肝脏胰岛素信号通路对改善胰岛素抵抗的影响

<正>胰岛素抵抗(Insulin resistance,IR)是引起人体一系列代谢综合征的一种常见病理基础[1],容易导致肥胖、高血压、高血脂、葡萄糖耐量受损以及2型糖尿病(Type 2 diabetes mellitus,T2DM)等症状的产生[2]。T2DM又是一种由胰岛素敏感性降低,胰岛β细胞功能异常[3],胰岛素抵抗等引起的代谢紊乱性疾病[4]。目前全球约有超过3.7亿人口患有不同程度的糖尿     

胰岛素对新生大鼠缺氧/复氧诱导心肌细胞凋亡的影响

目的探讨胰岛素对缺氧/复氧所诱导心肌细胞凋亡的影响及其机制。方法通过给原代培养乳鼠心室肌细胞行缺氧2h/复氧4h,建立缺氧/复氧(anoxia/reoxygenation)心肌细胞损伤模型。于复氧期开始随机给予0.9%生理盐水(VC组)、胰岛素(INS组)、LY294002(LY组)、胰岛素 LY294002(INS LY组)干预。于复氧4h后,利用2,4二硝基苯肼显色法检测乳酸脱氢酶(LDH)活性,硫代巴比妥酸显色法检测丙二醛(MDA)含量,原位末端标记法(TUNEL)和DNA梯带法(DNALadder)标测细胞凋亡,免疫印迹法(Westernblotting)检测磷酸化Akt表达,并比较各组间差异。结果与VC组相比,INS组中LDH活性、MDA含量、凋亡指数(AI)显著降低(P<0.01),磷酸化Akt表达明显增加(P<0.01);但上述指标变化可被LY294002(PI3K抑制剂)所抑制。结论在复氧早期给予胰岛素干预可显著地减少缺氧/复氧所诱导的心肌细胞凋亡,其保护机制与PI3K/Akt所介导的抗细胞凋亡作用有关。     

肝硬化患者胰岛素抵抗与血清生长激素、胰岛素样生长因子I轴的研究

目的研究肝硬化(LC)患者胰岛素抵抗指数(HOMA-IRI)、生长激素(GH)和胰岛素样生长因子I( IGF-I)水平的变化,探讨肝硬化发病中胰岛素抵抗(IR)、GH/IGF-I轴的作用以及对预后的影响.方法测定住院人群中LC组和对照组空腹血糖(FBG)、空腹血清胰岛素(FINS),采用稳态模型法计算HOMA-IRI,同时检测GH和IGF-I水平.结果①LC组FINS、IRI和血清GH水平显著高于对照组,IGF-Ⅰ水平显著低于对照组(P《0.05);②按Child-Pugh分级,肝硬化C级的FINS、IRI和GH水平显著高于肝硬化A、B级,IGF-Ⅰ显著低于肝硬化A、B级(P《0.05);肝硬化B级IRI、GH水平显著高于肝硬化A级, IGF-Ⅰ显著低于肝硬化A级(P《0.05);③肝炎后肝硬化组FINS、IRI和GH水平显著高于酒精性肝硬化组,IGF-Ⅰ水平显著低于酒精性肝硬化组(P《0.05);④肝硬化患者Child-Pugh积分与FINS、IRI、GH水平呈正相关(r=0.2772,P《0.01;r=0.1853,P《0.05;r=0.3231,P《0.01),但与IGF-Ⅰ水平呈负相关(r=-0.2487,P《0.05);IRI与GH水平呈正相关(r=0.2582,P《0.01),与IGF-Ⅰ水平呈负相关(r=-0.1948,P《0.05).结论肝硬化患者存在着胰岛素抵抗和GH/IGF-Ⅰ轴异常,胰岛素抵抗和GH/IGF-Ⅰ轴异常可能参与了肝硬化的病情进展并和肝功能损害程度直接相关;检测肝硬化患者血清FINS、IRI、GH和IGF-Ⅰ水平,可以作为判断肝功能分级和预后的重要指标.     

PI3K/Akt信号传导通路与肿瘤多药耐药研究进展

磷脂酰肌醇3-激酶/蛋白激酶B[phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt),PI3K/Akt]信号传导通路作为细胞生存重要通路之一,在促进细胞生长、增殖,促进细胞运动、侵袭,抑制细胞凋亡,促进血管生成,抵抗化疗和放疗等方面起重要作用.近年来,关于PI3K/Akt 信号通路与药物耐药性关系的研究越来越多,并被认为是化疗耐药治疗的新靶点.Akt是PI3K/Akt 通路中的关键性效应分子,多种肿瘤组织中都有Akt 的过度表达和活化.多项实验表明,化疗药物可增加Akt 磷酸化水平,使肿瘤细胞产生化疗耐受,深入研究其作用机制,可能为肿瘤的基因治疗、抗肿瘤药物开发提供新靶点.     

生长激素对体外培养大鼠胰岛的促胰岛素释放功能的影响

【目的】探讨生长激素(GH)对体外培养大鼠胰岛的胰岛素释放功能的影响。【方法】对体外培养大鼠胰岛进行形态学观察及鉴定,分正常对照组及GH干预组,进行胰岛素含量测定及胰岛素释放试验。【结果】HG干预组胰岛培养6d后培养液中胰岛素总量显著高于正常对照组(P<0.05),在低糖及高糖条件刺激下的胰岛素释放量均显著高于正常对照组(P<0.05),两组间的胰岛素释放指数无统计学差异。【结论】GH对体外培养大鼠胰岛的胰岛素释放具促进作用,可能并不会因此加速胰岛功能的衰竭。为进一步探讨GH促进永生化后回复的胰岛细胞功能的恢复,提供了前期实验基础。     

肝硬化患者胰岛素抵抗与血清生长激素、胰岛素样生长因子Ⅰ轴的研究

目的：研究肝硬化（LC）患者胰岛素抵抗指数（HOMA-IRI）、生长激素（GH）和胰岛素样生长因子Ⅰ（IGF-Ⅰ）水平的变化，探讨肝硬化发病中胰岛素抵抗（IR）、GH／IGF-Ⅰ轴的作用以及对预后的影响。方法：测定住院人群中LC组和对照组空腹血糖（FBG）、空腹血清胰岛素（FINS），采用稳态模型法计算HOMA-IRI，同时检测GH和IGF-Ⅰ水平。结果：①LC组FINS、IRI和血清GH水平显著高于对照组，IGF-Ⅰ水平显著低于对照组（P〈0．05）；②按Child-Pugh分级，肝硬化C级的FINS、IRI和GH水平显著高于肝硬化A、B级，IGF-Ⅰ显著低于肝硬化A、B级（P〈0．05）；肝硬化B级IRI、GH水平显著高于肝硬化A级，IGF-Ⅰ显著低于肝硬化A级（P〈0．05）；③肝炎后肝硬化组FINS、IRI和GH水平显著高于酒精性肝硬化组，IGF-Ⅰ水平显著低于酒精性肝硬化组（P〈0．05）；④肝硬化患者Child-Pugh积分与FINS、IRI、GH水平呈正相关（r=0．2772，P〈0．01；r=0．1853，P〈0．05；r=0．3231，P〈0．01），但与IGF-Ⅰ水平呈负相关（r=0．2487，Pd0．05）；IRI与GH水平呈正相关（r=0．2582，P〈0．01），与IGF-Ⅰ水平呈负相关（r=0．1948，P〈0．05）。结论：肝硬化患者存在着胰岛素抵抗和GH／IGF-I轴异常，胰岛素抵抗和GH／IGF-Ⅰ轴异常可能参与了肝硬化的病情进展并和肝功能损害程度直接相关；检测肝硬化患者血清FINS、IRI、GH和IGF-Ⅰ水平，可以作为判断肝功能分级和预后的重要指标。     

PI3K/Akt信号传导途径——多发性骨髓瘤治疗的新靶点

PI3K/Akt途径是细胞内重要信号转导通路,它通过影响下游凋亡蛋白、细胞周期调节蛋白等效应分子的活化过程,对细胞内抑制凋亡、促进增殖发挥关键作用.PI3K/Akt通路分子的基因突变,或上游调控基因PTEN的调节,均可导致该通路过度激活、细胞生存与凋亡失衡及正常细胞发生恶性转化.研究发现PI3K/Akt途径对多发性骨髓瘤细胞的重要影响因子白细胞介素6和胰岛素样生长因子-1均有显著作用,并且该途径下游靶基因mTOR,p53、NF-кB和BAD等在多发性骨髓瘤细胞株中均发挥作用.新型的通路抑制剂已进入临床试验,抑制该信号通路成为肿瘤预防和靶向治疗及逆转耐药的热点.本文就PI3K/Akt信号转导途径及其在多发性骨髓瘤中的靶向治疗机制和针对该途径出现的治疗药物作一综述.     

抑制PI3K/Akt信号通路提高膀胱癌化疗效果的实验研究

目的:探讨通过抑制Akt信号通路提高抗癌药物紫杉醇对膀胱癌T-24的杀伤作用。方法:采用MTT法检测Akt抑制剂鱼藤素、紫杉醇单独以及两药联合应用对T-24细胞的增殖抑制率,采用流式细胞术(FCM)检测药物单独或联合作用对细胞周期的影响。结果:联合鱼藤素能够显著提高紫杉醇对T-24细胞的增殖抑制率(P<0.01),协同治疗指数<1,具有协同治疗作用;FCM结果显示联合鱼藤素使细胞阻滞在G0/G1期的比例增加,S期比例减少,与对照组比较,差异有统计学意义(P<0.05)。结论:抑制Akt信号通路能够显著提高紫杉醇对膀胱癌T-24细胞的杀伤作用。     

PI3K/Akt信号通路在肝脏缺血再灌注损伤中的研究进展

肝脏缺血再灌注损伤是导致术后肝脏功能延迟恢复和功能障碍的重要原因。有研究表明,PI3K/Akt信号通路在缺血和再灌注的过程中被激活,通过抑制或增强下游相关靶蛋白的表达发挥对肝脏的保护作用。因此,PI3K/Akt信号成为预防和改善肝脏缺血再灌注损伤的重要靶向通路。本文就PI3K/Akt信号通路在肝脏缺血再灌注损伤中作用的研究进展进行综述。     

PI3K/Akt信号通路与脑出血的研究进展

磷脂酰激醇3-激酶（PI3K）/蛋白激酶B（Akt）信号通路作为经典的细胞信号转导途径,在细胞生长、增殖、分化和凋亡等多种生物学过程中发挥作用。脑出血是一种高致残率和高致死率的脑血管疾病,该通路在脑出血发生发展中的研究也备受关注。该文以PI3K/Akt信号通路为主线,对该通路的结构及生物学特点、与脑出血之间的关系以及基于该通路探讨药物对脑出血的作用进行综述,为临床脑出血的治疗提供新的思路。     

On the diabetogenic effect of growth hormone in man: effects of growth hormone on glucagon and insulin secretion

Abstract. The effects of human growth hormone (GH) on glucose homeostasis and the secretion of insulin and glucagon was investigated in eighteen healthy subjects. GH (40 μg/kg) was given as a 30 min i.v. infusion and was followed immediately, or after 60 min, by either a glucose infusion, or an i.v. L-arginine infusion or i.v. insulin (005 IU/kg).
An insulin-like effect of GH was seen about 15 min after the start of the GH infusion, and became a diabetogenic action 90 min later. Basal and glucose stimulated insulin secretion were suppressed 60 min after the start of the GH infusion, while insulin response to i.v. L-arginine, on the whole, was uninfluenced. Basal glucagon as well as glucagon response to arginine or hypoglycaemia were uninfluenced by GH. GH did not alter the degree of hypoglycaemia reached after i.v. insulin, whereas the rapidity of blood glucose fall was significantly decreased. The restitution of blood glucose after its nadir was not modified by the hormone.
These results demonstrate that the diabetogenic action of GH is not mediated by GH effects on glucagon secretion, and that GH is of little importance in the acute counter-regulation of insulin-induced hypoglycaemia.     

Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice

Skeletal muscle development, nutrient uptake, and nutrient utilization is largely coordinated by growth hormone (GH) and its downstream effectors, in particular, IGF-1. However, it is not clear which effects of GH on skeletal muscle are direct and which are secondary to GH-induced IGF-1 expression. Thus, we generated mice lacking either GH receptor (GHR) or IGF-1 receptor (IGF-1R) specifically in skeletal muscle. Both exhibited impaired skeletal muscle development characterized by reductions in myofiber number and area as well as accompanying deficiencies in functional performance. Defective skeletal muscle development, in both GHR and IGF-1R mutants, was attributable to diminished myoblast fusion and associated with compromised nuclear factor of activated T cells import and activity. Strikingly, mice lacking GHR developed metabolic features that were not observed in the IGF-1R mutants, including marked peripheral adiposity, insulin resistance, and glucose intolerance. Insulin resistance in GHR-deficient myotubes derived from reduced IR protein abundance and increased inhibitory phosphorylation of IRS-1 on Ser 1101. These results identify distinct signaling pathways through which GHR regulates skeletal muscle development and modulates nutrient metabolism.     

The effect of administration of human growth hormone on the plasma growth hormone, cortisol, glucose, and free fatty acid response to insulin: evidence for growth hormone autoregulation in man

The effect of administration of human growth hormone (HGH) (3 mg every 6 hr for 6 days) on the endogenous GH response to insulin-induced hypoglycemia at 8, 12, 24, and 48 hr posttreatment was studied in 11 healthy male adults. Free fatty acid, cortisol, and glucose responses pre- and posttreatment with HGH were evaluated concurrently. Control subjects received saline injections to evaluate relationship of GH responses to the periodicity of insulin tolerance tests. The data were compared for each subject pre- and posttreatment with HGH as well as by comparison of the results of the saline-treated group with those of the HGH-treated group.The mean maximal GH concentration in response to insulin-induced hypoglycemia for all the subjects (n = 16) was 31.1 +/-3.6 ng/ml (+/-SEM) on day 1 of the control period and 23.4 +/-3.1 (SEM) on day 2, not statistically significant.A significant decrease in the maximal peak GH response (n = 8) after insulin-induced hypoglycemia was observed at 8 and 12 hr after HGH administration was terminated with mean peak values for GH of 4.6 +/-1.3 ng/ml and 10.4 +/-1.9 ng/ml, respectively (P < 0.01). A progressive return to control values was noted between 12 and 24 hr. The GH responsiveness of the saline-treated group (n = 5) was unchanged from that observed during the control period.The fasting glucose values were unchanged in the GH-treated group from those of the control period or of the saline-treated controls. Insulin resistance was apparent at 8 hr posttreatment with HGH. No differences in FFA response after insulin-induced hypoglycemia were observed in GH-treated or saline-treated subjects. The rise in plasma cortisol after insulin-induced hypoglycemia was comparable in the GH-treated and saline-treated group. Diurnal variation in plasma cortisol was maintained during the period of GH suppression.These observations support the concept that GH can modulate its secretion by means of an auto-feedback mechanism.     

Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice

Liver IGF-1-deficient (LID) mice have a 75% reduction in circulating IGF-1 levels and, as a result, a fourfold increase in growth hormone (GH) secretion. To block GH action, LID mice were crossed with GH antagonist (GHa) transgenic mice. Inactivation of GH action in the resulting LID + GHa mice led to decreased blood glucose and insulin levels and improved peripheral insulin sensitivity. Hyperinsulinemic-euglycemic clamp studies showed that LID mice exhibit severe insulin resistance. In contrast, expression of the GH antagonist transgene in LID + GHa mice led to enhanced insulin sensitivity and increased insulin-stimulated glucose uptake in muscle and white adipose tissue. Interestingly, LID + GHa mice exhibit a twofold increase in white adipose tissue mass, as well as increased levels of serum-free fatty acids and triglycerides, but no increase in the triglyceride content of liver and muscle. In conclusion, these results show that despite low levels of circulating IGF-1, insulin sensitivity in LID mice could be improved by inactivating GH action, suggesting that chronic elevation of GH levels plays a major role in insulin resistance. These results suggest that IGF-1 plays a role in maintaining a fine balance between GH and insulin to promote normal carbohydrate and lipid metabolism.