2型糖尿病患者噻唑烷二酮类药物疗效差异性的分析

临床研究表明,2型糖尿病患者噻唑烷二酮类药物疗效具有差异性,其差异性的原因可能与过氧化物酶体增殖物活化受体γ(PPARγ)、PPARγ协同刺激因子、脂联素、解耦联蛋白2、β3肾上腺素能受体基因、视黄醇结合蛋白4、细胞色素酶、脂素基因1等基因多态性相关,但是目前尚无一致性结论.目前国内、外关于PPARγ、PPARγ共激活因子、脂联素基因多态性与2型糖尿病患者噻唑烷二酮类药物疗效差异性的研究较多.     

脂联素与代谢综合征

脂联素 (adiponectin)是脂肪细胞特异性的一种血浆激素蛋白 ,其基因定位于 3q2 7。脂联素与肥胖、2型糖尿病、胰岛素抵抗、动脉粥样硬化以及糖尿病的血管病变等都有一定的相关性 ,在X综合征的发病过程中可能起着重要的作用 ,补充脂联素可能为胰岛素抵抗及 2型糖尿病的治疗提供一种手段。脂联素在血细胞形成和免疫反应中发挥负调控作用。过氧化物酶体增殖物激活受体γ(PPARγ)配基增加脂联素的表达及其在血浆中的浓度     

脂联素与代谢综合征

脂联素（adiponectin)是脂肪细胞特异性的一种血浆激素蛋白，其基因定位于3q27。脂联素与肥胖、2型糖尿病、胰岛素抵抗、动脉粥样硬化以及糖尿病的血管病变等都有一定的相关性，在X综合征的发病过程中 可能起着重要的作用，补充脂联素可能为胰岛素抵抗及2型糖尿病的治疗提供一种手段。脂联素在血细胞形成和免疫反应中发挥负调控作用。过氧化物酶体增殖物激活受体γ（PPARγ）配基增加脂联素的表达及其在血浆中的浓度。     

2型糖尿病合并肥胖患者脂联素水平与胰岛素抵抗的相关性

目的 研究2型糖尿病合并肥胖患者脂联素水平和胰岛素抵抗之间的相关性,探讨脂联素在2型糖尿病合并肥胖患者发生胰岛素抵抗中的作用.方法 选择30例2型糖尿病合并肥胖患者、25例2型糖尿病患者及25例非糖尿病对照人员(其中13例为肥胖者),检测体质指数、腰/臀比值、空腹血糖、糖化血红蛋白、血清空腹胰岛素、血脂、脂联素水平,计算胰岛素抵抗指数和胰岛素敏感指数.分析血清脂联素与胰岛素抵抗的相关性.结果 (1)糖尿病肥胖组的检测体质指数、糖化血红蛋白、空腹血糖、胰岛素抵抗指数、血清空腹胰岛素、腰/臀比值均高于对照肥胖组,脂联素、胰岛素敏感指数低于对照肥胖组(P<0.05).(2)糖尿病非肥胖组甘油三酯、糖化血红蛋白、空腹血糖、胰岛素抵抗指数、血清空腹胰岛素均高于对照非肥胖组,胰岛素敏感指数、脂联素低于对照非肥胖组(P<0.05).(3)糖尿病肥胖组甘油三酯、胆固醇、体质指数、糖化血红蛋白、空腹血糖、胰岛素抵抗指数、血清空腹胰岛素、腰/臀比值均高于糖尿病非肥胖组,胰岛素敏感指数、脂联素低于糖尿病非肥胖组(P<0.05).结论 脂联素与2型糖尿病肥胖患者的胰岛素抵抗发生有关,脂联素降低易导致胰岛素抵抗,脂联素水平可作为2型糖尿病合并肥胖患者发生胰岛素抵抗的监测标准.     

脂联素抵抗研究进展

脂联素与脂联素受体结合,经多种信号转导途径发挥改善胰岛素抵抗、调节糖脂代谢、负性调控炎性反应以及拮抗动脉粥样硬化的作用.一些病理牛理过程中脂联素水平升高,但没有显著保护性效应,提示存在脂联素抵抗.脂联素抵抗的机制包括脂联素聚合能力改变、脂联素受体(AdipoRs)表达减少及脂联素受体后AMP活化蛋白激酶(AMPK)、过氧化物酶体增殖物活化受体(PPAR)α等信号通路转导障碍.高血糖、肥胖、胰岛素抵抗等与脂联素抵抗密切相关,可以互为因果,形成恶性循环.     

脂肪组织分泌功能研究进展

脂肪组织是一个内分泌器官，分泌的细胞因子通过自分泌、旁分泌和血液循环的方式作用于远处的靶器官。在肥胖、胰岛素抵抗和2型糖尿病发病机制中发挥重要作用。本文综述禁食诱导脂肪因子、酰化刺激蛋白、脂联素、抵抗素、肿瘤坏死因子α和白介素-6研究进展。     

Cdk5与替米沙坦2型糖尿病预防作用的关系

细胞周期素依赖性蛋白激酶(Cdk)5介导的过氧化物酶体增殖物活化受体(PPAR)γ磷酸化通过干扰脂联素等胰岛素敏感性相关细胞因子的基因表达,引起胰岛素抵抗并最终引发2型糖尿病.替米沙坦一方面通过改变PPARγ的蛋白构象使其273位丝氨酸不能与Cdk5结合来调控PPARγ功能;另一方面,作为抑制血管紧张素Ⅱ1型受体阻断剂...     

胰岛素对高脂诱导胰岛素抵抗L6细胞固醇调节元件结合蛋白-1c表达的影响

目的 探讨胰岛素对高脂诱导胰岛素抵抗的骨骼肌细胞脂代谢及相关基因、蛋白表达的影响和机制.方法 L6成肌细胞诱导分化后行棕榈酸干预建立胰岛素抵抗模型,胰岛素干预后,分别检测3组脂代谢相关基因和蛋白表达的变化.结果 与对照组比较,高脂组诱导胰岛素抵抗后,固醇调节元件结合蛋白(SREBP)-1c mRNA和蛋白水平明显升高,IRS-1 mRNA和蛋白水平明显降低.胰岛素干预后,SREBP-1c表达下降,IRS-1表达升高.3组中肿瘤坏死因子(TNF)-α、stat3 mRNA表达无明显变化.结论 高脂诱导骨骼肌胰岛素抵抗下,胰岛素干预可能通过影响脂质代谢通路中关键的转录因子改善胰岛素抵抗.     

脂联素：心血管疾病新的危险预测因子

脂联素是脂肪组织特异性分泌的一种激素蛋白,众多研究表明其具有抗动脉粥样硬化、抗炎、改善胰岛素抵抗等作用.在冠心病、胰岛素抵抗、高脂血症、2型糖尿病和肥胖等疾病及存在胰岛素抵抗的病人中,脂联素水平明显下降,低脂联素可作为动脉粥样硬化的新型危险因子,同时是代谢综合征的独立危险因子和生物标记,高脂联素血症可能是充血性心力衰竭一个独立的预后预测因子.脂联素水平越高其预后越差.现综述了现阶段脂联素与心血管代谢疾病的最新研究进展.     

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     

Lipin与糖脂代谢

Lipin基因的表达产物是一组胞内蛋白质,介导生成胞内甘油三酯合成和糖异生关键酶的辅激活因子。Lipin主要分布在脂肪、骨骼肌、肝脏、下丘脑等代谢旺盛的组织和器官。Lipin家族主要包括lipin1、lipin2与lipin3,能够双向调控机体脂代谢,还与机体胰岛素抵抗、糖代谢异常密切相关,可能成为治疗肥胖及糖、脂代谢紊乱相关疾病的外周新靶点。     

Regulation of peroxisome proliferator activated receptor α-mediated pathways in alcohol fed cytochrome P450 2E1 deficient mice

Fatty acids are substrates and inducers for cytochrome P450 2E1 (CYP2E1) and peroxisome proliferator activated receptor α (PPARα). Previously, we have shown that the ethanol-induced CYP2E1 expression in rat is accompanied by the inhibition of the expression of the PPARα gene and the reduction in polyunsaturated fatty acid content. To further analyze the effect of CYP2E1 and ethanol in PPARα-mediated fatty acid homeostasis, the expression of PPARα and retinoid x receptor α (RXRα) and their target genes was examined in ethanol fed CYP2E1 deficient mice. Our data demonstrated that the expression of PPARα and RXRα genes was activated in the livers of CYP2E1-null mice suggesting a compensatory effect for the absence of CYP2El. In addition, the expression of PPARα target genes, which included the liver fatty acid-binding protein, malic enzyme, and CYP4A1 genes, was induced indicating the activation of PPARα-mediated pathways in CYP2E1 deficient mice. Ethanol inhibited the expression of some of the PPARα target genes in wild-type mouse livers, and the inhibitory effect of ethanol was particularly prominent in the CYP2E1-null mice. Morphologically, centrilobular fat accumulation was detected in the ethanol fed CYP2E1-null mouse livers suggesting that inhibition of PPARα-mediated pathways might be responsible for the ethanol-induced fatty liver in CYP2El-null mice. In addition, the expression of CYP2E1 was not changed in the PPARα-null mice. These data suggest that CYP2E1 and ethanol can regulate PPARα-mediated fatty acid homeostasis. CYP2E1-induced lipid peroxidation might play a major role in lipid metabolism, PPARα only becomes important when the CYP2E1 level is low and polyunsaturated fatty acids increase.     

The PPARβ/δ activator GW501516 prevents the down-regulation of AMPK caused by a high-fat diet in liver and amplifies the PGC-1α-Lipin 1-PPARα pathway leading to increased fatty acid oxidation

Metabolic syndrome-associated dyslipidemia is mainly initiated by hepatic overproduction of the plasma lipoproteins carrying triglycerides. Here we examined the effects of the peroxisome proliferator-activated receptors (PPAR)-β/δ activator GW501516 on high-fat diet (HFD)-induced hypertriglyceridemia and hepatic fatty acid oxidation. Exposure to the HFD caused hypertriglyceridemia that was accompanied by reduced hepatic mRNA levels of PPAR-γ coactivator 1 (PGC-1)-α and lipin 1, and these effects were prevented by GW501516 treatment. GW501516 treatment also increased nuclear lipin 1 protein levels, leading to amplification in the PGC-1α-PPARα signaling system, as demonstrated by the increase in PPARα levels and PPARα-DNA binding activity and the increased expression of PPARα-target genes involved in fatty acid oxidation. These effects of GW501516 were accompanied by an increase in plasma β-hydroxybutyrate levels, demonstrating enhanced hepatic fatty acid oxidation. Moreover, GW501516 increased the levels of the hepatic endogenous ligand for PPARα, 16:0/18:1-phosphatidilcholine and markedly enhanced the expression of the hepatic Vldl receptor. Interestingly, GW501516 prevented the reduction in AMP-activated protein kinase (AMPK) phosphorylation and the increase in phosphorylated levels of ERK1/2 caused by HFD. In addition, our data indicate that the activation of AMPK after GW501516 treatment in mice fed HFD might be the result of an increase in the AMP to ATP ratio in hepatocytes. These findings indicate that the hypotriglyceridemic effect of GW501516 in HFD-fed mice is accompanied by an increase in phospho-AMPK levels and the amplification of the PGC-1α-lipin 1-PPARα pathway.     

Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum

The three lipin phosphatidate phosphatase (PAP) enzymes catalyze a step in glycerolipid biosynthesis, the conversion of phosphatidate to diacylglycerol. Lipin-1 is critical for lipid synthesis and homeostasis in adipose tissue, liver, muscle, and peripheral nerves. Little is known about the physiological role of lipin-2, the predominant lipin protein present in liver and the deficient gene product in the rare disorder Majeed syndrome. By using lipin-2-deficient mice, we uncovered a functional relationship between lipin-1 and lipin-2 that operates in a tissue-specific and age-dependent manner. In liver, lipin-2 deficiency led to a compensatory increase in hepatic lipin-1 protein and elevated PAP activity, which maintained lipid homeostasis under basal conditions, but led to diet-induced hepatic triglyceride accumulation. As lipin-2-deficient mice aged, they developed ataxia and impaired balance. This was associated with the combination of lipin-2 deficiency and an age-dependent reduction in cerebellar lipin-1 levels, resulting in altered cerebellar phospholipid composition. Similar to patients with Majeed syndrome, lipin-2-deficient mice developed anemia, but did not show evidence of osteomyelitis, suggesting that additional environmental or genetic components contribute to the bone abnormalities observed in patients. Combined lipin-1 and lipin-2 deficiency caused embryonic lethality. Our results reveal functional interactions between members of the lipin family in vivo, and a unique role for lipin-2 in central nervous system biology that may be particularly important with advancing age. Additionally, as has been observed in mice and humans with lipin-1 deficiency, the pathophysiology in lipin-2 deficiency is associated with dysregulation of lipid intermediates.     

Association of a polymorphism in the lipin 1 gene with systolic blood pressure in men

BACKGROUND: Lipin 1 plays a role in abdominal obesity, insulin resistance, and hypertriglyceridemia. The gene is located at 2p25.1, a susceptibility locus for hypertension. We studied the association of tagging single-nucleotide polymorphisms (SNPs) in the lipin 1 (LPIN1) gene with hypertension and blood pressure. METHODS: Twelve tagging SNPs from the HapMap database were genotyped using Sequenom MassArray in 268 hypertensive subjects and 407 normotensive controls, of whom 268 matched the cases in age and sex. RESULTS: None of the tagging SNPs were found to be associated with hypertension after correcting for multiple testing, although carriers of the minor allele of rs10520097 had nominally lower odds for hypertension (P = 0.014). After excluding subjects who were on antihypertensive medications, the minor allele of rs10495584 was nominally associated with lower mean systolic and diastolic blood pressures in men (121.1 +/- 14.2 and 76.3 +/- 10.2 mm Hg vs. 127.4 +/- 15.2 and 80.1 +/- 10.5 mm Hg, P = 0.002 and 0.007, respectively), but not in women (P > 0.05). The association of rs10495584 with systolic blood pressure in men remained significant after correcting for multiple testing and adjustment for age, waist circumference, insulin resistance, triglyceride, and high-density lipoprotein (HDL) cholesterol (beta = -0.158, P = 0.005). An analysis of statistically similar SNPs (ssSNPs) in the regions surrounding rs10495584 suggested that its effect may be caused by its high linkage disequilibrium (LD) with the SNP, rs11524, in which the major allele forms an exonic splicing silencer sequence. CONCLUSION: Our study provides further evidence that lipin 1 may play a role in blood pressure regulation, especially in men.