Pancreatic Beta Cells Are Highly Susceptible to Oxidative and ER Stresses during the Development of Diabetes

The
complex interplay of many cell types and the temporal heterogeneity
of pancreatic islet composition obscure the direct role of resident
alpha and beta cells in the development of Type 1 diabetes. Therefore,
in addition to studying islets isolated from non-obese diabetic mice,
we analyzed homogeneous cell populations of murine alpha (αTC-1)
and beta (NIT-1) cell lines to understand the role and differential
survival of these two predominant islet cell populations. A total
of 56 proteins in NIT-1 cells and 50 in αTC-1 cells were differentially
expressed when exposed to proinflammatory cytokines. The major difference
in the protein expression between cytokine-treated NIT-1 and αTC-1
cells was free radical scavenging enzymes. A similar observation was
made in cytokine-treated whole islets, where a comprehensive analysis
of subcellular fractions revealed that 438 unique proteins were differentially
expressed under inflammatory conditions. Our data indicate that beta
cells are relatively susceptible to ER and oxidative stress and reveal
key pathways that are dysregulated in beta cells during cytokine exposure.
Additionally, in the islets, inflammation also leads to enhanced antigen
presentation, which completes a three-way insult on beta cells, rendering
them targets of infiltrating T lymphocytes.

多种细胞类型间的复杂相互作用以及胰腺胰岛组成的时间异质性，掩盖了驻留α细胞与β细胞在1型糖尿病（Type 1 diabetes）发病过程中的直接作用。因此，本研究除了对非肥胖糖尿病小鼠（non-obese diabetic mice）分离得到的胰岛进行研究外，还分析了小鼠源α（αTC-1）与β（NIT-1）细胞系的均一细胞群体，以阐明这两种主要胰岛细胞群的功能及其差异化存活机制。当暴露于促炎细胞因子（proinflammatory cytokines）时，NIT-1细胞中共鉴定出56种差异表达蛋白，αTC-1细胞中则为50种。细胞因子处理后的NIT-1与αTC-1细胞间的蛋白表达差异主要集中在自由基清除酶类。对细胞因子处理后的完整胰岛进行的类似研究也得到了相同结果：通过对亚细胞组分的全面分析发现，炎症条件下共有438种独特蛋白呈现差异表达。本研究数据表明，β细胞相对更容易受到内质网（ER）与氧化应激的影响，并揭示了细胞因子暴露过程中β细胞内失调的关键通路。此外，胰岛中的炎症反应还会增强抗原呈递过程，从而完成对β细胞的三重打击，使其成为浸润性T淋巴细胞（T lymphocytes）的攻击靶点。