Impaired Insulin/IGF Signaling in Experimental Alcohol-Related Myopathy

Alcohol-related myopathy (Alc-M) is highly prevalent among heavy drinkers, although its pathogenesis is not well understood. We hypothesize that Alc-M is mediated by combined effects of insulin/IGF resistance and oxidative stress, similar to the effects of ethanol on liver and brain. We tested this hypothesis using an established model in which adult rats were pair-fed for 8 weeks with isocaloric diets containing 0% (N = 8) or 35.5% (N = 13) ethanol by caloric content. Gastrocnemius muscles were examined by histology, morphometrics, qRT-PCR analysis, and ELISAs. Chronic ethanol feeding reduced myofiber size and mRNA expression of IGF-1 polypeptide, insulin, IGF-1, and IGF-2 receptors, IRS-1, and IRS-2. Multiplex ELISAs demonstrated ethanol-associated inhibition of insulin, IRS-1, Akt, and p70S6K signaling, and increased activation of GSK-3β. In addition, ethanol-exposed muscles had increased 4-hydroxy-2-nonenal immunoreactivity, reflecting lipid peroxidation, and reduced levels of mitochondrial Complex IV, Complex V, and acetylcholinesterase. These results demonstrate that experimental Alc-M is associated with inhibition of insulin/IGF/IRS and downstream signaling that mediates metabolism and cell survival, similar to findings in alcoholic liver and brain degeneration. Moreover, the increased oxidative stress, which could be mediated by mitochondrial dysfunction, may have led to inhibition of acetylcholinesterase, which itself is sufficient to cause myofiber atrophy and degeneration.     

Experimental Alcohol-Related Peripheral Neuropathy: Role of Insulin/IGF Resistance

The mechanisms of alcohol-related peripheral neuropathy (ALPN) are poorly understood. We hypothesize that, like alcohol-related liver and brain degeneration, ALPN may be mediated by combined effects of insulin/IGF resistance and oxidative stress. Adult male Long Evans rats were chronically pair-fed with diets containing 0% or 37% ethanol (caloric), and subjected to nerve conduction studies. Chronic ethanol feeding slowed nerve conduction in the tibial (p = 0.0021) motor nerve, and not plantar sensory nerve, but it did not affect amplitude. Histological studies of the sciatic nerve revealed reduced nerve fiber diameters with increased regenerative sprouts, and denervation myopathy in ethanol-fed rats. qRT-PCR analysis demonstrated reduced mRNA levels of insulin, IGF-1, and IGF-2 polypeptides, IGF-1 receptor, and IRS2, and ELISAs revealed reduced immunoreactivity for insulin and IGF-1 receptors, IRS-1, IRS-4, myelin-associated glycoprotein, and tau in sciatic nerves of ethanol-fed rats (all p < 0.05 or better). The findings suggest that ALPN is characterized by (1) slowed conduction velocity with demyelination, and a small component of axonal degeneration; (2) impaired trophic factor signaling due to insulin and IGF resistance; and (3) degeneration of myelin and axonal cytoskeletal proteins. Therefore, ALPN is likely mediated by molecular and signal transduction abnormalities similar to those identified in alcoholic liver and brain degeneration.     

长期酒精摄入对雄性大鼠胰岛素敏感性及肝脏IR、IRS-1、IRS-2 mRNA表达的影响

目的从基因表达水平探讨长期酒精摄入影响肝脏胰岛素敏感性的分子机制。方法清洁级Wistar雄性大鼠40只,随机分为对照组和低、中、高剂量酒精组,每天摄入酒精剂量分别为0、0·8、1·6和2·4g/kg bw。给予酒精19周后,测定空腹血糖、血胰岛素,计算胰岛素抵抗指数(HOMA-IR)。提取肝脏总RNA,通过RT-PCR测定胰岛素受体(IR)、胰岛素受体底物1(IRS-1)、胰岛素受体底物2(IRS-2)的mRNA表达水平。结果与对照组相比,高剂量组血糖升高(P<0·05);各剂量组血胰岛素浓度均升高,低、中剂量组升高有显著性差异(P<0·05);各剂量组HOMA-IR均显著高于对照组(P<0·05)。各剂量组IR mRNA表达均降低;IRS-1及IRS-2mRNA表达在低、中剂量组升高,高剂量组降低。结论长期过量酒精摄入可以引起雄性大鼠胰岛素抵抗,肝脏IR、IRS-1、IRS-2mRNA表达降低是酒精影响胰岛素敏感性的分子机制之一。     

长期酒精摄入对大鼠骨骼肌组织IR、IRS-1和PI-3K基因表达的影响

目的研究酒精长期作用下对大鼠骨骼肌胰岛素受体(IR)、胰岛素受体底物-1(IRS-1)、磷脂酰肌醇3-激酶p85亚单位(PI-3K)mRNA表达的影响,探讨酒精与胰岛素抵抗的关系及相关分子机制。方法清洁级Wistar大鼠80只(雌雄各半),按体重随机分为对照组和低、中、高剂量组,分别给予蒸馏水以及10%、20%和33%酒精溶液,灌胃剂量为每天10ml/kgbw。第19周末,断头处死大鼠,测定空腹血糖和血胰岛素,计算HOMA胰岛素抵抗指数(HOMA-IR)。提取骨骼肌总RNA,通过RT-PCR测定IR、IRS-1、PI-3K(p85)mRNA表达水平。结果雄性大鼠,与对照组比较高剂量组空腹血糖,低、中剂量组空腹胰岛素水平升高,各酒精剂量组HOMA-IR指数均升高。IRmRNA的表达在中、高剂量组降低,而IRS-1、PI-3K(p85)mRNA表达水平表现为随着酒精剂量的增加先升高后降低,与对照组比较差异有显著性(P<0.05);与对照组比较,雌性大鼠高剂量组空腹血糖升高、空腹血胰岛素下降,IR、IRS-1、PI-3K(p85)mRNA的表达在中、高剂量组降低(P<0.05)。各剂量组HOMA-IR指数与对照组比较差异无显著性。结论长期摄入过量酒精可以造成骨骼肌组织IR、IRS-1、PI-3K(p85)mRNA表达的降低,这可能是酒精降低胰岛素敏感性,引起胰岛素抵抗的分子机制。     

Obesity in insulin receptor substrate-2-deficient mice: disrupted control of arcuate nucleus neuropeptides

OBJECTIVE: Disturbances in insulin signaling have been shown to induce obesity and/or hyperphagia in brain insulin receptor or insulin receptor substrate-2 (IRS-2) knockout (KO) mice. This study aimed to examine the central and peripheral mechanisms underlying the phenotype in IRS-2 KO mice. RESEARCH METHODS AND PROCEDURES: We measured the histological characterization of adipose tissues, mRNA levels of pro-opiomelanocortin, agouti-related protein, and neuropeptide Y in the hypothalamus and uncoupling proteins (UCPs) in peripheral tissues of IRS-2 KO mice. RESULTS: Female IRS-2 KO mice showed increased daily food intake. Body weight and adiposity were increased in both sexes, although these differences were more pronounced in female than in male IRS-2 KO mice. Both male and female IRS-2 KO mice showed decreased UCP1 mRNA expression in brown adipose tissue with defective thermoregulation, and UCP2 mRNA expression was increased in the white adipose tissue of female knockout mice. Furthermore, arcuate nucleus mRNA expression of pro-opiomelanocortin, was decreased in both male and female IRS-2 KO mice, whereas expression of agouti-related protein and neuropeptide Y were increased in female IRS-2 KO mice. DISCUSSION: In IRS-2 KO mice, disrupted control of hypothalamic neuropeptide levels and UCP mRNA expression may contribute to the development of obesity.     

Metabolic differences between genetically lean and fat chickens are partly attributed to the alteration of insulin signaling in liver.

Insulin signaling [tyrosine phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), Src homology and collagen protein (Shc) and phosphatidyl inositol 3'-kinase activity (PI 3'-kinase)] was studied in the liver and thigh muscles of fat (FL) and lean (LL) chickens. These lines result from a divergent selection on abdominal fat pad size. The divergence is of metabolic origin. Extreme nutritional states were studied (fed, 48-h starved and 30-min refed). Such conditions significantly altered insulin signaling in chicken liver, but surprisingly not in the muscle (except the phosphorylation of Shc in the refed state). No major differences that could account for this divergence were found in muscle. Liver IR number and Shc protein did not differ between genotypes. Liver IRS-1 (protein and messenger) was lower in the fed state and higher in the starved state in FL compared to that in LL chickens. In the fed state, tyrosine phosphorylation of liver IR, IRS-1 and Shc action was higher in FL than in LL chickens that in the absence of insulin resistance rely on higher plasma insulin levels. In the starved state, phosphorylation of liver IR was lower, but the phosphorylation of IR and IRS-1 were higher in LL than in FL chickens, most likely in response to higher plasma glucose and insulin in the lean genotype. In the refed state, the phosphorylation of liver IR and IRS-1 did not differ between genotypes despite significantly lower plasma insulin in FL chickens. Finally, PI 3'-kinase was not affected by the genotype. A significant activation of early steps of insulin signaling in liver of fed FL chickens may at least partly account for their increased liver lipogenesis and ultimately their fattening.     

胰岛素受体底物-1在子宫内膜癌中的表达

目的:探讨胰岛素受体底物-1在子宫内膜癌中的表达及其与子宫内膜癌发生的关系。方法:采用免疫组织化学SP法分别对子宫内膜癌、子宫内膜非典型增生、子宫内膜单纯增生和分泌期子宫内膜各30例进行胰岛素样生长因子-1受体、胰岛素受体底物-1、雌激素受体的表达进行检测,同时检测各组细胞的Ki-67指数。结果:胰岛素受体底物-1在4种子宫内膜组织中均有表达,但在子宫内膜癌中表达增强,与分泌期子宫内膜的表达相比差异显著,胰岛素受体底物-1在子宫内膜组织中的表达定位在胞浆;胰岛素样生长因子-1受体定位在胞膜,其在子宫内膜癌中的表达减弱,与分泌期子宫内膜相比差异显著;ER与IGF-1R和IRS-1在4种不同子宫内膜组织中的表达无统计学意义;Ki-67指数在子宫内膜癌及癌前病变与子宫内膜良性病变及正常子宫内膜间相比较统计学差异显著;Ki-67指数与IRS-1间存在正相关。结论:胰岛素受体底物-1在子宫内膜癌的发生、发展中可能起着重要的调节作用。     

二甲双胍对卵巢颗粒细胞IRS-1及ERK-2基因表达的影响

目的：探讨二甲双胍对多囊卵巢综合征（PCOS）卵巢颗粒细胞胰岛素受体底物-1（IRS-1）及细胞外信号调节激酶-2（ERK-2）的基因表达的影响。方法：收集行体外受精-胚胎移植（IVF-ET）治疗的PCOS患者卵泡颗粒细胞进行体外培养,用二甲双胍处理48 h,采用实时荧光定量聚合酶链反应（PCR）测定颗粒细胞IRS-1及ERK-2基因的相对表达量,另收集行IVF-ET非PCOS患者颗粒细胞作为对照组。结果：PCOS患者颗粒细胞IRS-1基因、ERK-2基因相对表达量与对照组相比明显升高（P＜0.05）,二甲双胍处理后PCOS患者颗粒细胞IRS-1基因相对表达量升高、而ERK-2基因表达量下降（P＜0.05）。结论：PCOS患者颗粒细胞IRS-1与ERK-2基因受二甲双胍作用时表达不同步,二甲双胍可能通过降低PCOS患者颗粒细胞丝裂原活化蛋白激酶（MAPK）信号传导通路活性,减轻MAPK信号通路对磷脂酰肌醇3 激酶（PI3K）通路的负反馈作用,改善PCOS患者卵巢胰岛素抵抗状态。     

Ethanol impairs insulin's actions through phosphatidylinositol 3-kinase

Insulin plays an important role in cell metabolism and proliferation. In the present study, we examined the effect of ethanol on insulin actions such as glucose uptake, DNA synthesis, and c-Jun gene expression. Acute treatment with ethanol (200 mM) for 60 minutes inhibited insulin-stimulated 2-deoxyglucose uptake by 50% in 3T3-L1 adipocytes. Insulin-induced DNA synthesis and c-Jun protein expression were also reduced by ethanol treatment in Rat-1 fibroblasts overexpressing normal human insulin receptor. Ethanol has no effect on tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1. However, association of the insulin receptor and IRS-1 with the Src homology 2 domain of the p85 subunit of phosphatidylinositol 3-kinase (PI3-kinase) was reduced by ethanol. Pretreatment with the antidiabetic drug troglitazone, an insulin-sensitizer, reversed ethanol's inhibition. These results suggest that ethanol specifically inhibits the association of the insulin receptor and IRS-1 with the p85 subunit of PI3-kinase, which is required for increased glucose uptake, DNA synthesis, and c-Jun expression by insulin.     

Effects of chronic prenatal ethanol exposure on mitochondrial glutathione and 8-iso-prostaglandin F2alpha concentrations in the hippocampus of the perinatal guinea pig

It is hypothesised that oxidative stress is a key mechanism of ethanol neurobehavioural teratogenicity, resulting in altered endogenous antioxidant status and increased membrane lipid peroxidation in the hippocampus of chronic prenatal ethanol exposure (CPEE) offspring. To test this hypothesis, timed pregnant guinea-pigs (term, approximately gestational day (GD) 68) received chronic daily oral administration of (i) 4 g ethanol kg(-1) maternal bodyweight, (ii) isocaloric sucrose with pair feeding, or (iii) water. At GD 65 (term fetus) and postnatal day (PD) 0 (neonate), individual offspring were killed, the brain was excised and the hippocampi were dissected. Glutathione (GSH) concentration was measured in the cytosolic and mitochondrial fractions of hippocampal homogenate. The occurrence of lipid peroxidation was determined by measuring the concentration of 8-iso-prostaglandin F2+/- (8-iso-PGF2+/-). There was CPEE-induced decreased brain weight and hippocampal weight at GD 65 and PD 0, decreased mitochondrial GSH concentration in the hippocampus at PD 0, with no change in mitochondrial GSH concentration at GD 65 or cytosolic GSH concentration at GD 65 or PD 0, and no change in mitochondrial or whole-homogenate 8-iso-PGF2+/- concentration in the hippocampus at GD 65 or PD 0. The data demonstrate that CPEE produces selective mitochondrial dysfunction in the hippocampus of the neonatal guinea-pig, involving GSH depletion.     

明日叶查尔酮对2型糖尿病大鼠肝细胞胰岛素受体与胰岛素受体底物-2 mRNA表达的影响

目的研究明日叶查尔酮(Ashitabe chalcone,AC)对糖尿病大鼠肝细胞胰岛素受体(insulin receptor,InsR)和胰岛素受体底物-2(insulin receptor substrate-2,IRS-2)mRNA表达的影响。方法将用高脂饲料喂养加链尿佐菌素腹腔注射诱发的2型糖尿病大鼠随机分为糖尿病对照组和高、低剂量AC组,每组10只,均喂饲高脂饲料,分别每日经口灌胃给予明日叶查尔酮的剂量为0、30、10 mg/kg。另设一个正常对照组为正常大鼠喂饲普通饲料,实验周期4 w。用放射免疫分析法检测血清胰岛素水平、逆转录聚合酶链式反应方法检测肝细胞InsR和IRS-2 mRNA表达水平、免疫组化法测肝细胞InsR蛋白表达水平、葡萄糖氧化酶法测血糖含量。结果与正常对照组比较,糖尿病对照组空腹血糖和血清胰岛素升高,而InsR和IRS-2 mRNA表达水平降低。与糖尿病组比较,高剂量AC组空腹血糖和血清胰岛素降低,而InsR和IRS-2mRNA表达水平升高,各项差异均有显著性意义(P<0.05)。结论明日叶查尔酮可上调2型糖尿病大鼠肝细胞InsR和IRS-2mRNA表达水平,改善胰岛素抵抗状况。     

Amino acids do not alter the insulin-induced activation of the insulin signaling pathway in neonatal pigs

Feeding stimulates protein synthesis in skeletal muscle and liver of neonates and this response can be reproduced in muscle by the infusion of insulin or amino acids and in liver by the infusion of amino acids, but not insulin. Activation of insulin signaling components leading to translation initiation is associated with the feeding-induced stimulation of muscle protein synthesis in neonates. In this study, we examined the individual roles of insulin and amino acids in the activation of insulin signaling components leading to translation initiation, specifically, the insulin receptor (IR), insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI 3-kinase), protein kinase B (PKB) and ribosomal protein S6. Insulin secretion was blocked by somatostatin in food-deprived, 7-d-old pigs (n=8-12/group); insulin was infused to achieve plasma levels of approximately 0, 17, 52, and 255 pmol/L (approximately 0, 2, 6, 30 microU/mL), and amino acids were clamped at food-deprived or fed levels. In skeletal muscle, insulin increased the activation of IR, IRS-1, PI 3-kinase, PKB and S6 and stimulated protein synthesis. In liver, insulin increased the activation of IR, IRS-1, PI 3-kinase, PKB and S6, but had no effect on protein synthesis. Raising amino acids from the food-deprived to the fed level did not alter the insulin-induced activation of IR, IRS-1, PI 3-kinase and PKB but increased S6 phosphorylation and protein synthesis in skeletal muscle and liver. The results suggest that the stimulation of protein synthesis in muscle by insulin involves activation of insulin signaling components, and the stimulation of protein synthesis in muscle and liver by amino acids occurs by mechanisms independent of the early steps of this pathway. Furthermore, amino acids do not alter the insulin-stimulated activation of early steps in the insulin signaling pathway.     

Increased risk for gestational diabetes mellitus associated with insulin receptor and insulin-like growth factor II restriction fragment length polymorphisms

Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition during pregnancy. We have examined restriction fragment length polymorphisms (RFLPs) near "candidate diabetogenic genes" as one approach to identify molecular markers for GDM genes. Genotypes for insulin hypervariable region (HVR), insulin-like growth factor II (IGF2), insulin receptor (INSR), and glucose transporter (GLUT1) RFLPs were studied in 96 GDM and 164 control subjects, matched to GDM for race, age, and gravidity. Logistic regression analysis was used to explore the relationship between genotypes at these candidate gene loci and GDM, while adjusting for the effects of potential confounding variables. Among black subjects, the INSR allele 1 (P = 0.001) and interactions between INSR allele 1 with body mass index (BMI) (P = 0.002) and history of DM in subject's mother (P = 0.004) contributed significantly to GDM risk. Among Caucasian subjects, a similar relationship between the INSR allele 1 (P = 0.007) and INSR allele 1-BMI interactions (P = 0.011) on GDM risk were observed. In Caucasians, an additional significant risk factor was determined by an INSR allele 1-IGF2 allele 2 interaction (P = 0.018). No risk factors were identified in Hispanic subjects. These data continue to support the hypothesis that GDM is a heterogeneous disorder with respect to phenotypic and genotypic features. Furthermore, our data suggest that risk for GDM in black and Caucasian subjects is not due to obesity perse but to interactions between obesity and INSR alleles. In Caucasian women, INSR and IGF2 alleles interact to confer additional risk for GDM. Thus genes underlying susceptibility to GDM in some women may be similar to genes conferring risk to NIDDM, while in others novel genes may contribute to GDM risk.     

胰岛素样生长因子-1对脓毒症大鼠血浆应激激素和胰岛素样生长因子-1受体表达的影响

目的探讨胰岛素样生长因子-1（IGF-1）对脓毒症大鼠血浆应激激素及骨骼肌IGF-1受体（IGF-1R）蛋白质和mRNA表达的影响。方法选择71只SD大鼠采用盲肠结扎穿孔法建立腹腔感染及颈静脉置管肠外营养（PN）模型后，将存活的30只大鼠随机分为脓毒症组（n=10）、PN组（n=10）及IGF-1组（n=10），另设正常组（n=10）。正常组和脓毒症组给予生理盐水，PN组给予营养支持，IGF-1组为PN＋IGF-1静脉注射，连续5天。第6天行颈动脉置管，开腹取门静脉血测定胰岛素、胰高血糖素、肾上腺素、皮质醇和IGF-1水平；免疫组织化学法及实时定量PCR法测定肝脏和骨骼肌IGF-1R蛋白质和mRNA的表达。结果与对照组相比，脓毒症组大鼠血浆胰岛素、胰高血糖素、肾上腺素、皮质醇水平显著升高，IGF-1显著下降（P〈0．01）；IGF-1组前5项指标较脓毒症组和PN组显著降低，IGF-1则显著升高（P〈0．05，P〈0．01）。脓毒症组肝脏和骨骼肌IGF-1R蛋白质及mRNA表达较对照组显著增强（P〈0．05，P〈0．01）；IGF-1组的IGF-1R蛋白质及mRNA表达较脓毒症组和PN组显著降低（P〈0．01）。结论IGF-1可改善应激激素之间的平衡，降低脓毒血症大鼠IGF-1R在蛋白质和mRNA水平的表达，从而有利于血糖的控制。     

禁食和再喂养期间大鼠小肠胰岛素和胰岛素样生长因子-1受体的比较

胰岛素样生长因子-1（IGF-1）和胰岛素可能是肠道生长的重要调节因子。为了研究肠细胞萎缩和再生期间小肠IGF－1受体（IGF-IR）和胰岛素受体（IR），我们比较了禁食72小时和肠内再喂养24～72小时大鼠空肠IGF-IR和IR表达的指标。禁食引起肠萎缩，血浆胰岛素和IGF－1浓度降低以及空肠IGF-1信使RNA（mRNA）水平的明显降低，再喂养可逆转这些改变。禁食明显增加胰岛素与空肠特异性地结合，IR含量（达对照组的230％）和9．6kb和7．4kbIRmRNA转录本水平（分别达对照组的202％和218％）。再喂养时，这些IR指标迅速降到对照组水平。禁食时IGP-IR（用Scatchard分析）和IGF－1－RmRNA无明显的改变。再喂养后的前24小时间11-kbIGF－IRmRNA转录本明显增加（达对照组水平166％），IGF-IR数量增加3倍。我们的结论是：大鼠空肠的IR和IGF－IR受到不同营养物利用状态的调节。再喂养时空肠IGF－1和IGF－IR表达的向上调节表明，IGF作用途径在对肠内营养物产生肠道营养反应的过程中起作用。     

A high fructose diet affects the early steps of insulin action in muscle and liver of rats

A high fructose diet induces insulin resistance in rats, although the exact molecular mechanism involved is unknown. In this study, we used immunoprecipitation and immunoblotting to examine the levels and phosphorylation status of the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1), as well as the association of the IRS-1 with phosphatidylinositol 3-kinase (PI 3-kinase), and phosphotyrosine phosphatase (SHP2) in the liver and muscle of rats fed a control or high fructose diet for 28 d. There were no differences in IR and the IRS-1 protein levels in the liver and muscle of rats fed the control and high fructose diets. However, tyrosine-phosphorylation of the insulin receptor after insulin stimulation was reduced to 71 +/- 2% (P < 0.05) of control in the liver of the fructose-fed rats. In samples previously immunoprecipitated with anti-IRS-1 antibody and blotted with antiphosphotyrosine antibody, the insulin-stimulated IRS-1 phosphorylation levels in the liver and muscle of the fructose-fed group were only 70 +/- 6% (P < 0.05) and 76 +/- 5% (P < 0.05) of those of control rats, respectively. The insulin-stimulated IRS-1 association with PI 3-kinase was reduced to 84 +/- 3% (P < 0.05) in the liver and to 84 +/- 4% (P < 0.05) in the muscle of the fructose-fed group compared with control rats. Insulin-stimulated IRS-1 association with SHP2 was reduced to 79 +/- 5% (P < 0.05) in liver of the fructose-fed rats. These data suggest that changes in the early steps of insulin signal transduction may have an important role in the insulin resistance observed in these rats.     

中国菰米对高脂膳食诱导大鼠胰岛素抵抗机制的研究

目的探讨中国菰米对高脂膳食诱导的胰岛素抵抗大鼠的影响及其作用机制。方法 44只雄性SD大鼠按胰岛素抵抗指数(HOMA-IR)随机分为阴性对照、模型、米面和菰米4组,以对应的饲料连续喂养8 w,测定各组大鼠空腹血糖(FBG)、胰岛素(FINS)以及游离脂肪酸(FFA)水平,并计算HOMA-IR;采用RT-PCR或Western blotting法检测大鼠肝脏组织中蛋白酪氨酸磷酸酶-1B(PTP-1B)和胰岛素受体底物-2(IRS-2)mRNA或蛋白的表达。结果模型组大鼠HOMA-IR值及血清FFA显著高于阴性对照组;米面组与模型组HOMA-IR值及血清FFA无显著性差异;菰米组大鼠血清FBG、FINS和FFA浓度及HOMA-IR值显著低于米面组和模型组。菰米组大鼠肝组织中PTP-1B基因和蛋白的表达均明显低于模型组和米面组,而IRS-2 mRNA的表达明显升高。结论菰米具有降低胰岛素抵抗大鼠血糖、胰岛素及FFA水平,并通过抑制PTP-1B的相对表达,进而促进IRS-2的磷酸化,增强胰岛素信号的转导作用,可改善机体胰岛素的敏感性。     

Mechanism involved in genistein activation of insulin-like growth factor 1 receptor expression in human breast cancer cells

Our previous studies have shown that genistein can enhance the insulin-like growth factor (IGF)-1 receptor signalling pathway via an oestrogen receptor (ER) in human breast cancer MCF-7 cells. The present study aims to investigate how genistein regulates IGF-1 receptor expression in human MCF-7 cells. Genistein at 1 microm stimulated the growth of MCF-7 cells and this effect could be completely blocked by the IGF-1 receptor antagonist JB-1, suggesting that IGF-1 receptor is essential for mediating the proliferative effects of genistein in MCF-7 cells. Genistein increased IGF-1 receptor promoter activity. This effect could be completely abolished by co-treatment of MCF-7 cells with ICI 182,780 (10- 6 m). Genistein increased IGF-1 receptor gene expression and this effect could be completely blocked by the IGF-1 receptor antagonist JB-1. Co-treatment of MCF-7 cells with cycloheximide (5 microg/ml) completely blocked the induction of IGF-1 receptor protein and mRNA expression by genistein. The results indicated that the induction of IGF-1 receptor promoter activity by genistein required the action of ER while the stimulatory actions of genistein on IGF-1 receptor expression required the activity of the IGF-1 receptor and de novo protein synthesis. These data provide evidence to support the hypothesis that the inductive effects of genistein on IGF-1 receptor expression require the cross-talk between IGF-1 receptor and the ER-dependent pathways.