Cell Discovery
·
2023
·Vol. 9
·期 1
·1-18
·
IF 33.5
Gao Xiu Kui,Sheng Zu Kang,Lu Ye Hong,Sun Yu Ting,Rao Xi Sheng,Shi Lin Jing,Cong Xiao Xia,Chen Xiao,Wu Hao Bo,Huang Man,Zheng Qiang,Guo Jian-sheng,Jiang Liang Jun,Zheng Li Ling,Zhou Yi Ting
The scaffold protein IRS-1 is an essential node in insulin/IGF signaling. It has long been recognized that the stability of IRS-1 is dependent on its endomembrane targeting. However, how IRS-1 targets the intracellular membrane, and what type of intracellular membrane is actually targeted, remains poorly understood. Here, we found that the phase separation-mediated IRS-1 puncta attached to endoplasmic reticulum (ER). VAPB, an ER-anchored protein that mediates tethers between ER and membranes of other organelles, was identified as a direct interacting partner of IRS-1. VAPB mainly binds active IRS-1 because IGF-1 enhanced the VAPB-IRS-1 association and replacing of the nine tyrosine residues of YXXM motifs disrupted the VAPB-IRS-1 association. We further delineated that the Y745 and Y746 residues in the FFAT-like motif of IRS-1 mediated the association with VAPB. Notably, VAPB targeted IRS-1 to the ER and subsequently maintained its stability. Consistently, ablation of VAPB in mice led to downregulation of IRS-1, suppression of insulin signaling, and glucose intolerance. The amyotrophic lateral sclerosis (ALS)-derived VAPB P56S mutant also impaired IRS-1 stability by interfering with the ER-tethering of IRS-1. Our findings thus revealed a previously unappreciated condensate-membrane contact (CMC), by which VAPB stabilizes the membraneless IRS-1 signalosome through targeting it to ER membrane.
研究领域:
细胞生物学
·
分子生物学
·
内分泌学
·
神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2019
·Vol. 294
·期 52
·20164-20176
·
IF 4.106
Shijiao Tian,Wenming Jia,Mei Lu,Juan Zhao,Xiulian Sun
Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Although aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to insulin resistance, the underlying mechanism remains elusive. In this study, we used several approaches, including adeno-associated virus-based protein overexpression, immunoblotting, immunoprecipitation, immunohistochemistry, and in situ proximal ligation assays, to investigate the function of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in IRS-1 regulation and the downstream insulin signaling in neurons. We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing turnover of the IRS-1 protein. We further observed that DYRK1A directly interacted with IRS-1 and phosphorylated IRS-1's multiple serine residues. Of note, DYRK1A and IRS-1 were coordinately up-regulated in the prefrontal cortex of db/db mice brain. Furthermore, DYRK1A overexpression ameliorated chronic high insulin-induced insulin resistance in SH-SY5Y cells as well as in primary rat neurons. These findings suggest that DYRK1A protects against insulin resistance in the brain by elevating IRS-1 expression.
研究领域:
神经科学
·
内分泌学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
·
2020
·Vol. 11
·期 11
·9535-9546
·
IF 4.171
Na Deng,Ruixue Guo,Bisheng Zheng,Tong Li,Rui Hai Liu
The effects of whole grain highland barley (WGH) with rich phenolics on glucose metabolism, the insulin pathway, and microRNA (miRNA) expression in db/db mice were explored in the present study. Supplementation with WGH decreased the levels of blood glucose, glycosylated serum protein (GSP), insulin, and inflammatory cytokines in db/db mice. Furthermore, WGH administration triggered a remarkable amelioration of glucose intolerance and insulin resistance. The hepatic glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxylase (PEPCK) activities and the G6PC, PEPCK, and forkhead transcription factor 1 (FOXO1) mRNA levels in the WGH-treated group were also reduced. Moreover, WGH promoted the glycogen storage in the liver via up-regulating the activities of hexokinase (HK) and glycogen synthase (GS) and the phosphorylation of glycogen synthase kinase 3β (GSK3β) protein, while down-regulating the GSK3β mRNA level. The protein expression of phosphatidylinositol 3-kinase (PI3K), the phosphorylation of protein kinase B (Akt), and the mRNA levels of insulin receptor substrate-1 (IRS-1), PI3K and Akt were also up-regulated by WGH treatment. Moreover, WGH significantly augmented the expression of miRNA-26a and miRNA-451, but reduced those of miRNA-126a and miRNA-29a. These results demonstrated that WGH exhibits a hypoglycemic effect through regulating the IRS-1/PI3K/Akt pathway and related miRNAs, further modulating the expression of G6PC, PEPCK, and FOXO1 mRNAs and p-GSK3β protein, thus inhibiting hepatic gluconeogenesis, improving glycogen synthesis and alleviating insulin resistance. Therefore, this study suggested WGH as an effective candidate to ameliorate the hyperglycemia of type 2 diabetes mellitus.
研究领域:
营养学
·
分子生物学
·
糖尿病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Aging-US
·
2023
·
IF 5.2
Huahua Li,Jin Zheng,Yacen Wu,Hong Zhou,Suli Zeng,Quanqing Li
Backgrounds: High glucose (HG) caused oxidative stress and mitochondrial dysfunction, resulting in insulin resistance in podocytes, a key mechanism of diabetic nephropathy. Dendrobium officinale polysaccharide (DOP) was able to improve insulin resistance and antioxidant capability. Objective: The purpose of this study is to explore the mechanism by which DOP decreases the podocyte injury induced by HG. Methods: MPC5 cells were treated with HG, DOP, and IRS-1/2 inhibitor NT157. Afterwards, glucose consumption, generations of ROS and MDA were measured using the detection kits. Mitophagy was monitored using both MtphagTracyker and LysoTracker. The mitochondrial membrane potential was evaluated by JC-1 staining. DOP was also used in a mouse model of diabetes, with the measurements of urine albumin, blood creatinine and blood urea nitrogen. Results: Treatment with DOP suppressed the HG-induced reduction of glucose consumption, the phosphorylation of IRS-1 (phospho Y632), AKT (phospho Ser473 and Thr308) and Nephrin. In addition, HG-induced augment of ROS and MDA, formation of γ-H2A.X foci and translocation of AKT to nucleus were inhibited by DOP. DOP enhanced mitophagy, which was associated with decreased mitochondrial membrane potential and ROS production. DOP conferred protective effect on podocyte in the diabetic mouse by reducing the albumin/creatinine ratio and blood urea nitrogen, and restoring Nephrin expression in podocytes. Conclusions: DOP alleviates HG-induced podocyte injuryby regulating IRS-1/AKT signal and promoting mitophagy.
研究领域:
药理学
·
细胞生物学
·
糖尿病
·
肾病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2025
·
IF 2.2
Rongyan Zhu,Liu Yang,Yulan Li
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age and is frequently associated with impaired glucose metabolism. Thioredoxin-interacting protein (TXNIP) plays a critical role in cellular metabolic regulation; however, its involvement in PCOS pathogenesis remains unclear. Bioinformatics analysis revealed significantly increased TXNIP expression in both PCOS patients and mouse ovarian granulosa cells (GCs). In vivo experiments using dehydroepiandrosterone (DHEA)-induced PCOS mouse models showed that TXNIP knockdown restored the expression of glycolysis-related enzymes, including HK2, PFKM, and PKM2. This restoration enhanced glycolytic function by suppressing IRS-1 phosphorylation and activating the PI3K signaling pathway. In vitro, dihydrotestosterone (DHT)treatment elevated TXNIP expression and suppressed glycolytic activity in KGN cells. Silencing TXNIP restored glycolytic metabolites such as pyruvate and lactate and promoted glycolytic flux, while TXNIP overexpression further impaired these functions. Additionally, treatment with the IRS-1 inhibitor NT157 confirmed that TXNIP regulates glycolysis in GCs through the IRS-1/PI3K signaling axis. This study is the first to demonstrate that TXNIP contributes to glycolytic dysfunction in PCOS GCs via the IRS-1/PI3K pathway, highlighting a potential target for PCOS diagnosis and therapy.
研究领域:
生殖生物学
·
代谢病学
·
内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
·
2024
·
IF 3.3
Li Wang,En-Zhong Chi,Xin-Huai Zhao
BACKGROUND Tea dregs, typically generated during the production of instant tea or tea beverages, have conventionally been regarded as waste material and routinely discarded. Nevertheless, contemporary research endeavors are concentrating on discovering efficient methods for utilizing the potential of this discarded resource. RESULTS In this study, we employed a sequential extraction method using chemical chelating agents to extract and isolate four distinct cell wall polysaccharides, designated as CWTPS-1 through CWTPS-4, from the tea dregs of Liubao brick tea. A comprehensive investigation into their physicochemical, structural, and hypoglycemic properties was conducted. The analysis of chemical composition and physicochemical characteristics revealed that all four CWTPSs were characterized as acidic polysaccharides, albeit with varying chemical compositions and physicochemical attributes. Specifically, the xyloglucan fractions, CWTPS-3 and CWTPS-4, were found to be rich in glucose and xylose, displaying a more uniform molecular weight distribution, greater structural stability, and a more irregular surface compared to the others. Moreover, they exhibited a higher diversity of monosaccharide residues. Importantly, our research unveiled that all four CWTPSs exhibited the capacity to modulate key glucose-regulated and antioxidant enzyme activities within HepG2 cells via the IRS-1-PI3K/Akt signaling pathway, thereby ameliorating cellular insulin resistance. Furthermore, our correlation analysis highlighted significant associations between monosaccharide composition and neutral sugar content with the observed hypoglycemic activity of CWTPSs. CONCLUSIONS This study highlights the potential of utilizing tea dregs as a valuable resource, making a significant contribution to the advancement of the tea industry. Furthermore, CWTPS-4 exhibits promising prospects for further development as a functional food ingredient or additive. This article is protected by copyright. All rights reserved.
研究领域:
食品科学
·
药理学
·
生物化学
·
农业废弃物管理
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
·
2024
·
IF 4.5
Qiuming Liu,Qingyu Ma,Jiao Li,Liping Sun,Yongliang Zhuang
Scope Type 2 diabetes mellitus (T2DM) is a metabolic disease with a major global public health effect. Rambutan peel polyphenols (RPPs) have been reported to exert hypoglycemic activity. However, few studies have been explored from the viewpoint of gut microbiota and its metabolites. Methods and results RPPs are administered by gavage to a mice model of T2DM established by using a high-fat diet combined with streptozotocin. It finds that RPPs treatment alleviates hyperglycemia symptoms by improving glucolipid metabolism and liver function. Immunohistochemistry indicates that the antihyperglycemic effect of RPPs is regulated by the IRS-1/PI3K/AKT/GSK3β signaling pathway. RPPs treatment remodels the structure of gut microbiota ( Odoribacter , Lachnospiraceae_NK4A136_group , Lactobacillus , Turicibacter , Erysipelatoclostridium , and Tuzzerella ) and enriches the metabolites (RPPs-derived urolithins, short-chain fatty acids, dehydrocholic acid, (+)-catechin, dihydroberberine, pterostilbene, and artesunate) associated with diabetes regulation in T2DM mice. The effects of RPPs in ameliorating glycolipid metabolism disorders are correlated with differential gut microbiota and metabolites. Conclusion The gut microbiota and its metabolites are key targets for the hypoglycemic effects of RPPs.
研究领域:
药理学
·
营养学
·
微生物学
·
内分泌学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2020
·
IF 10.652
Yi Zhang,Jian Li,Zhen Wang,Ming-Ze Xu,Zhi Zeng,Jin-peng Huang,Yan-Qing Guan
Exogenous insulin administration is still the most used treatment for diabetes (mainly used for type-1 diabetes in clinic), however type 2 diabetes (T2D) with the characteristics of insulin resistance accounts for the vast majority proportion (90–95%) of diabetic population, which makes insulin function failure. Currently, many efforts have been devoted to insulin delivery with nanomedicine means, whereas the treatment of insulin resistance in T2D using nanotechnology strategy is rarely reported. In this study, we transformed a plant-derived natural insulin sensitizer into biocompatible nano-transport system, where the natural insulin sensitizer oleanolic acid (OA) was conjugated onto natural polymer polygalacturonic acid (PGA) to form self-assembled micelles as oral administrated nanomedcine for insulin resistance treatment in T2D. In vitro and in vivo investigation demonstrated that OA loaded PGA-OA micelles possess stability to cross the gastrointestinal barriers and improve drug intestinal absorption, remarkably maintaining plasma drug concentration for a longer time. Therefore, this formulation manifested good reversal effect on insulin resistance in the T2D rat model, and thereby exhibited long-term outcomes in glucose level control even after drug withdrawal. Additionally, the molecular mechanism of OA loaded PGA-OA mediated insulin-resistant reversal was found that it was probable mediated by promoting IRS-1/PI3K/AKT signaling pathway and inhibiting the activity of PTP1B enzyme simultaneously. In this regard, such a facile, safe and potent nanomedicine strategy may be promising alternative for long-acting insulin-resistant treatment in T2D therapy.
研究领域:
药剂学
·
纳米技术
·
糖尿病
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2017
·
IF 3.154
Jiarui Nie,Yaning Chang,Yujia Li,Yingjun Zhou,Jiawen Qin,Zhen Sun,Haibin Li
Caffeic acid phenethyl ester (CAPE), extracted from propolis, was evaluated for the ameliorative effects on insulin resistance and the mechanisms were identified, using non-insulin-dependent diabetes mellitus (NIDDM) model mice and insulin resistance (IR) model cells. After 5 weeks of CAPE supplementation, insulin sensitivity, hyperlipidemia, and peroxisome proliferator-activated receptor-α (PPAR-α) levels were improved in mice. Proinflammatory cytokines in serum and the expressions of tumor necrosis factor-alpha (TNF-α) mRNA in tissues were markedly downregulated from CAPE-treated mice. In vitro, CAPE supplement significantly improved glucose consumption, glucose uptake, glycogen content, and oxidative stress and decreased expression of glucose-6-phosphatase (G6Pase) mRNA in cells. Both in vivo and in vitro, CAPE enhanced p-Akt (Ser473) and p-insulin receptor substrate (IRS)-1 (Tyr612), but inhibited p-JNK (Thr183/Tyr185), p-NF-κB p65 (Ser536), and nuclear translocation of p-NF-κB p65 (Ser536). In summary, CAPE can ameliorate insulin resistance through modulation of JNK and NF-κB signaling pathway in mice and HepG2 cells.
研究领域:
药理学
·
内分泌学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）