The calcium-regulated transcription coactivator, Ca2 +-responsive transactivator (CREST) was expressed in pancreatic β-cells. Moreover, CREST expression became significantly increased in pancreatic islets isolated from hyperglycemic Goto–Kakizaki rats compared with normoglycemic Wistar controls. In addition, culture of β-cells in the presence of high glucose concentrations also increased CREST expression in vitro. To further investigate the role of this transactivator in the regulation of β-cell function, we established a stable β-cell line with inducible CREST expression. Hence, CREST overexpression mimicked the glucotoxic effects on insulin secretion and cell growth in β-cells. Moreover, high glucose-induced apoptosis was aggravated by upregulation of the transactivator but inhibited when CREST expression was partially silenced by siRNA technology. Further investigation found that upregulation of Bax and downregulation of Bcl2 was indeed induced by its expression, especially under high glucose conditions. In addition, as two causing factors leading to β-cell apoptosis under diabetic conditions, endoplasmic reticulum stress and high free fatty acid, mimicked the high glucose effects on CREST upregulation and generation of apoptosis in β-cells, and these effects were specifically offset by the siRNA knockdown of CREST. These results indicated that CREST is implicated in β-cell apoptosis induced by culture in high glucose and hence that CREST may become a potential pharmacological target for the prevention and treatment of type 2 diabetes mellitus.
Xiuli Men, Liang Peng, Haiyan Wang, Wenjian Zhang, Shiqing Xu, Qing Fang, Honglin Liu, Wenying Yang and Jinning Lou
C Y Shan, J H Yang, Y Kong, X Y Wang, M Y Zheng, Y G Xu, Y Wang, H Z Ren, B C Chang and L M Chen
For centuries, Berberine has been used in the treatment of enteritis in China, and it is also known to have anti-hyperglycemic effects in type 2 diabetic patients. However, as Berberine is insoluble and rarely absorbed in gastrointestinal tract, the mechanism by which it works is unclear. We hypothesized that it may act locally by ameliorating intestinal barrier abnormalities and endotoxemia. A high-fat diet combined with low-dose streptozotocin was used to induce type 2 diabetes in male Sprague Dawley rats. Berberine (100 mg/kg) was administered by lavage to diabetic rats for 2 weeks and saline was given to controls. Hyperinsulinemia and insulin resistance improved in the Berberine group, although there was no significant decrease in blood glucose. Berberine treatment also led to a notable restoration of intestinal villi/mucosa structure and less infiltration of inflammatory cells, along with a decrease in plasma lipopolysaccharide (LPS) level. Tight junction protein zonula occludens 1 (ZO1) was also decreased in diabetic rats but was restored by Berberine treatment. Glutamine-induced glucagon-like peptide 2 (GLP2) secretion from ileal tissue decreased dramatically in the diabetic group but was restored by Berberine treatment. Fasting insulin, insulin resistance index, plasma LPS level, and ZO1 expression were significantly correlated with GLP2 level. In type 2 diabetic rats, Berberine treatment not only augments GLP2 secretion and improves diabetes but is also effective in repairing the damaged intestinal mucosa, restoring intestinal permeability, and improving endotoxemia. Whether these effects are mechanistically related will require further studies, but they certainly support the hypothesis that Berberine acts via modulation of intestinal function.
Yuan Ni, Dan Xu, Feng Lv, Yang Wan, Guanlan Fan, Wen Zou, Yunxi Chen, Linguo Pei, Jing Yang and Hui Wang
Prenatal ethanol exposure (PEE) adversely affects the offspring reproductive system. We aimed to confirm the susceptibility to premature ovarian insufficiency (POI) in female PEE offspring and elucidate its intrauterine programming mechanism. The pregnant Wistar female rats were intragastrically administered with 4 g/kg × day of ethanol from gestational day (GD) 9 to 20. Offspring reproductive parameters were detected on GD20, postnatal week (PW) 6 and PW12. The PEE foetuses showed a decreased number of oocytes, increased ovarian cell apoptosis and upregulated expression levels of ovarian insulin-like growth factor 1 (IGF1) signalling pathway and steroidogenic enzymes. The proportion of atretic follicles in adult rats was increased, while the number of anti-Müllerian hormone-positive antral follicles was decreased. The serum oestradiol (E2) levels were decreased, but the follicle stimulation hormone levels were elevated. The ovarian Igf1 signalling pathway was transformed from activation during puberty to relative inhibition in adulthood, and the expression levels of ovarian steroidogenic enzymes were inhibited in adulthood. Furthermore, we treated the human granulosa cell line KGN with different ethanol concentrations (15, 30, 60, 120 mM) and found that the expression of IGF1 signalling pathway components, 3β-HSD and P450arom, as well as the production of E2, was increased. After IGF1 siRNA transfection, P450arom expression and E2 production were downregulated. These results suggest that PEE induces POI susceptibility in adult females, which may be caused by over-activation of the foetal ovarian Igf1 signalling pathway and steroidogenesis under PEE, resulting in accelerated early development of folliculogenesis and depletion of primordial follicles.
Te Du, Liu Yang, Xu Xu, Xiaofan Shi, Xin Xu, Jian Lu, Jianlu Lv, Xi Huang, Jing Chen, Heyao Wang, Jiming Ye, Lihong Hu and Xu Shen
Vincamine, a monoterpenoid indole alkaloid extracted from the Madagascar periwinkle, is clinically used for the treatment of cardio-cerebrovascular diseases, while also treated as a dietary supplement with nootropic function. Given the neuronal protection of vincamine and the potency of β-cell amelioration in treating type 2 diabetes mellitus (T2DM), we investigated the potential of vincamine in protecting β-cells and ameliorating glucose homeostasis in vitro and in vivo. Interestingly, we found that vincamine could protect INS-832/13 cells function by regulating G-protein-coupled receptor 40 (GPR40)/cAMP/Ca2+/IRS2/PI3K/Akt signaling pathway, while increasing glucose-stimulated insulin secretion (GSIS) by modulating GPR40/cAMP/Ca2+/CaMKII pathway, which reveals a novel mechanism underlying GPR40-mediated cell protection and GSIS in INS-832/13 cells. Moreover, administration of vincamine effectively ameliorated glucose homeostasis in either HFD/STZ or db/db type 2 diabetic mice. To our knowledge, our current work might be the first report on vincamine targeting GPR40 and its potential in the treatment of T2DM.
Jiean Xu, Qiuhua Yang, Xiaoyu Zhang, Zhiping Liu, Yapeng Cao, Lina Wang, Yaqi Zhou, Xianqiu Zeng, Qian Ma, Yiming Xu, Yong Wang, Lei Huang, Zhen Han, Tao Wang, David Stepp, Zsolt Bagi, Chaodong Wu, Mei Hong and Yuqing Huo
Insulin resistance-related disorders are associated with endothelial dysfunction. Accumulating evidence has suggested a role for adenosine signaling in the regulation of endothelial function. Here, we identified a crucial role of endothelial adenosine kinase (ADK) in the regulation of insulin resistance. Feeding mice with a high-fat diet (HFD) markedly enhanced the expression of endothelial Adk. Ablation of endothelial Adk in HFD-fed mice improved glucose tolerance and insulin sensitivity and decreased hepatic steatosis, adipose inflammation and adiposity, which were associated with improved arteriole vasodilation, decreased inflammation and increased adipose angiogenesis. Mechanistically, ADK inhibition or knockdown in human umbilical vein endothelial cells (HUVECs) elevated intracellular adenosine level and increased endothelial nitric oxide synthase (NOS3) activity, resulting in an increase in nitric oxide (NO) production. Antagonism of adenosine receptor A2b abolished ADK-knockdown-enhanced NOS3 expression in HUVECs. Additionally, increased phosphorylation of NOS3 in ADK-knockdown HUVECs was regulated by an adenosine receptor-independent mechanism. These data suggest that Adk-deficiency-elevated intracellular adenosine in endothelial cells ameliorates diet-induced insulin resistance and metabolic disorders, and this is associated with an enhancement of NO production caused by increased NOS3 expression and activation. Therefore, ADK is a potential target for the prevention and treatment of metabolic disorders associated with insulin resistance.
Wang-Yang Xu, Yan Shen, Houbao Zhu, Junhui Gao, Chen Zhang, Lingyun Tang, Shun-Yuan Lu, Chun-Ling Shen, Hong-Xin Zhang, Ziwei Li, Peng Meng, Ying-Han Wan, Jian Fei and Zhu-Gang Wang
Obesity and type 2 diabetes (T2D) are both complicated endocrine disorders resulting from an interaction between multiple predisposing genes and environmental triggers, while diet and exercise have key influence on metabolic disorders. Previous reports demonstrated that 2-aminoadipic acid (2-AAA), an intermediate metabolite of lysine metabolism, could modulate insulin secretion and predict T2D, suggesting the role of 2-AAA in glycolipid metabolism. Here, we showed that treatment of diet-induced obesity (DIO) mice with 2-AAA significantly reduced body weight, decreased fat accumulation and lowered fasting glucose. Furthermore, Dhtkd1−/− mice, in which the substrate of DHTKD1 2-AAA increased to a significant high level, were resistant to DIO and obesity-related insulin resistance. Further study showed that 2-AAA induced higher energy expenditure due to increased adipocyte thermogenesis via upregulating PGC1α and UCP1 mediated by β3AR activation, and stimulated lipolysis depending on enhanced expression of hormone-sensitive lipase (HSL) through activating β3AR signaling. Moreover, 2-AAA could alleviate the diabetic symptoms of db/db mice. Our data showed that 2-AAA played an important role in regulating glycolipid metabolism independent of diet and exercise, implying that improving the level of 2-AAA in vivo could be developed as a strategy in the treatment of obesity or diabetes.