Rhodes,CJ和Arvan,P.(2007)Proc。Natl.Acad.Sci.USA 104,15841-15846)。本文中,我们生成了转基因小鼠,除了表达内源性胰岛素原外,它还通过Ins1启动子表现出hProCpepGFP的β细胞特异性表达。在这些小鼠中,hProCpepGFP蛋白水平受到生理调节,hProCpepGFP被包装并加工成CpepGFP,后者共同存储在β分泌颗粒中。 CpepGFP荧光的可视化提供了可以量化的胰岛胰岛素含量的定量指标,在健康和疾病状态的活体动物中可以遵循该指标。我们检查了与因新生儿胰岛素折叠错误表达而发展为新生儿糖尿病的秋田小鼠交配的hProCpepGFP转基因小鼠中胰腺胰岛素的损失。秋田动物中旁观者胰岛素的丢失最初被检测为CpepGFP /胰岛素产生的一种阻滞,伴随着前体的细胞内积累,随后最终是胰腺β细胞的丢失。数据支持将胰岛素原错误折叠会干扰内质网旁的胰岛素原,从而导致β细胞衰竭。

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