Increased ectodomain shedding of cell adhesion molecule 1 from pancreatic islets in type 2 diabetic pancreata: correlation with hemoglobin A1c levels.
Increased ectodomain shedding of cell adhesion molecule 1 from pancreatic islets in type 2 diabetic pancreata: correlation with hemoglobin A1c levels.
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DOI：
10.1371/journal.pone.0100988
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ito A
中科院分区：
文献类型：
--
作者：
Inoue T;Hagiyama M;Yoneshige A;Kato T;Enoki E;Maenishi O;Chikugo T;Kimura M;Satou T;Ito A
肺气肿和2型糖尿病（T2 DM），都是由生活方式因素引起的，经常并发。这些疾病分别影响表达细胞粘附分子1（CADM 1）（免疫球蛋白超家族成员）的肺泡细胞和胰岛细胞。全长CADM 1的蛋白酶介导的胞外域脱落产生具有促凋亡活性的C末端片段（CTF）。在肺气肿的肺中，CADM 1脱落率增加，因此肺泡细胞中CTFs的水平增加。在这项研究中，CADM 1在胰岛细胞中的表达通过蛋白质印迹法检测。从尸检时分离自T2 DM患者（n = 12）或无胰腺疾病患者（n = 8）的胰腺福尔马林固定、石蜡包埋切片中提取蛋白质。 在调整相邻切片中存在的胰岛细胞数量后，我们发现T2 DM胰岛中全长CADM 1减少，而胞外域脱落增加。患者存活时测量的血红蛋白A1 c水平与全长CADM 1水平呈负相关（P = 0.041），与胞外域脱落率呈正相关（P = 0.001）。 在T2 DM胰岛细胞的免疫荧光图像中，在细胞质中检测到CADM 1，但不在细胞膜上。一致地，当用佛波酯和胰蛋白酶处理MIN 6-m9小鼠β细胞以诱导脱落时，CADM 1免疫染色在细胞质中弥漫。当一种形式的CTFs在MIN 6-m9细胞中外源性表达时，它弥漫性地定位于细胞质中并增加凋亡细胞的数量。这些结果表明，增加的CADM 1胞外域脱落通过减少全长CADM 1并产生在细胞质中积累并促进β细胞凋亡的CTF而导致T2 DM中的血糖失调。因此，本研究确定了肺气肿和T2 DM共有的分子改变。
Pulmonary emphysema and type 2 diabetes mellitus (T2DM), both caused by lifestyle factors, frequently concur. Respectively, the diseases affect lung alveolar and pancreatic islet cells, which express cell adhesion molecule 1 (CADM1), an immunoglobulin superfamily member. Protease-mediated ectodomain shedding of full-length CADM1 produces C-terminal fragments (CTFs) with proapoptotic activity. In emphysematous lungs, the CADM1 shedding rate and thus the level of CTFs in alveolar cells increase. In this study, CADM1 expression in islet cells was examined by western blotting. Protein was extracted from formalin-fixed, paraffin-embedded sections of pancreata isolated from patients with T2DM (n = 12) or from patients without pancreatic disease (n = 8) at autopsy. After adjusting for the number of islet cells present in the adjacent section, we found that full-length CADM1 decreased in T2DM islets, while ectodomain shedding increased. Hemoglobin A1c levels, measured when patients were alive, correlated inversely with full-length CADM1 levels (P = 0.041) and positively with ectodomain shedding rates (P = 0.001). In immunofluorescence images of T2DM islet cells, CADM1 was detected in the cytoplasm, but not on the cell membrane. Consistently, when MIN6-m9 mouse beta cells were treated with phorbol ester and trypsin to induce shedding, CADM1 immunostaining was diffuse in the cytoplasm. When a form of CTFs was exogenously expressed in MIN6-m9 cells, it localized diffusely in the cytoplasm and increased the number of apoptotic cells. These results suggest that increased CADM1 ectodomain shedding contributes to blood glucose dysregulation in T2DM by decreasing full-length CADM1 and producing CTFs that accumulate in the cytoplasm and promote apoptosis of beta cells. Thus, this study has identified a molecular alteration shared by pulmonary emphysema and T2DM.
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