title: MEK/ERK pathway activation by insulin receptor isoform alteration is associated with the abnormal proliferation and differentiation of intestinal epithelial cells in diabetic mice.
abstract: In previous studies, we have reported the abnormal proliferation and differentiation of intestinal epithelial cells (IECs) in diabetes mellitus (DM) mice. The insulin receptor (IR) and its downstream mitogen-activated protein kinase kinase (MAPKK also known as MEK)/extracellular-regulated protein kinase (ERK) pathway is a classic pathway associated with cell proliferation and differentiation. The purpose of the present study is to investigate the role of the MEK/ERK pathway in abnormal proliferation and differentiation of IECs in DM mice. DM mouse models were induced by intraperitoneal injection of streptozotocin. The expression levels of the IR and its isoforms in IECs of DM mice and in IEC-6 cells were investigated. To ensure that the downstream pathways were monitored, QPCR and Western blotting were performed to detect the expression levels of MEK1/2, ERK1/2, PI3K, and Akt. Moreover, siRNA for IR-A and U0126, a specific inhibitor of MEK, were used to further investigate the relationship between the IR/MEK/ERK pathway and abnormal proliferation and differentiation of IECs in DM mice. In DM mice, excessive proliferation, disturbed differentiation, and a high ratio of IR-A/IR-B were detected in IECs. The expression levels of MEK1, MEK2, and ERK1/2 and their phosphorylated proteins in DM mice were significantly higher than those in the control group (P < 0.05), which could be offset by using siRNA for IR-A. The abnormal proliferation and differentiation of IECs in DM mice were normalized after the in vivo administration of U0126. The abnormal proliferation and differentiation of IECs in DM mice are associated with high IR-A/IR-B ratio and increased IR/MEK/ERK pathway activity.
authors.affiliation: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ouyang
authors.affiliation: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China. yutao2014@126.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China.
authors.forename: Ti-Dong
authors.initials: TD
authors.lastname: Shan
authors.affiliation: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China.
authors.forename: Jie-Yao
authors.initials: JY
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China.
authors.forename: Can-Ze
authors.initials: CZ
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China.
authors.forename: Wa
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China.
authors.forename: Zhong-Sheng
authors.initials: ZS
authors.lastname: Xia
authors.affiliation: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China. qikuichen@yahoo.com.
authors.forename: Qi-Kui
authors.initials: QK
authors.lastname: Chen
mesh_terms: D000818:Animals; D002070:Butadienes / Q000008:administration & dosage / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin
chemical_list: D002070:Butadienes; D009570:Nitriles; D020033:Protein Isoforms; C113580:U 0126; D013311:Streptozocin; D011972:Receptor, Insulin
keywords: Diabetes mellitus; Differentiation; Insulin receptor; Intestinal epithelial cell; Proliferation