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The Identification of Potential Factors Associated with the Development of Type 2 Diabetes: A Quantitative Proteomics Approach*S⃞

机译：识别与2型糖尿病发展相关的潜在因素：蛋白质组学定量方法*S⃞

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Type 2 diabetes (T2D) arises when pancreatic β-cells fail to compensate for systemic insulin resistance with appropriate insulin secretion. However, the link between insulin resistance and β-cell failure in T2D is not fully understood. To explore this association, we studied transgenic MKR mice that initially develop insulin resistance in skeletal muscle but by 8 weeks of age have T2D. In the present study, global islet protein and gene expression changes were characterized in diabetic MKR versus non-diabetic control mice at 10 weeks of age. Using a quantitative proteomics approach (isobaric tags for relative and absolute quantification (iTRAQ)), 159 proteins were differentially expressed in MKR compared with control islets. Marked up-regulation of protein biosynthesis and endoplasmic reticulum stress pathways and parallel down-regulation in insulin processing/secretion, energy utilization, and metabolism were observed. A fraction of the differentially expressed proteins identified (including GLUT2, DNAJC3, VAMP2, RAB3A, and PC1/3) were linked previously to insulin-secretory defects and T2D. However, many proteins for the first time were associated with islet dysfunction, including the unfolded protein response proteins (ERP72, ERP44, ERP29, PPIB, FKBP2, FKBP11, and DNAJB11), endoplasmic reticulum-associated degradation proteins (VCP and UFM1), and multiple proteins associated with mitochondrial energy metabolism (NDUFA9, UQCRH, COX2, COX4I1, COX5A, ATP6V1B2, ATP6V1H, ANT1, ANT2, ETFA, and ETFB). The mRNA expression level corresponding to these proteins was examined by microarray, and then a small subset was validated using quantitative real time PCR and Western blot analyses. Importantly ∼54% of differentially expressed proteins in MKR islets (including proteins involved in proinsulin processing, protein biosynthesis, and mitochondrial oxidation) showed changes in the proteome but not transcriptome, suggesting post-transcriptional regulation. These results underscore the importance of integrated mRNA and protein expression measurements and validate the use of the iTRAQ method combined with microarray to assess global protein and gene changes involved in the development of T2D.
机译：当胰岛β细胞无法通过适当的胰岛素分泌来补偿全身性胰岛素抵抗时，就会出现2型糖尿病（T2D）。但是，尚不完全了解T2D中胰岛素抵抗与β细胞衰竭之间的联系。为了探讨这种关联，我们研究了最初在骨骼肌中产生胰岛素抵抗但到8周龄已患有T2D的转基因MKR小鼠。在本研究中，与10周龄的非糖尿病对照小鼠相比，糖尿病MKR的总体胰岛蛋白和基因表达变化得到了表征。使用定量蛋白质组学方法（等压标记用于相对和绝对定量（iTRAQ）），与对照胰岛相比，MKR中有159种蛋白质差异表达。观察到蛋白质生物合成和内质网应激途径的明显上调，以及胰岛素加工/分泌，能量利用和代谢中的平行下调。鉴定出的一部分差异表达蛋白（包括GLUT2，DNAJC3，VAMP2，RAB3A和PC1 / 3）事先与胰岛素分泌缺陷和T2D相关。但是，许多蛋白质首次与胰岛功能障碍有关，包括未折叠的蛋白质反应蛋白（ERP72，ERP44，ERP29，PPIB，FKBP2，FKBP11和DNAJB11），内质网相关的降解蛋白（VCP和UFM1）和与线粒体能量代谢相关的多种蛋白质（NDUFA9，UQCRH，COX2，COX4I1，COX5A，ATP6V1B2，ATP6V1H，ANT1，ANT2，ETFA和ETFB）。通过微阵列检查与这些蛋白质相对应的mRNA表达水平，然后使用定量实时PCR和蛋白质印迹分析验证一小部分。重要的是，MKR胰岛中约有54％的差异表达蛋白质（包括与胰岛素原加工，蛋白质生物合成和线粒体氧化有关的蛋白质）的蛋白质组发生了变化，但转录组没有发生变化，这表明转录后的调控。这些结果强调了整合mRNA和蛋白质表达测量的重要性，并验证了将iTRAQ方法与微阵列相结合来评估T2D发育中涉及的全球蛋白质和基因变化的重要性。

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