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1.
Maternal insulin resistance results in poor pregnancy outcomes. In vivo and in vitro exposure of the murine blastocyst to high insulin or IGF1 results in the down-regulation of the IGF1 receptor (IGF1R). This in turn leads to decreased glucose uptake, increased apoptosis, as well as pregnancy resorption and growth restriction. Recent studies have shown that blastocyst activation of AMP-activated protein kinase (AMPK) reverses these detrimental effects; however, the mechanism was not clear. The objective of this study was to determine how AMPK activation rescues the insulin-resistant blastocyst. Using trophoblast stem (TS) cells derived from the blastocyst, insulin resistance was recreated by transfecting with siRNA to Igf1r and down-regulating expression of the protein. These cells were then exposed to AMPK activators 5-aminoimidazole-4-carboxamide riboside and phenformin, and evaluated for apoptosis, insulin-stimulated 2-deoxyglucose uptake, PI3-kinase activity, and levels of phospho-AKT, phospho-mTor, and phospho-70S6K. Surprisingly, disrupted insulin signaling led to decreased AMPK activity in TS cells. Activators reversed these effects by increasing the AMP/ATP ratio. Moreover, this treatment increased insulin-stimulated 2-deoxyglucose transport and cell survival, and led to an increase in PI3-kinase activity, as well as increased P-mTOR and p70S6K levels. This study is the first to demonstrate significant crosstalk between the AMPK and insulin signaling pathways in embryonic cells, specifically the enhanced response of PI3K/AKT/mTOR to AMPK activation. Decreased insulin signaling also resulted in decreased AMPK activation. These findings provide mechanistic targets in the AMPK signaling pathway that may be essential for improved pregnancy success in insulin-resistant states. 相似文献
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目的:观察紫色马铃薯花色苷对HepG2细胞胰岛素抵抗模型糖代谢的作用并对其机制进行初探。方法:以高浓度葡萄糖培养基为诱导因素诱导HepG2细胞建立胰岛素抵抗细胞模型,通过葡萄糖氧化酶法、四唑盐比色实验(MTT)和蛋白质印迹法(Western blot)检测紫色马铃薯花色苷对胰岛素抵抗细胞模型的葡萄糖消耗量、细胞存活率和胰岛素信号通路的蛋白表达的影响。结果:与空白对照组相比,当诱导培养基中葡萄糖浓度为50 mmol/L时吸光度的差值最大,所以选50 mmol/L的葡萄糖培养基来建立胰岛素抵抗细胞模型;花色苷的处理胰岛素抵抗细胞的浓度为40~100 μg/mL时,葡萄糖消耗量可高达19.55 mmol/L显著(p<0.05)高于模型对照组;花色苷浓度为40~100 μg/mL时细胞存活率基本上可以保持在80%,细胞毒性较小;花色苷可以调节因高浓度葡萄糖诱导而导致的IR、IRS-1、IRS-2水平下降的情况,降低p-IRS-1的表达水平,还可以阻止GLUT-2水平的降低。结论:紫色马铃薯花色苷可以改善HepG2细胞胰岛素抵抗模型的胰岛素信号通路抑制的情况,改善胰岛素抵抗模型的糖代谢。 相似文献
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Previous studies have shown that hyperinsulinemia is not only a marker of insulin resistance, but also the causative factor
of peripheral tissue insulin resistance. It also has been suggested that prolonged high-dose insulin treatment can mimic the
effects of hyperinsulinemia and exacerbate insulin resistance in skeletal muscle cells. However, how to prevent or reverse
insulin resistance induced by hyperinsulinemia remains largely unclear. In the past few decades, the use of myricetin as an
anti-diabetic agent has gained much attention, but little information is available regarding the effects of myricetin on glucose
uptake and hyperinsulinemia-induced insulin resistance in skeletal muscle cells. The present study focuses on the effect of
myricetin on insulin signaling in skeletal muscle cell line C2C12 myotubes. Initially, the effect of myricetin under normal
condition was determined. We found that myricetin’s enhancement in glucose uptake coincided with both protein kinase B (Akt)
and AMP-activated protein kinase (AMPK) activities. After that, the role of hyperinsulinemia was investigated. It was showed
that prolonged high-dose insulin treatment inhibited both Akt and AMPK activities. As the results, the low-dose insulin stimulation
of glucose uptake was inhibited by hyperinsulinemia. However, the treatment of myricetin improved low-dose insulin-stimulated
glucose uptake in the hyperinsulinemic state, and this effect essentially depended on the AMPK signal pathway. Together, our
data suggest a putative link between hyperinsulinemia and insulin resistance in C2C12 myotubes, and the myricetin treatment
stimulates glucose uptake and attenuates insulin resistance. 相似文献
5.
在本研究中,先诱导大鼠骨骼肌细胞分化为成熟的肌管细胞,然后以肌管细胞为模型,在胰岛素敏感和胰岛素抵抗的情况下,通过蛋白免疫印迹的方法检测金线莲苷对蛋白激酶Akt和AMPK的活化,以荧光标记的2-脱氧葡萄糖为能量底物检测金线莲苷处理前后细胞对葡萄糖的摄取。结果显示在正常细胞中,10 nM金线莲苷作用24 h可显著增加Akt(34.53%,p0.05)和AMPK的活性(149.92%,p0.05),同时促进细胞对葡萄糖的摄取(43.35%,p0.05)。在胰岛素抵抗的细胞中,金线莲苷对AMPK的活化不受影响,并且可改善胰岛素对Akt的激活作用(79.05%,p0.05)。在正常及胰岛素抵抗的情况下,金线莲苷对胰岛素诱导的葡萄糖摄取都具有协同作用。这些结果表明金线莲苷可通过调控Akt和AMPK的活性改善细胞胰岛素抵抗,促进胰岛素抵抗细胞对葡萄糖的摄取。 相似文献
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苦荞是芦丁含量最高的粮食作物,但不同的加工过程会导致芦丁降解为单糖苷结构的异槲皮素及其前体槲皮素,进而影响生物活性。本研究比较芦丁及其降解产物(槲皮素、异槲皮素)这三类含有不同糖苷结构的黄酮在C2C12小鼠骨骼肌细胞中促进葡萄糖摄取的功效差异,并探究其作用机制。研究结果表明,苦荞与水接触会导致苦荞中的核心黄酮组分-芦丁降解为槲皮素。芦丁及其降解产物(槲皮素、异槲皮素)均能有效促进C2C12细胞对葡萄糖的摄取,作用顺序为:槲皮素>异槲皮素>芦丁。糖苷键的增加会降低槲皮素促进骨骼肌细胞糖摄取的效果。芦丁和异槲皮素不能激活胰岛素依赖型信号通路中的IRS-1表达及AKT的磷酸化,但高浓度下(400 μmol/L),芦丁和异槲皮素可以通过非胰岛素依赖型的信号通路中的p-AMPK/p-ACC促进葡萄糖摄取作用,且异槲皮素的作用大于芦丁。槲皮素虽然抑制了IRS-1的表达及AKT的磷酸化,但槲皮素通过AMPK/ACC的磷酸化显著了促进C2C12细胞对葡萄糖的摄取。本研究揭示芦丁及其降解产物在细胞水平上的降血糖作用及机理的差异,对于充分理解苦荞黄酮降血糖机制提供了科学依据。 相似文献
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采用胰岛素诱导HepG2细胞建立胰岛素抵抗模型(IR),研究D-松醇复配Mn2+对细胞葡萄糖消耗量和糖原合成量的影响。实时荧光全定量分析(RT-PCR)实验检测AMPK信号通路相关基因mRNA表达水平。结果表明当胰岛素浓度为1×10-3 mmol/L,作用时间为36 h时,细胞葡萄糖消耗量达到最低,产生最大的胰岛素抵抗效应。与模型对照组相比,当D-松醇浓度为100 mg/L,复配MnSO4为10 mg/L时,葡萄糖消耗量和糖原含量均极显著升高(p<0.01)。此外,复配组AMPKα-1、AMPKα-2和GLUT4基因表达水平均显著上调(p<0.05),G6Pase基因mRNA表达水平显著下调(p<0.05)。D松醇复配Mn2+可显著促进胰岛素抵抗细胞葡萄糖的利用,增加糖原合成,其作用机制可能涉及AMPK参与的抑制糖异生等生化调控过程起到降血糖作用。 相似文献
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目的:探讨p-辛弗林对肝细胞葡萄糖生成的影响及其作用机制。方法:采用MTS法检测p-辛弗林对HepG2肝细胞株的细胞活力的影响,确定受试物的作用浓度后,比色法测定葡萄糖的生成、葡萄糖-6-磷酸酶(glucose-6-phosphatase,G6Pase)和磷酸烯醇丙酮酸羧基激酶(phosphoenolpyruvate carboxykinase,PEPCK)活力,Western blot蛋白印迹法检测腺苷酸活化蛋白激酶(adenosine 5’-monophosphate-activated protein kinase,AMPK)、磷酸化AMPK(p-AMPK)、乙酰辅酶A羧化酶(acetyl coenzyme A synthetase,ACC)、磷酸化ACC(p-ACC)、叉头框转录因子1(forkhead box class O1,FoxO1)以及磷酸化FoxO1(p-FoxO1)的表达;利用AMPK选择性抑制剂Compound C和AMPK siRNA作用HepG2肝细胞株后,检测p-辛弗林对HepG2肝细胞株葡萄糖的生成、G6Pase和PEPCK活力的影响。结果:p-辛弗林能剂量依赖性地抑制肝细胞葡萄糖的生成,激活AMPK信号通路,促进p-AMPK、p-ACC和p-FoxO1水平增加,极显著抑制G6Pase和PEPCK的活性(P<0.01)。p-辛弗林的这些影响部分地被Compound C和AMPK siRNA所抑制(P<0.01)。结论:p-辛弗林能够通过激活AMPK-FoxO1信号通路抑制肝细胞葡萄糖生成。 相似文献
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J.A.D.R.N. Appuhamy W.A. Nayananjalie E.M. England D.E. Gerrard R.M. Akers M.D. Hanigan 《Journal of dairy science》2014
Regulation of mammary protein synthesis potentially changes the relationships between AA supply and milk protein output represented in current nutrient requirement models. Glucose and AA regulate muscle protein synthesis via cellular signaling pathways involving mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK). The objective of this study was to investigate the effects of essential AA (EAA) and acetate or glucose on mTOR and AMPK signaling pathways and milk protein synthesis rates. A bovine mammary epithelial cell line, MAC-T, was subjected to different media containing 0 or 3.5 mmol/L EAA concentrations with 0 or 5 mmol/L acetate or 0 or 17.5 mmol/L glucose in 2 separate 2 × 2 factorial studies. In a separate set of experiments, lactogenic bovine mammary tissue slices were subjected to the same treatments except that the low EAA treatment contained a low level of EAA (0.18 mmol/L). Supplementation of EAA enhanced phosphorylation of mTOR (Ser2448) and eukaryotic initiation factor 4E binding protein 1 (4EBP1, Thr37/46), and reduced phosphorylation of eukaryotic elongation factor 2 (eEF2, Thr56) in MAC-T cells. Concentration of ATP and phosphorylation of AMPK increased and decreased, respectively, in the presence of EAA in MAC-T cells. Acetate, EAA, or glucose numerically reduced AMPK phosphorylation by about 16% in mammary tissue slices. Provision of EAA increased phosphorylation of mTOR and 4EBP1, intracellular total EAA concentration, and casein synthesis rates in mammary tissue slices, irrespective of the presence of acetate or glucose in the medium. Phosphorylation of mTOR had a marginally negative association with AMPK phosphorylation, which was positively related to eEF2 phosphorylation. Casein synthesis rates were positively and more strongly linked to mTOR phosphorylation than the negative link between eEF2 phosphorylation and casein synthesis rates. A 100% increase in mTOR phosphorylation was associated with an increase in the casein synthesis rate of 0.74%·h−1, whereas a 100% increase in eEF2 phosphorylation was related to a decline in the casein synthesis rate of 0.33%·h−1. Although AMPK phosphorylation was responsive to cellular energy status and had a negative effect on mTOR-mediated signals in bovine mammary epithelial cells, its effect on milk protein synthesis rates appeared to be marginal compared with the mTOR-mediated regulation of milk protein synthesis by EAA. 相似文献
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目的:探讨石榴花水提物(pomegranate flower water extract,PFW)对2型糖尿病小鼠肝脏胰岛素信号传导的影响及机制。方法:将C57BL/6J随机分为正常组、模型组、二甲双胍组(Met)、石榴花水提物低剂量组(PFWL)和石榴花水提物高剂量组(PFWH)。连续给药11周后,称小鼠体质量,检测空腹血糖(FBG)、胰岛素(INS)、甘油三酯(TG)和总胆固醇(TC)的含量,计算胰岛素抵抗指数(HOMA-IR);苏木素-伊红(HE)染色观察肝组织病理变化;Western blot法检测肝组织中胰岛素受体底物1(IRS1)、p-IRS1(Ser307)、蛋白激酶B(AKT)、p-AKT(Ser473)、糖原合成酶激酶-3
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Minh Truong Do Hyung Gyun Kim Jae Ho Choi Tilak Khanal Bong Hwan Park Thu Phuong Tran Yong Pil Hwang MinKyun Na Hye Gwang Jeong 《Food chemistry》2013
Phillyrin, an active constituent found in many medicinal plants and certain functional foods, has anti-obesity activity in vivo. The aim of our study was to provide new data on the molecular mechanism(s) underlying the role of phillyrin in the prevention of high glucose-induced lipid accumulation in human HepG2 hepatocytes. We found that phillyrin suppressed high glucose-induced lipid accumulation in HepG2 cells. Phillyrin strongly inhibited high glucose-induced fatty acid synthase (FAS) expression by modulating sterol regulatory element-binding protein-1c (SREBP-1c) activation. Moreover, use of the pharmacological AMP-activated protein kinase (AMPK) inhibitor compound C revealed that AMPK is essential for suppressing SREBP-1c expression in phillyrin-treated cells. Finally, we found that liver kinase B1 (LKB1) phosphorylation is required for the phillyrin-enhanced activation of AMPK in HepG2 hepatocytes. These results indicate that phillyrin prevents lipid accumulation in HepG2 cells by blocking the expression of SREBP-1c and FAS through LKB1/AMPK activation, suggesting that phillyrin is a novel AMPK activator with a role in the prevention and treatment of obesity. 相似文献
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荔枝核提取物及其阳离子树脂分离物体外降血糖作用 总被引:1,自引:0,他引:1
研究荔枝核乙醇提取物(LSE)和其阳离子树脂分离物(FCE)体外降血糖作用。采用高糖和高胰岛素所致的两种HepG2细胞模型,在模型培养中添加不同浓度的LSE与FCE,以葡萄糖试剂盒测定,MTT法等进行对HepG2细胞葡萄糖消耗作用的研究。结果表明:在高糖环境下,LSE和FCE均能促进HepG2细胞的葡萄糖消耗,而FCE的促进作用显著高于相近浓度的LSE,提示离子交换树脂分离物贡献了荔枝核提取物的降糖作用;此外,FCE还可与低剂量胰岛素协同增加细胞的葡萄糖消耗。在胰岛素抵抗模型中,FCE能显著降低胰岛素抵抗,增加细胞的葡萄糖消耗。荔枝核提取物和其阳离子树脂分离物具有体外降血糖作用。 相似文献
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本文研究了表没食子儿茶素没食子酸酯(EGCG)对小鼠非酒精性脂肪性肝病(NAFLD)的干预作用。应用高脂饲料喂养Apo E-/-小鼠建立NAFLD小鼠模型,研究EGCG对NAFLD小鼠血液和肝组织中糖脂代谢、脂肪酸氧化、氧化应激水平、肝组织结构以及AMPK/SIRT1/SREBP-1c/PPARγ信号通路相关基因表达的影响。结果表明EGCG治疗后肝组织病理学变化明显改善,小鼠体质量、肝质量、肝质量指数较模型组显著降低至110.98%、115.01%,115.64%、136.48%和104.20%、118.70%(p<0.01);血液和肝组织中糖脂代谢、脂肪酸氧化、氧化应激水平改善幅度在11.85%~86.06%之间,与模型组比较具有显著性差异(p<0.05或p<0.01);升高肝组织中AMPKα、SIRT1 mRNA及p-AMPKα、SIRT1蛋白表达幅度在13.21%~75.82%之间,降低肝组织FASN、ACC-1、SREBP-1c、SCD-1、PPARγm RNA和FASN、p-ACC-1、p-SREBP-1c、SCD-1、PPARγ蛋白表达幅度在19.59%~92.07%之间,改善p-AMPKα/AMPKα、p-ACC-1/ACC-1和p-SREBP-1c/SREBP-1c比率在39.20%~93.07%之间,与模型组比较具有显著性差异(p<0.05或p<0.01)。本研究表明EGCG可通过调控AMPK/SIRT1/SREBP-1c/PPARγ信号通路相关基因的表达来改善NAFLD小鼠糖脂代谢、脂肪酸氧化和氧化应激状态。 相似文献
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目的:本文通过提取和分离生姜姜辣素,探究姜辣素对HepG2细胞胰岛素抵抗的预防作用。方法:采用乙醇作为溶剂,水浴振荡提取得到姜辣素粗提物,通过乙酸乙酯萃取和石油醚对姜辣素粗提物进行纯化。测定姜辣素对1,1-二苯基-2-苦肼基(DPPH)和2,2'-联氮-双-3-乙基苯并噻唑啉-6-磺酸(ABTS)自由基清除率进行抗氧化活性分析。构建HepG2细胞胰岛素抵抗模型,测定姜辣素对细胞的葡萄糖消耗量、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)活力和PI3K/AKT通路有关基因表达量的影响。结果:采用正交试验确定乙醇提取姜辣素的最佳条件为:料液比1:50 g/mL、提取时间80 min、乙醇体积分数60%、提取温度50 ℃。在此条件下,姜辣素的得率为 1.885%±0.071%。乙酸乙酯和石油醚萃取后姜辣素含量大于34.55%。抗氧化分析结果表明,姜辣素对DPPH和ABTS+自由基半数清除浓度(EC50)分别为0.501和0.111 mg·mL?1。使用25 μg·mL?1胰岛素处理HepG2细胞48 h后,细胞的葡萄糖消耗量显著降低(P<0.05)。姜辣素显著提高了细胞的葡萄糖消耗量、SOD和CAT活力(P<0.05),并呈现剂量依赖性。此外,姜辣素处理组均显著上调PI3K、IRS-2和AKT基因的表达量(P<0.05),并能显著下调GSK-3β、FoxOI和PEPCK的表达量。结论:生姜姜辣素具有良好的抗氧化活性,且通过激活PI3K/AKT通路预防HepG2细胞的胰岛素抵抗作用。 相似文献
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Changkeun Kang Hyunkyoung Lee Eun-Sun Jung Ramin Seyedian MiNa Jo Jehein Kim Jong-Shu Kim Euikyung Kim 《Food chemistry》2012
Saffron (Crocus sativus Linn.) has been an important subject of research in the past two decades because of its various biological properties, including anti-cancer, anti-inflammatory, and anti-atherosclerotic activities. On the other hand, the molecular bases of its actions have been scarcely understood. Here, we elucidated the mechanism of the hypoglycemic actions of saffron through investigating its signaling pathways associated with glucose metabolism in C2C12 skeletal muscle cells. Saffron strongly enhanced glucose uptake and the phosphorylation of AMPK (AMP-activated protein kinase)/ACC (acetyl-CoA carboxylase) and MAPKs (mitogen-activated protein kinases), but not PI 3-kinase (Phosphatidylinositol 3-kinase)/Akt. Interestingly, the co-treatment of saffron and insulin further improved the insulin sensitivity via both insulin-independent (AMPK/ACC and MAPKs) and insulin-dependent (PI 3-kinase/Akt and mTOR) pathways. It also suggested that there is a crosstalk between the two signaling pathways of glucose metabolism in skeletal muscle cells. These results could be confirmed from the findings of GLUT4 translocation. Taken together, AMPK plays a major role in the effects of saffron on glucose uptake and insulin sensitivity in skeletal muscle cells. Our study provides important insights for the possible mechanism of action of saffron and its potential as a therapeutic agent in diabetic patients. 相似文献
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Jeong Hee Kim Jong Whi Kim Seong Cheol Kim Young Jae Lee 《Food science and biotechnology》2013,22(4):1091-1096
Kiwi fruit has long been believed to be beneficial to human health due to its numerous biological actions; however the pharmacological mechanisms associated with these benefits are incompletely understood. In the present study, the effects of ‘Halla Gold’ (Actinidia chinensis var.), a new kiwifruit cultivar bred by the Jeju Rural Development Administration (RDA), on chronic insulin-induced insulin resistance in L6 skeletal muscle cells was investigated. Chronic insulin reduced phosphorylation of Akt and GSK-3α/β, and increased phosphorylation of glycogen synthase (GS). Furthermore, glucose consumption and glucose transporter 4 (Glut4) translocation to the plasma membrane were inhibited. However, ‘Halla Gold’ extract (HGE) increased phosphorylation of Akt and GSK-3α/β concomitantly with decreased phosphorylation of GS. Moreover, HGE improved insulin-stimulated glucose consumption by facilitating Glut4 translocation and this stimulation was suppressed by inhibition of PI3 kinase. Together, our data suggest that ‘Halla Gold’ extract abolishes chronic insulin-induced insulin resistance through the PI3K/Akt pathway. 相似文献
19.
Korean red ginseng attenuates hepatic lipid accumulation via AMPK activation in human hepatoma cells
Hai-Yan Quan Hai-Dan Yuan Do Yeon Kim Ya Zhang Sung Hyun Chung 《Food science and biotechnology》2010,19(1):207-212
In this study, we examined Korean red ginseng (KRG) extract affects on the lipid metabolism in HepG2 cells. Increase in AMP-activated
protein kinase (AMPK) phosphorylation was observed when the cells were treated with KRG. Activation of AMPK was also demonstrated
by measuring the phosphorylation of acetyl-CoA caboxylase (ACC), a substrate of AMPK. KRG down-regulated gene expressions
of sterol regulatory element binding protein 1c (SREBP1c) and its target proteins, such as fatty acid synthase (FAS) and stearoyl-CoA
desaturase (SCD1) in time- and dose-dependent fashions. In contrast, gene expressions of peroxisome proliferator-activated
receptor α (PPARα) and CD36 were increased. These effects were reversed in the presence of compound C, an AMPK inhibitor.
However, there were no differences in gene expressions of SREBP2, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, and
low-density-lipoprotein receptor (LDLR). Taken together, KRG induced supression of SREBP1c and activation of PPARα via AMPK
and these effects seem to be one of anti-hyperlipidemic mechanism of KRG in HepG2 cells. 相似文献
20.
Shiwei Hu Yaoguang Chang Min He Jingfeng Wang Yuming Wang Changhu Xue 《Journal of food science》2014,79(7):H1424-H1429
This study was to investigate the effects of fucosylated chondroitin sulfate (CHS) from sea cucumber on insulin sensitivity in skeletal muscle of type 2 diabetic mice induced by a high‐fat high‐sucrose diet (HFSD). CHS supplementation for 19 wk significantly improved insulin sensitivity by 20%, and reduced blood glucose and insulin levels. Western blotting assay showed that CHS significantly increased insulin‐stimulated glucose transporter 4 (GLUT4) translocation to 1.7‐fold, phosphorylation of phosphoinositide 3‐kinase (PI3K) at p85 to 5.0‐fold, protein kinase B (PKB) at Ser473 to 1.5‐fold, and Thr308 to 1.6‐fold in skeletal muscle. However, PI3K, PKB, and GLUT4 total proteins expression were unchangeable. In addition, qRT‐PCR analysis proved that the insulin signaling was activated by CHS treatment, showing the increased mRNA expressions of glucose uptake‐related key genes. It indicated that CHS improved insulin sensitivity by activation of PI3K/PKB signaling in skeletal muscle of type 2 diabetic mice. Identification of potential mechanism by which CHS increased insulin sensitivity might provide a new functional food or pharmaceutical application of sea cucumber. 相似文献