We have previously shown that insulin plays an important role in the nutrient-induced insulin resistance. In this study, we tested the hypothesis that chronic exposure to excess long-acting insulin (glargine) can cause typical type 2 diabetes mellitus (T2DM) in normal mice fed on a chow diet. C57BL/6 mice were treated with glargine once a day for 8 weeks, followed by evaluations of food intake, body weight, blood levels of glucose, insulin, lipids, and cytokines, insulin signaling, histology of pancreas, ectopic fat accumulation, oxidative stress level, and cholesterol content in mitochondria in tissues. Cholesterol content in mitochondria and its association with oxidative stress in cultured hepatocytes and β-cells were also examined. Results show that chronic exposure to glargine caused insulin resistance, hyperinsulinemia, and relative insulin deficiency (T2DM). Treatment with excess glargine led to loss of pancreatic islets, ectopic fat accumulation in liver, oxidative stress in liver and pancreas, and increased cholesterol content in mitochondria of liver and pancreas. Prolonged exposure of cultured primary hepatocytes and HIT-TI5 β-cells to insulin induced oxidative stress in a cholesterol synthesis-dependent manner. Together, our results show that chronic exposure to excess insulin can induce typical T2DM in normal mice fed on a chow diet.
Xuefeng Yang, Shuang Mei, Haihua Gu, Huailan Guo, Longying Zha, Junwei Cai, Xuefeng Li, Zhenqi Liu, and Wenhong Cao
Yujiao Dai, Peng Hao, Zhimei Sun, Zhiyi Guo, Hong Xu, Lihui Xue, Hongyu Song, Yida Li, Shuang Li, Mingming Gao, Teng Si, Yuxin Zhang, and Yajuan Qi
Yes-associated protein (YAP), as a co-activator of transcription factors, is a downstream protein in the Hippo signaling pathway with important functions in cell proliferation, apoptosis, invasion and migration. YAP also plays a key role in the development of CCl4 induced liver fibrosis. However, the mechanism of YAP during the hepatic fibrosis progression and reversion is still unclear. Mild liver fibrosis was developed after 4M (month) high fat diet (HFD) stimulation, and we found that YAP signaling pathway was activated. Here, we aimed to reveal whether liver specifically knockout of YAP gene in the liver can improve liver fibrosis induced by insulin resistance (IR) using HFD stimulation, and further to explain its specific mechanism. We found that liver specific YAP gene knock-out improved IR-induced liver fibrosis and liver dysfunction, which mechanism is related to the inhibition of insulin signal pathway at FoxO1 level. These findings provide a new idea, and YAP is expected to be a new target to reverse the early stage of liver fibrosis induced by IR.
Yan Su, Sujuan Guo, Chunyan Liu, Na Li, Shuang Zhang, Yubin Ding, Xuemei Chen, Junlin He, Xueqing Liu, Yingxiong Wang, and Rufei Gao
Embryo implantation is essential for normal pregnancy. Decidualization is known to facilitate embryo implantation and maintain pregnancy. Uterine stromal cells undergo transformation into decidual cells after embryo attachment to the endometrium. Pyruvate kinase M2 (PKM2) is a rate limiting enzyme in the glycolysis process which catalyzes phosphoenolpyruvic acid into pyruvate. However, little is known regarding the role of PKM2 during endometrial decidualization. In this study, PKM2 was found to be mainly located in the uterine glandular epithelium and luminal epithelium on day 1 and day 4 of pregnancy and strongly expressed in the decidual zone after embryo implantation. PKM2 was dramatically increased with the onset of decidualization. Upon further exploration, PKM2 was found to be more highly expressed at the implantation sites than at the inter-implantation sites on days 5 to 7 of pregnancy. PKM2 expression was also significantly increased after artificial decidualization both in vivo and in vitro. After PKM2 expression was knocked down by siRNA, the number of embryo implantation sites in mice on day 7 of pregnancy was significantly reduced, and the decidualization markers BMP2 and Hoxa10 were also obviously downregulated in vivo and in vitro. Downregulated PKM2 could also compromise cell proliferation in primary endometrial stromal cells and in Ishikawa cells. The migration rate of Ishikawa cells was also obviously suppressed by si-PKM2 according to the wound healing assay. In conclusion, PKM2 might play an important role in decidualization during early pregnancy, and cell proliferation might be one pathway for PKM2 regulated decidualization.