血脂变化对OLETF大鼠肝脏、脂肪组织胰岛素受体底物1和含2个SH结构的蛋白酪氨酸磷酸酶蛋白表达的影响

目的观察血脂变化对OLETF大鼠胰岛素受体底物-1(IRS-1)和含2个SH结构的蛋白酪氨酸磷酸酶(SH-PTP2)蛋白表达的影响。方法 14只OLETF大鼠被随机分为降脂治疗组和对照组。采用Western杂交技术检测OLETF大鼠肝脏、脂肪组织内IRS-1及SH-PTP2的蛋白表达水平。结果降脂治疗组血糖及血脂水平较对照组下降(P<0.05),肝脏、脂肪组织内IRS-1蛋白表达较对照组增加(t=14.61,15.76,P均<0.01),而SH-PTP2的蛋白表达较对照组减少(t=-3.07、-28.76,P均<0.01)。结论降脂治疗可增加OLETF大鼠肝脏、脂肪组织内IRS-1蛋白表达,减少其SH-PTP2蛋白表达,并可能因此影响其胰岛素信号传导,改善其靶组织对胰岛素的敏感性。     

二甲双弧对OLETF大鼠靶组织内胰岛素受体底物—1蛋白表达水平的影响

目的 探讨二甲双胍作用的分子机制。方法 用Ｗｅｓｔｅｒｎ杂交检测二甲双胍治疗后自发发病的２型糖尿病模型（ＯＬＥＴＦ大鼠）肝脏、肌肉、脂肪组织内ＩＲＳ－１（胰岛素受体底物）蛋白表达水平的改变,并与治疗前比较。结果 二甲双胍治疗后ＯＬＥＴＦ大鼠肝脏组织内ＩＲＳ－１的蛋白表达较治疗前明显增加（Ｐ〈０．００１）,肌肉组织的ＩＲＳ－１的蛋白表达亦较治疗前增加,但差别无统计学意义（Ｐ〉０．０５）,脂肪组织内ＩＲＳ－１的蛋白表达则较治疗前减少（Ｐ〈０．０５）。结论 二甲双胍治疗后能使ＯＬＥＴＦ大鼠靶组织内ＩＲＳ－１蛋白表达发生改变,特别是它能明显增加肝脏组织ＩＲＳ－１的蛋白表达,这可能是其抗高血糖、改善组织胰岛素敏感性的机制之一。     

二甲双胍对自发2型糖尿病OLETF大鼠脂肪分解的影响及机制

目的研究二甲双胍对不同周龄OLETF大鼠脂肪分解的影响及其机制。方法OLETF大鼠分为OLETF未干预组和二甲双胍干预组,观察不同周龄OGTT(血糖+FIns)和FFA水平的变化。取附睾脂肪组织测定培养液中甘油释放量,Western blot检测脂滴包被蛋白(Perilipin)、磷酸化和总细胞外信号调节激酶(ERK)、激素敏感性脂肪酶(HSL)和脂肪组织甘油三酯水解酶(ATGL)的表达。结果 18周龄时,二甲双胍抑制糖尿病OLETF大鼠附睾脂肪组织增强的脂肪分解达23.96%(P0.05),28周龄时,二甲双胍失去对脂肪分解的抑制作用。二甲双胍增加OLETF大鼠附睾脂肪组织Perilipin表达并减少ERK磷酸化,但不影响HSL表达,早期增加ATGL表达但后期无明显影响。结论在OLETF大鼠肥胖和糖尿病早期,二甲双胍增加Perilipin表达和减少ERK磷酸化抑制脂肪分解,从而减少FFA释放,改善IR。     

二甲双胍对高脂诱导胰岛素抵抗大鼠vaspin mRNA表达水平的影响

采用高脂喂养并利用清醒状态下正糖-高胰岛素钳夹技术评估胰岛素抵抗大鼠模型.胰岛素抵抗大鼠脂肪组织vaspin mRNA表达量明显低于对照组(P＜0.05),二甲双胍治疗后表达升高(P＜0.05),提示二甲双胍在改善大鼠胰岛素抵抗状态的同时能上调胰岛素抵抗大鼠内脏脂肪组织vaspin mRNA的表达.     

二甲双胍对胰岛素抵抗大鼠内脏脂肪组织chemerin表达的影响

将雄性4周龄SD大鼠分为正常饲料组和高脂饲料组,喂养10周后分别以二甲双胍治疗(200mg/kg)6周.以正常血糖-高胰岛素钳夹试验评估胰岛素敏感性,留取肾周脂肪组织,采用实时定量PCR及Western印迹法检测脂肪组织中chemerin mRNA和蛋白的表达水平.结果显示,高脂饲料诱导的胰岛素抵抗、大鼠肾周脂肪组织chemerin mRNA和蛋白水平高于正常饲料喂养大鼠(均P＜0.05),二甲双胍治疗6周后明显降低(均P＜0.01).脂肪组织中chemerin mRNA、蛋白表达水平均与附睾脂肪质量指数显著相关(均P＜0.05).     

二甲双胍对高糖高脂饮食诱导的糖尿病大鼠脂肪肝的干预作用

目的 观察高糖、高脂饮食诱导的糖尿病大鼠肝脏病理改变,探讨二甲双胍的干预作用.方法 40只SD大鼠随机分为正常对照(NC)组、糖尿病对照(DM-C)组和DM+二甲双胍干预(DM-M)组.比较各组生化指标、肝重及肝脏指数的改变.HE染色观察大鼠肝脏形态学变化;免疫组化法检测肿瘤坏死因子α(TNF-α)在肝脏的表达.结果 高糖、高脂饲养4周后诱导大鼠出现胰岛素抵抗;8周成功建立T2DM大鼠模型.18周末 DM-C 组大鼠肝脏出现严重脂肪变性,TNF-α在肝脏的蛋白表达水平增加(P<0.01).经二甲双胍治疗后,DM-M组大鼠肝脏脂肪变性程度明显减轻,TNF-α的蛋白表达水平下降(P<0.05).结论 二甲双胍可降低高糖、高脂饮食诱导的糖尿病大鼠肝脏脂肪含量,降低TNF-α在肝组织的蛋白表达,对治疗2型糖尿病脂肪肝具有一定的作用.     

二甲双胍对高糖高脂饮食诱导的糖尿病大鼠脂肪肝治疗作用的研究

目的探讨二甲双胍对脂肪肝的治疗作用及在改善胰岛素抵抗、调节糖脂代谢中的作用机制。方法2003年2月至2003年7月河北医科大学第三医院通过高糖、高脂饮食诱导并结合小剂量链脲佐菌素注射的方法,建立2型糖尿病大鼠合并脂肪肝的动物模型,再给予二甲双胍625mg/(kg.d)灌胃进行干预治疗10周。18周末检测大鼠血糖、血脂、肝功、肝脏脂质定量、肝脏指数、胰岛素抵抗指数及肝组织学变化,肿瘤坏死因子-α(TNF-α)在肝组织的蛋白表达。结果二甲双胍可以显著降低血糖、血脂、肝脏脂质量,增加胰岛素敏感性,改善肝脏脂肪变程度,降低TNF-α在肝组织的蛋白表达。结论二甲双胍对2型糖尿病合并脂肪肝大鼠的肝脏脂肪变性具有一定的治疗意义。     

二甲双胍对心力衰竭大鼠心功能的影响及其机制

目的 探讨二甲双胍对心力衰竭大鼠心功能的影响及其可能的作用机制.方法 选择成年Wistar大鼠67只,采取结扎冠状动脉前降支的方法建立心力衰竭模型,随机分为二甲双胍治疗组19只、AMPK激动剂(AIC-AR)治疗组20只、生理盐水对照组13只,同时设假手术组15只,分别给予相应的处理.4周后,观察各组左室射血分数(LVEF)、血流动力学指标、血浆BNP水平,并留取心肌组织检测p-AMPKαThr-172蛋白表达.结果 与生理盐水对照组比较,二甲双胍治疗组、AICAR治疗组LVEF、左室收缩压和左室压力最大上升和下降速率均显著提高(P均＜0.05),左室舒张末压显著降低(P均＜0.05).所有心力衰竭大鼠用药前血浆BNP水平高于假手术组(P均＜0.05);药物干预4周后,二甲双胍治疗组、AICAR治疗组血浆BNP水平较生理盐水对照组明显降低(P均＜0.05).免疫组化显示,二甲双胍治疗组、AICAR治疗组P-AMPKαThr-172蛋白表达明显升高(P均＜0.05).结论 二甲双胍可明显改善心力衰竭大鼠的心功能状态,这种作用与激活AMPK信号转导通路有关.     

二甲双胍降低大鼠肝脏胆固醇和甘油三酯含量的机制探讨

目的 观察二甲双胍对长期高饱和脂肪酸饲养大鼠肝脏腺苷酸活化蛋白激酶α(AMPKα)和PPARα表达和活性的影响,探讨二甲双胍降低肝脏胆固(TC)和甘油三酯(TG)含量的可能机制.方法 Wistar雄性大鼠30只,随机等分为:对照组(C组)、高脂组(HF组)和高脂加二甲双胍组(Met组,高脂喂养4个月,第5个月加用二甲双胍胃1个月),喂养共5个月,测定血清、肝脏组织中的TC和TG含量;分别应用实时PCR、Western印迹检测肝脏AMPKα 和PPARα 的基因转录、蛋白表达和活性水平;PPARα 转录因子DNA结合活性测定用ELISA法.结果 与C组比较,HF组大鼠肝脏AMPKα2和PPAα mRNA表达水平显著降低(均P＜0.05);AMPKα 蛋白表达及活性显著降低(均P＜0.05),PPARα蛋白表达及DNA结合活性分别降低 48.6%、21.6%(均P＞0.05); 肝脏TC、TG含量(均P＜0.05)和血TC、TG水平(均P＜0.01)均显著增高.与HF组比较,Met组肝脏AMPKα2 mRNA和蛋白表达及活性显著增高(均P＜0.05),PPARα蛋白表达增高56.5%(P＞0.05),其DNA结合活性显著增高(P＜0.05);肝脏TC、TG含量血TC、TG水平均显著降低(均P＜0.05).结论 二甲双胍降低长期高脂饲养所致的大鼠肝脏、血中TC、TG水平的增高,可能与其激活肝细胞AMPKα及PPARα有关.     

罗格列酮和二甲双胍治疗对胰岛素抵抗KKAy糖尿病小鼠肝及横纹肌组织PTEN蛋白表达的影响

目的观察罗格列酮和二甲双胍治疗后胰岛素抵抗KKAy糖尿病小鼠肝及横纹肌组织PTEN蛋白表达的变化。方法 KKAy小鼠制备糖尿病模型后随机分为未治疗组、罗格列酮治疗组及二甲双胍治疗组。C57BL小鼠普通饲料喂养,为对照组。4周后处死小鼠,Western blot检测肝及横纹肌PTEN蛋白、胰岛素刺激后磷酸化473Akt的表达并进行定量分析。结果罗格列酮及二甲双胍处理后KKAy糖尿病小鼠肝及横纹肌组织磷酸Akt升高倍数与KKAy糖尿病小鼠相比均无明显变化(P0.05),罗格列酮和二甲双胍处理后肝及骨骼肌PTEN蛋白表达与糖尿病未治疗组相比差异没有统计学意义(P0.05)。结论罗格列酮和二甲双胍不会影响PI3k-Akt通路活性及PTEN蛋白的表达,两者改善血糖和胰岛素抵抗可能与胰岛素敏感组织PTEN蛋白的表达无关。     

Short-term in vivo inhibition of insulin receptor substrate-1 expression leads to insulin resistance, hyperinsulinemia, and increased adiposity

Insulin receptor substrate-1 (IRS-1) has an important role as an early intermediary between the insulin and IGF receptors and downstream molecules that participate in insulin and IGF-I signal transduction. Here we employed an antisense oligonucleotide (IRS-1AS) to inhibit whole-body expression of IRS-1 in vivo and evaluate the consequences of short-term inhibition of IRS-1 in Wistar rats. Four days of treatment with IRS-1AS reduced the expression of IRS-1 by 80, 75, and 65% (P < 0.05) in liver, skeletal muscle, and adipose tissue, respectively. This was accompanied by a 40% (P < 0.05) reduction in the constant of glucose decay during an insulin tolerance test, a 78% (P < 0.05) reduction in glucose consumption during a hyperinsulinemic-euglycemic clamp, and a 90% (P < 0.05) increase in basal plasma insulin level. The metabolic effects produced by IRS-1AS were accompanied by a significant reduction in insulin-induced [Ser (473)] Akt phosphorylation in liver (85%, P < 0.05), skeletal muscle (40%, P < 0.05), and adipose tissue (85%, P < 0.05) and a significant reduction in insulin-induced tyrosine phosphorylation of ERK in liver (20%, P < 0.05) and skeletal muscle (30%, P < 0.05). However, insulin-induced tyrosine phosphorylation of ERK was significantly increased (60%, P < 0.05) in adipose tissue of IRS-1AS-treated rats. In rats treated with IRS-1AS for 8 d, a 100% increase (P < 0.05) in relative epididymal fat weight and a 120% (P < 0.05) increase in nuclear expression of peroxisome proliferator-activated receptor-gamma were observed. Thus, acute inhibition of IRS-1 expression in rats leads to insulin resistance accompanied by activation of a growth-related pathway exclusively in white adipose tissue.     

Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway

Aim/hypothesis Several epidemiological studies have suggested an association between chronic hyperinsulinaemia and insulin resistance. However, the causality of this relationship remains uncertain.Methods We performed chronic hyperinsulinaemic–euglycaemic clamps and delineated, by western blotting, an IR/IRSs/phosphatidylinositol 3-kinase(PI[3]K)/Akt pathway in insulin-responsive tissues of hyperinsulinaemic rats. IRS-1/2 serine phosphorylation, IR/protein tyrosine phosphatase 1B (PTP1B) association, and mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70 S6K) activity were also evaluated in the liver, skeletal muscle and white adipose tissue of hyperinsulinaemic animals.Results We found that chronic hyperinsulinaemic rats have insulin resistance and reduced levels of glycogen content in liver and muscle. In addition, we demonstrated an impairment of the insulin-induced IR/IRSs/PI(3)K/Akt pathway in liver and muscle of chronic hyperinsulinaemic rats that parallels increases in IRS1/2 serine phosphorylation, IR/PTP1B association and mTOR activity. Despite a higher association of IR/PTP1B, there was an increase in white adipose tissue of chronic hyperinsulinaemic rats in IRS-1/2 protein levels, tyrosine phosphorylation and IRSs/PI(3)K association, which led to an increase in basal Akt serine phosphorylation. No increases in IRS-1/2 serine phosphorylation and mTOR activity were observed in white adipose tissue. Rapamycin reversed the insulin resistance and the changes induced by hyperinsulinaemia in the three tissues studied.Conclusions/interpretation Our data provide evidence that chronic hyperinsulinaemia itself, imposed on normal rats, appears to have a dual effect, stimulating insulin signalling in white adipose tissue, whilst decreasing it in liver and muscle. The underlying mechanism of these differential effects may be related to the ability of hyperinsulinaemia to increase mTOR/p70 S6K pathway activity and IRS-1/2 serine phosphorylation in a tissue-specific fashion. In addition, we demonstrated that inhibition of the mTOR pathway with rapamycin can prevent insulin resistance caused by chronic hyperinsulinaemia in liver and muscle. These findings support the hypothesis that defective and tissue-selective insulin action contributes to the insulin resistance observed in hyperinsulinaemic states.     

Ⅱ型糖尿病病人脂肪组织胰岛素受体底物1和含2个SH2结构的蛋白酪氨酸磷酸酶

OBJECTIVE: To investigate the protein expression of insulin receptor substrate-1 (IRS-1), protein tyrosine phosphatase with two src-homology 2 (SH-PTP(2)) in adipose tissues of type II diabetic patients, and explore molecular mechanisms of insulin resistance from adipose tissues of type II diabetic individuals. METHODS: The levels of protein expression of IRS-1 and SH-PTP(2) in adipose tissues from type II diabetic individuals were measured by Western blot analysis; meanwhile compared the level of protein expression of one's own abdominal subcutaneous and omentum majus adipose tissue from patients with type II diabetes mellitus. RESULTS: The expression of IRS-1 protein in abdominal subcutaneous (A) 2.14 +/- 0.67 and omentum majus 3.25 +/- 0.70 adipose tissues from patients with type II diabetes mellitus was significantly lower than that of control group [subcutaneous: 4.33 +/- 0.57 (P < 0.001), omentum majus: 8.65 +/- 2.85 (P < 0.05)]. The expression of SH-PTP(2) protein had no difference compared with control group (P > 0.05). The protein expression of IRS-1 was significantly lower in abdominal subcutaneous adipose tissue (1.09 +/- 0.13) than that in omentum majus adipose tissue (2.10 +/- 0.22) from the type II diabetic patients (P < 0.05), but the protein expression of SH-PTP(2) was significantly higher in subcutaneous adipose tissue (70.75 +/- 2.18) than that in omentum majus (43.69 +/- 11.07, P < 0.05). CONCLUSION: The abnormal changes in expression of IRS-1 and SH-PTP(2) protein in adipose tissues of the patients with type II diabetic mellitus may be one of the mechanisms of leading to insulin resistance. The abdominal subcutaneous adipose tissue of type II diabetic patients, as visceral adipose tissues, contributes to their insulin resistance.     

Metformin promotes induction of lipoprotein lipase in skeletal muscle through activation of adenosine monophosphate-activated protein kinase

Metformin is known to increase lipoprotein lipase (LPL) mass level in serum. Lipoprotein lipase is produced by adipose tissue and skeletal muscles. This study aimed to examine the effect of metformin on LPL production in adipocytes and skeletal muscle cells and to investigate the mechanism by which metformin enhances LPL production. 3T3-L1 preadipocytes and L6 skeletal muscle cells were incubated with metformin or 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Lipoprotein lipase activity, LPL protein expression, and LPL messenger RNA (mRNA) expression were measured. Metformin increased LPL activity only in skeletal muscle cells. To clarify the mechanism of this phenomenon, AICAR, which is well known as an activator of adenosine monophosphate-activated protein kinase (AMPK), was used. Metformin and AICAR enhanced phosphorylated AMPK in skeletal muscle cells by Western blot analysis. Like metformin, AICAR increased LPL activity only in skeletal muscle cells. Both metformin and AICAR also enhanced LPL protein and LPL mRNA expressions in skeletal muscle cells but not in adipocytes. Phosphorylated AMPK protein expression was decreased when AMPK signaling was interfered by AMPKα small interfering RNA. Lipoprotein lipase activity and LPL expression, which were enhanced by 1 μmol/L metformin, were reduced by AMPKα small interfering RNA. These results suggest that metformin increases LPL activity, LPL protein expression, and LPL mRNA expression through activation of AMPK in skeletal muscle cells but not in adipocytes.     

Reduction of adiposity with prolonged growth hormone treatment in old obese rats: effects on glucose handling and early insulin signaling.

OBJECTIVES: Growth Hormone (GH) promotes loss of body fat and causes insulin resistance. It is debated whether reduction of body fat mass during long term growth hormone (GH) administration improves carbohydrate metabolism. To answer this question we assessed carbohydrate handling and tissue specific function of the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) during prolonged GH treatment of obese rats. METHODS: Body fat % estimated by DEXA scanning, plasma IGF-I, glucose and insulin were studied in 17 months old dietary induced obese rats treated for 4, 21 or 41 days (GH: 4 mg/kg/d or saline total n=90). Adipose tissue, muscle and liver samples were obtained after 21 days and expression and tyrosine phosphorylation of IR and IRS-1 proteins and the degree of IRS-1-Janus Kinase-2 (JAK2) interaction were analyzed by immunoprecipitation and immunoblotting. RESULTS: Forty-one days GH treatment caused the body fat to decline significantly to 20+/-3% (Mean+/-SEM), whereas it remained steady on 51+/-4% in the pair fed group. Insulin levels in response to OGTT were significantly elevated throughout the experiment. IR amount was elevated in adipose tissue but decreased in liver after GH treatment while IR phosphorylation was increased in muscle only. IRS-1 amount was elevated in adipose tissue and muscle while IRS-1 phosphorylation was increased only in liver. The association of IRS-1 with JAK-2 was increased in liver and muscle. CONCLUSIONS: An extensive reduction of fat mass did not improved signs of insulin resistance in GH treated old obese rats. The molecular events associated with GH treatment included tissue specific changes in the function of IR and IRS-1 suggesting the liver to be the primary site of insulin resistance. Furthermore, the association of IRS-1with JAK-2 in the course of GH signaling could present a mechanism for GH to directly induce insulin resistance.     

Insulin receptor substrate-4 is expressed in muscle tissue without acting as a substrate for the insulin receptor

Insulin receptor substrate (IRS) proteins represent key elements of the insulin-signaling cascade. IRS-4 is the most recently characterized member of the IRS family with an undefined in vivo function. In contrast to IRS-1 and IRS-2, IRS-4 exhibits a limited tissue expression, and IRS-4 protein has not been detected in any mouse or primary human tissue so far. The purpose of the present study was to analyze the expression of IRS-4 in rat muscle and human skeletal muscle cells and assess involvement of IRS-4 in initial insulin signaling. Using immunoblotting and immunoprecipitation, the specific expression of IRS-4 protein could be demonstrated in rat soleus and cardiac muscle and human skeletal muscle cells, but it was not significantly detectable in quadriceps and gastrocnemius. A prominent down-regulation of IRS-4 was observed in heart and soleus muscle of WOKW rats, an animal model of the metabolic syndrome. In human skeletal muscle cells, both IRS-1 and IRS-2 are rapidly phosphorylated on tyrosine in response to insulin, whereas essentially no tyrosine phosphorylation of IRS-4 was observed in response to both insulin and IGF-I. Instead, a 2-fold increase in IRS-4 tyrosine phosphorylation was observed in myocytes subjected to osmotic stress. In conclusion, IRS-4 protein is expressed in heart and skeletal muscle in a fiber type specific fashion. Our data suggest that IRS-4 does not function as a substrate of the insulin and the IGF-I receptor in primary muscle cells but may be involved in nonreceptor tyrosine kinase signaling.     

Impaired ('diabetic') insulin signaling and action occur in fat cells long before glucose intolerance--is insulin resistance initiated in the adipose tissue?

This review postulates and presents recent evidence that insulin resistance is initiated in the adipose tissue and also suggests that the adipose tissue may play a pivotal role in the induction of insulin resistance in the muscles and the liver. Marked impairments in insulin's intracellular signaling cascade are present in fat cells from type 2 diabetic patients, including reduced IRS-1 gene and protein expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities. In contrast, upstream insulin signaling in skeletal muscle from diabetic subjects only shows modest impairments and PKB/Akt activation in vivo by insulin appears normal. However, insulin-stimulated glucose transport and glycogen synthesis are markedly reduced.Similar marked impairments in insulin signaling, including reduced IRS-1 expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities are also seen in some (approximately 30%) normoglycemic individuals with genetic predisposition for type 2 diabetes. In addition, GLUT4 expression is markedly reduced in these cells, similar to what is seen in diabetic cells. The individuals with reduced cellular expression of IRS-1 and GLUT4 are also markedly insulin resistant and exhibit several characteristics of the Insulin Resistance Syndrome.Thus, a 'diabetic' pattern is seen in the fat cells also in normoglycemic subjects and this is associated with a marked insulin resistance in vivo. It is proposed that insulin resistance and/or its effectors is initiated in fat cells and that this may secondarily encompass other target tissues for insulin, including the impaired glucose transport in the muscles.     

Regulation of insulin receptor substrate-2 tyrosine phosphorylation in animal models of insulin resistance

Insulin induces a wide variety of growth and metabolic responses in many cell types. These actions are initiated by insulin binding to its receptor and involve a series of alternative and complementary pathways created by the multiple substrates of the insulin receptor (insulin receptor substrates [IRSs]). We investigated IRS-1 and IRS-2 tyrosine phosphorylation; their association with phosphatidylinositol-3-OH kinase (PI3-K); and the phosphorylation of Akt, a serine-threonine kinase situated downstream of PI3-K, in liver and muscle of two animal models of insulin resistance: epinephrine- or dexamethasone-treated rats. We used in vivo insulin infusion followed by tissue extraction, immunoprecipitation, and immunoblotting. IRS-1 and IRS-2 protein expression did not change in liver and muscle of the epinephrine-treated rats, but in dexamethasone-treated rats IRS-1 presented an increase in liver and a decrease in muscle tissue. PI3-K and Akt protein expression did not change in liver or muscle of the two animal models of insulin resistance. There was a downregulation in insulin-induced IRS-1 and IRS-2 tyrosine phosphorylation and association with PI3-K in both models of insulin resistance. In parallel, insulin-induced Akt phosphorylation was reduced in both tissues of epinephrine-treated rats, and in liver but not in muscle of dexamethasonetreated rats. The reduction in insulin-induced Akt phosphorylation may help to explain the insulin resistance in liver and muscle of epinephrine-treated rats and in the liver of dexamethasone-treated rats.