RETRACTED ARTICLE: MEK/ERK pathway activation by insulin receptor isoform alteration is associated with the abnormal proliferation and differentiation of intestinal epithelial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.

Chronic Exposure to Palmitate Impairs Insulin Signaling in an Intestinal L-cell Line: A Possible Shift from GLP-1 to Glucagon Production

“…In recent years it has been demonstrated that up-regulation of IR-A, characterized by a high IR-A/IR-B ratio, was able to activate the ERK 44/42 pathway in diabetic mice [39]. In agreement with these data, in our model, we observed that the IR-A/IR-B ratio was increased in GLUTag cells after palmitate treatment with respect to control cells.…”

“…The IR gene undergoes differential splicing that generates two IR isoforms, IR-A and IR-B. Since it has been reported that the IR-A isoform could up-regulate p-ERK 44/42 protein expression [39], to better investigate basal ERK 44/42 phosphorylation induced by chronic palmitate exposure we analyzed the mRNA expression levels of IR-A and IR-B by RT-PCR and, as shown in Figure 5, we found that the IR-A to IR-B mRNA ratio was significantly higher in cells cultured with palmitate compared with control cells.…”

Downregulation of lncRNA MALAT1 suppresses abnormal proliferation of small intestinal epithelial stem cells through miR‑129‑5p expression in diabetic mice

“…Recent evidence suggests that Wnt/β-catenin signaling is activated under diabetic conditions (23) and that increased proliferation of IEcs in diabetic rats has been associated with the accumulation of β-catenin (23). In our previous study, the abnormal proliferation of IEcs in dM mice was observed (24); however, the potential mechanisms underlying the association between Wnt/β-catenin signaling pathway activation and abnormal IESc proliferation in dM are still poorly understood.…”

“…Taken together, the data indicate that MALAT1 appears to play an important role in regulating the cell fate of the IESc in dM. Although the classical pathway for controlling IESc proliferation has been studied, little is known about the underlying molecular mechanisms controlling IESc proliferation (10,17,24,35). In our previous studies, we found an increase in the number of goblet cells, Paneth cells, and absorptive cells and a reduction in endocrine cells in dM mice (10,17).…”

Microbiota: a Sword that Breaks Through Diabetes

“…Extracellular-signal regulated kinase (ERK) is a protease involved in the regulation of cell proliferation and differentiation. Alteration of the insulin receptor subtype activates the ERK pathway and is associated with abnormal proliferation and differentiation of intestinal epithelial cells in diabetic mice [81]. Probiotics such as bifidobacteria are involved in regulating the ERK pathway, increasing insulin sensitivity and resisting the onset of diabetes.…”