腺苷酸活化蛋白激酶与胰岛素抵抗

哺乳动物组织中，腺苷酸活化蛋白激酶（AMPK）是细胞内重要的能量代谢感受器，属于代谢敏感性蛋白激酶家族。它是调节多种代谢过程的重要信号分子，对于糖脂代谢尤有积极的调节作用。有证据表明，在抗糖尿病药物中，二甲双胍和噻唑烷二酮类药物均是通过激活AMPK而发挥胰岛素增敏作用的。     

腺苷酸活化蛋白激酶与胰岛素抵抗

腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK）是一类重要的蛋白激酶,通过改变细胞代谢和调节基因转录恢复细胞ATP水平。AMPK参与了肌肉收缩介导的葡萄糖转运和脂肪酸氧化,抑制肝脏葡萄糖、胆固醇和甘油三酯产生,并具有调节食物摄取和体重的作用。AMPK信号通路是目前具有吸引力的治疗肥胖、胰岛素抵抗、2型糖尿病和其它代谢病的药理靶点。     

LKB1-AMPK信号通路与胰岛素抵抗

腺苷酸活化蛋白激酶（AMP—activated protein kinase，AMPK）广泛存在于各种真核细胞中，被认为是真核生物的“细胞能量调节器”，受AMP／ATP比值的调节。一磷酸腺苷（AMP）与AMPK-7调节亚基相结合，启动上游激酶LKB1磷酸化AMPK一口催化亚基，从而致使AMPK活化，开启分解代谢途径产生ATP，同时关闭合成代谢途径以减少ATP消耗。新近的研究发现二甲双胍类和噻唑烷二酮类（TZDs）抗糖尿病药物可以激活AMPK，     

抵抗素与肝脏胰岛素抵抗的关系

抵抗素是一种脂肪细胞因子,研究发现高抵抗素水平可诱导肝脏胰岛素抵抗发生,其机制可能是抑制腺苷酸活化蛋白激酶(AMPK)磷酸化,上调糖异生关键酶PEPCK和G6Pase的表达促进糖异生,从而使肝糖输出增多。肝脏是胰岛素作用的重要靶点,也是机体代谢的关键器官。肝脏胰岛素抵抗时,糖脂代谢紊乱加重机体胰岛素抵抗,促进2型糖尿病的发生。AMPK是物质代谢的关键激酶,通过磷酸化作用调节糖脂代谢相关酶的活性以及调节机体的能量平衡。抵抗素通过AMPK调节肝糖代谢这一观点为探讨抵抗素在胰岛素抵抗中的作用提供了新的思路。     

脂联素与胰岛素抵抗

脂联素是最近发现的一种脂肪特异性蛋白质、胰岛素、噻唑烷二酮类、β肾上腺能拮抗剂等 ,也参与调节脂联素的分泌与表达 ,动物实验及临床研究均表明 ,脂联素与空腹胰岛素浓度负相关 ,与胰岛素敏感指数正相关 ,罗格列酮治疗可使血浆脂联素明显增加 ,胰岛素敏感性增加。脂联素通过抑制单核细胞黏附 ,减低其细胞周期活性 ,降低血管壁脂蛋白的沉积 ,而抑制动脉硬化过程。     

高糖、不同类型高脂肪酸饮食对老年大鼠胰岛素抵抗及其血清脂联素的影响

目的探讨高糖(HS)及不同类型高脂肪酸饮食对老年大鼠胰岛素抵抗(IR)及其血清脂联素水平的影响。方法用HS、高饱和脂肪酸(HSF)、高不饱和脂肪酸(HUF)饲料饲养大鼠24 w,连续抽血观察其体重、血糖、胰岛素、总胆固醇(TC)、甘油三酯(TG)、游离脂肪酸(FFA)、脂联素的变化,用正葡萄糖高胰岛素钳夹技术的葡萄糖输注率(GIR)评价IR。结果HS、HSF及HUF组大鼠均在第8周出现高胰岛素血症,12 w后GIR明显下降,以HSF下降最低。与同一时期正常对照组(NC)相比,HS组的大鼠分别在第8、12、16周时出现明显的高血糖、FFA和TG升高、血清脂联素水平降低(P<0.05,P<0.01),HSF和HUF组大鼠分别在第8、12周出现明显的高血糖、高FFA(P<0.05,P<0.01);在第20周后出现血清脂联素水平降低(P<0.05)。相关分析表明GIR降低为血清脂联素下降的独立危险因素。结论HS、HUF和HSF饮食长期摄入均可引起大鼠IR,其程度与饮食结构关系密切;血清脂联素的降低与IR有明显相关性。     

脂联素与胰岛素抵抗

脂肪组织是重要的内分泌器官,能以旁分泌、自分泌和内分泌方式产生生物活性因子或因子样分子,称为脂肪细胞因子,包括肿瘤坏死因子α(tumor necrosis factorα,TNF-α)、     

老年大鼠骨骼肌腺苷酸活化蛋白激酶对胰岛素敏感性的影响

胰岛素抵抗（insulin resistanse IR）是2型糖尿病的主要发病机制和心血管疾病的危险因素。随着年龄的增长,IR和2型糖尿病的发生呈增高趋势,但年龄相关的IR发生的确切机制仍不清楚。有研究表明,腺苷酸活化蛋白激酶（AMPK）通过使其下游酶的磷酸化,在提高脂肪酸氧化方面起了关键作用。我们于2006年10月至2007年2月观察了老年大鼠骨骼肌AMPKα表达和活性，探讨其在脂质堆积和IR中的作用。     

血浆脂联素与2型糖尿病胰岛素抵抗关系的研究

目的　测定 2型糖尿病患者血浆脂联素的水平 ,并分析它与体重指数、血糖、胰岛素、血脂和胰岛素抵抗的关系 ,从而探讨脂联素在糖尿病发病中的作用。方法　健康对照组 2 8例 ,2型糖尿病组 60例 ,根据体重指数又将糖尿病组分为非肥胖糖尿病组 3 0例 (BMI <2 5kg/m2 )和肥胖糖尿病组 3 0例 (BMI >2 5kg/m2 )。用ELISA方法检测空腹血浆脂联素浓度 ,同时测定各组的空腹血糖、胰岛素、血脂的水平 ;根据HOMA模型提出的公式 ,计算分析胰岛素抵抗指数 ,并分析各指标间的相关性。结果　 (1)糖尿病各组血浆脂联素的水平明显低于正常对照组 ,且肥胖糖尿病组脂联素的水平低于非肥胖组 ,差异均有显著性 (P 0 .0 1) ;(2 )血浆脂联素浓度与体重指数、空腹胰岛素、胰岛素抵抗指数 (IR)、甘油三酯呈显著负相关。结论　脂联素参与了胰岛素抵抗的发生过程 ,与糖尿病的发生发展密切相关 ;脂联素可作为评价胰岛素抵抗程度的一种新的敏感指标     

脂联素与炎症及胰岛素抵抗关系的研究进展

胰岛素抵抗是由免疫系统介导的慢性、非特异性炎症过程。而脂联素具有抗炎、促炎的双重作用。其与炎症因子的相互作用可能是脂联素增强胰岛素敏感性的机制之一,也可能是胰岛素抵抗时低脂联素血症的原因。对脂联素与炎症、胰岛素抵抗关系的研究可为胰岛素抵抗的治疗提供新的思路。     

Epigallocatechin-3-O-gallate (EGCG) attenuates FFAs-induced peripheral insulin resistance through AMPK pathway and insulin signaling pathway in vivo

We aimed to investigate the effects and possible mechanisms of Epigallocatechin-3-O-gallate (EGCG) on free fatty acids (FFAs)-induced peripheral insulin resistance in vivo. Overnight-fasted Wistar rats were subjected to 48-h intravenous infusion of either saline or Intralipid plus heparin (IH) with or without different doses of EGCG co-injection. Hyperinsulinemic-euglycemic clamp was performed in awake rats to assess peripheral insulin sensitivity. Co-injection with EGCG significantly prevented FFAs-induced peripheral insulin resistance, decreased plasma markers of oxidative stress: malondialdehyde (MDA) and 8-isoprostaglandin, and increased antioxidant enzymes: superoxide dismutases (SOD) and Glutathione peroxidase (GPx). Furthermore, EGCG treatment reversed IH-induced: (1) decrease in Thr172 phosphorylation of AMP activated protein kinase (AMPK); (2) increase in protein kinase Cθ(PKCθ) membrane translocation and Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1); (3) decrease in Ser473 phosphorylation of Akt and Glucose transporter 4 (GLUT4) translocation in skeletal muscle and adipose tissue. Our data suggest that EGCG treatment ameliorated FFAs-induced peripheral insulin resistance in vivo, and this might be through decreasing oxidative stress and PKCθ membrane translocation, activating the AMPK pathway and improving insulin signaling pathway in vivo. This study suggests the therapeutic value of EGCG in protecting from insulin resistance caused by elevated FFAs.     

非酒精性脂肪肝与血清脂联素及胰岛素抵抗的关系

NAFLD通常与超重或肥胖、2型糖尿病、高血压和高脂血症等代谢紊乱有关,胰岛素抵抗可能在脂肪肝形成过程中起重要作用。而脂联素作为一种新发现的由脂肪细胞分泌的激素,具有降低血脂、降低血糖、改善胰岛素敏感性以及拮抗动脉粥样硬化的作用,能拮抗胰岛素低抗。但是目前这     

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin

Aims/hypothesis Thiazolidinediones can enhance clearance of whole-body non-esterified fatty acids and protect against the insulin resistance that develops during an acute lipid load. The present study used [³H]-R-bromopalmitate to compare the effects of the thiazolidinedione, rosiglitazone, and the biguanide, metformin, on insulin action and the tissue-specific fate of non-esterified fatty acids in rats during lipid infusion.Methods Normal rats were treated with rosiglitazone or metformin for 7 days. Triglyceride/heparin (to elevate non-esterified fatty acids) or glycerol (control) were then infused for 5 h, with a hyperinsulinaemic clamp being performed between the 3rd and 5th hours.Results Rosiglitazone and metformin prevented fatty-acid-induced insulin resistance (reduced clamp glucose infusion rate). Both drugs improved insulin-mediated suppression of hepatic glucose output but only rosiglitazone enhanced systemic non-esterified fatty acid clearance (plateau plasma non-esterified fatty acids reduced by 40%). Despite this decrease in plateau plasma non-esterified fatty acids, rosiglitazone increased fatty acid uptake (two-fold) into adipose tissue and reduced fatty acid uptake into liver (by 40%) and muscle (by 30%), as well as reducing liver long-chain fatty acyl CoA accumulation (by 30%). Both rosiglitazone and metformin increased liver AMP-activated protein kinase activity, a possible mediator of the protective effects on insulin action, but in contrast to rosiglitazone, metformin had no significant effect on non-esterified fatty acid kinetics or relative tissue fatty acid uptake.Conclusions/interpretation These results directly demonstrate the lipid steal mechanism, by which thiazolidinediones help prevent fatty-acid-induced insulin resistance. The contrasting mechanisms of action of rosiglitazone and metformin could be beneficial when both drugs are used in combination to treat insulin resistance.Abbreviations AMPK AMP-activated protein kinase - ¹⁴C-2DG [¹⁴C]-2-deoxyglucose - GIR glucose infusion rate - HGO hepatic glucose output - LCACoA long-chain fatty acyl CoA - PPAR peroxisome proliferator-activated receptor - TZDs thiazolidinediones     

非酒精性脂肪性肝病患者血清瘦素和脂联素与胰岛素抵抗的关系

目的 探讨非酒精性脂肪性肝病(NAFLD)患者血清瘦素、脂联素的变化及其与胰岛素抵抗的关系. 方法 选取NAFLD患者60例,同期门诊体检健康者60名为对照组,ELJSA法测定血清瘦素、脂联素水平,并检测体质量指数、腰臀比、甘油三酯、总胆固醇、高密度脂蛋白胆固醇(HDL-C)、空腹血糖、ALT、AST、γ-谷氨酰转肽酶(GGT),稳态模型评估的胰岛素抵抗指数(HOMA-IR).采用SPSS10.0软件包进行统计学分析,计量资料差异性比较用方差分析和t检验,多因素相关性用Spearman分析和Logistic回归分析. 结果 血清瘦素、脂联素水平NAFLD组分别为(12.37±1.99)μg/L和(12.69±2.83)mg/L,对照组分别为(5.20±1.03)μg/L和(22.83±4.61)mg/L,t值分别为24.661和14.516,P值均<0.01;HOMA-IR,NAFLD组为4.86±0.63,对照组为1.91±0.41,t值为30.451,P<0.01.Logistic多因素回归分析显示瘦素与腰臀围之比、HOMA-IR、空腹血糖呈独立正相关,β值分别为8.175、0.974和0.564,P值均<0.01;脂联素与HOMA-IR、体质量指数呈独立负相关,β值分别为-0.495和-0.314,P值均<0.01.结论 NAFLD患者血清瘦素、脂联素的变化与胰岛素抵抗有关.     

非酒精性脂肪肝患者胰岛素抵抗与脂联素基因表达的关系

目的探讨NAFLD患者胰岛素抵抗（IR）与脂肪组织脂联素基因表达的关系。方法用SYBR GreenI实时定量RT-PCR方法检测脂肪组织脂联素mRNA的表达水平，用稳态模型法计算IR指数。结果肥胖和非肥胖NAFLD患者及对照组IR指数分别为：3．0±0．8、2．8±0．9和2．0±0．6、1．2±0．5，其脂肪组织脂联素基因表达和血浆脂联素浓度较对照各组显著降低（P〈0．05），IR与脂联素基因表达（r=0．5，P〈0．05）和血浆脂联素浓度负相关（，=0．4，P〈0．05），与血清甘油三酯正相关（r=0．3，P〈0．05）。结论NAFLD患者的IR与脂肪组织脂联素基因低表达有关，脂联素基因低表达在IR和NAFLD发病中起了一定作用。     

脂毒性及其防治的一个关键靶点——AMPK

当过多摄人的能量超出了脂肪组织的贮存容量时,脂质溢出进入胰腺、肝脏及骨骼肌等非脂肪组织贮存,诱发胰岛素抵抗,损伤胰岛β细胞功能,导致2型糖尿病及其并发症的发生。运动,饮食控制及激活“代谢总开关”一磷酸腺苷活化蛋白激酶(AMPK)的药物,二甲双胍、罗格列酮可促进外周组织的脂质氧化,降低脂质的异位堆积,阻止或延缓2型糖尿病的发生。因此,AMPK可能成为防治脂毒性的关键靶点。     

Effects of resistin expression on glucose metabolism and hepatic insulin resistance

In order to observe the effect of increased serum resistin on glucose metabolism, insulin sensitivity, and hepatic insulin resistance (IR), mice were intravenously injected with recombinant adenovirus carrying the resistin gene (Adv-resistin-EGFP). Changes in hepatic glucose metabolism were observed using the Periodic Acid-Schiff method. Hepatic AMP-activated protein kinase (AMPK) activation was assessed by Western blot analysis, and glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was determined using real-time RT-PCR. Although no effect on fasting blood glucose was detected, increased fasting insulin levels, decreased glucose tolerance and insulin sensitivity, and reduced hepatic glycogen levels and AMPK activation were seen in the Adv-resistin-EGFP mice. Finally, elevated G6Pase and PEPCK mRNA expression levels were detected upon overexpression of resistin. Resistin may inhibit hepatic AMPK activity, which results in elevated expression of gluconeogenic enzymes thereby affecting glucose metabolism and leading to decreased glycogen storage that contributes to the development of hepatic IR.