PPARs:脂代谢调节与胰岛素增敏治疗药物的作用靶标

过氧化物酶体增殖物激活受体 (PPARs)是核受体超家族成员之一。PPARα、PPARγ可分别被氯贝特类和TZD类药物特异性激活 ,调节脂代谢、改善胰岛素抵抗 ;有研究表明PPARβ也参与脂肪代谢。因此 ,以PPARs为药物靶标 ,发现和优化单一或双重激动剂将为肥胖和 2型糖尿病的预防和治疗提供有效药物     

噻唑烷二酮类的降糖外作用

噻唑烷二酮(thiazolidinedione,TZD)类是近年来发现的一类新型口服胰岛素增敏剂,包括一系列具有2,4-噻唑烷二酮结构的化合物,如Ciglitazone,Pioglizone,Troglizone,Rosiglizone,Englitazone等,它们具有不同的侧链取代基团而药理特点各不相同.目前认为TZD的作用靶点是过氧化物酶体增殖激活受体(PPARγ).它属于核受体超家族成员,最初于脂肪细胞中检测到,有诱导脂肪细胞分化的作用,之后发现它还广泛表达于T淋巴细胞、巨噬细胞、肥大细胞、内皮细胞、血管平滑肌细胞及癌细胞等.配体与PPARγ结合并使之激活后与维甲酸类X受体(RXR)或糖皮质激素受体形成异二聚体,再结合于特定DNA序列而使靶基因激活.TZD是PPARγ的高亲和力配体.     

人过氧化物酶体增殖物激活受体γ-胰高血糖素样肽-1表达载体的构建

<正>胰岛素抵抗和胰岛素分泌缺陷在2型糖尿病发病过程中占据着重要地位。针对既能减轻胰岛素抵抗、又可增加胰岛素分泌的药物研究对于2型糖尿病及其并发症的治疗具有非常重要的意义。过氧化物酶体增殖物激活受体γ(peroxisome proliferator activated receptorγ,PPARγ)可以增加外周组织的胰岛素敏感性,从而改善胰岛素抵抗,调节糖代谢,降     

选择性PPARγ调节剂治疗糖尿病的研究新进展

过氧化物酶体增殖物激活受体γ是一类主要调控糖脂代谢与脂肪细胞分化的核受体,与肥胖、胰岛素抵抗和糖尿病的发生发展密切相关,其激动剂作为胰岛素增敏剂治疗2型糖尿病也被临床广泛应用。近年来,随着对PPARγ信号通路和胰岛素增敏剂的深入研究,使我们对选择性PPARγ调节剂类胰岛素增敏剂的认识不断完善和更新。该文主要阐述选择性PPARγ调节剂类胰岛素增敏剂的作用机制和药物研究的最新进展。     

糖尿病新靶点药物的研发进展

当前糖尿病临床治疗的热点是改善胰岛素抵抗、防止胰岛β-细胞衰竭.现就过氧化酶体增殖激活受体(PPAR)类药物、抑制糖异生促进外围组织对糖的摄取与利用的药物、胰高血糖素抑制剂等一些新的作用靶点糖尿病药物的研发进展及其在糖尿病治疗药物中的地位与前景进行讨论.     

选择性PPARγ调节剂治疗二型糖尿病的分子机制研究进展

第一类胰岛素增敏剂——过氧化物酶体增殖体激活受体γ(PPARγ)激动剂噻唑烷二酮类药物(TZDs)曾在二型糖尿病(T2DM)治疗中具有不可替代的作用。但由于TZDs类药物存在增重、水肿、骨折、充血性心力衰竭等严重副作用,保留TZDs类药物的胰岛素增敏效果而无其副作用的选择性PPARγ调节剂(SPPARγM)是新型胰岛素增敏剂的发展方向。现有实验主要对SPPARγM候选分子影响PPARγ受体构象改变、受体磷酸化、受体对共调节因子的选择性募集和PPARγ下游靶基因选择性开启等几个层次的分子作用机制作了初步探讨。该文综述了SPPARγM治疗二型糖尿病的分子机制研究进展。     

噻唑烷二酮类药物临床安全性评价

噻唑烷二酮类药物(TZD)是一类新型口服降糖药,主要通过激活过氧化物酶体增生物激活受体γ(PPARγ)增强胰岛素敏感性.临床资料一致表明,这类药物中的罗格列酮和吡格列酮均可显著增加心力衰竭风险.资料显示,罗格列酮可能增加缺血性心脏病变包括心肌梗死(MI)的发病风险,虽然该绝对风险极低,但吡格列酮则不增加该风险.此外,TZD可抑制骨形成,加速骨丢失,增加女性2型糖尿病患者四肢骨折风险.本文总结近年来已完成或正在进行的以及荟萃分析的TZD相关的临床研究结果,以期对TZD的临床安全性进行客观评估.     

罗格列酮治疗2型糖尿病多项临床观察

噻唑烷二酮（TZD）是一类新型的治疗糖尿病药物。此类药物通过选择性地激活，广泛存在于脂肪组织中的过氧化物酶体、增殖激活受体γ（PPARγ受体）从而增强外周组织和肝脏对胰岛素的敏感性，使外周组织对葡萄糖的摄取增加，肝糖产生和输出减少，从而具有降低血糖的作用。笔者对应用胰岛素或两种常规口服降糖药（磺脲类合并双胍类）治疗血糖控制不住T2DM、服用罗格列酮12周后，观察罗格列酮对T2DM患者的降糖作用及安全性。     

基于PPAR抗糖尿病药物的研究进展

过氧化物酶体增殖激活受体(PPAR)是核受体超家族成员，在控制脂肪的贮藏和分解代谢方面起着重要作用，其中，PPARγ参与调节脂质的合成、碳水化合物的代谢及脂肪细胞的分化。基于PPARy的结构进行药物设计，开发了噻唑烷二酮(TZD)类抗糖尿病药物，该类药物中罗格列酮和吡格列酮均已上市，并获得了良好的效益。多种具有PPARα／PPARγ双重激动作用的化合物也合成出来，其中如TZD类的KRP-297，非TZD类的muraglitazar和naveglitazar等均在临床试验中表现出较好的降糖作用并具有调节血脂的作用，但此类化合物多处于临床试验阶段。另外，还开发了一些PPARγ部分激动剂和部分拮抗剂，但对此类化合物的研究还处于初期研究阶段，它们的有效性和安全性还有待进一步的考察。     

PPARα/γ双重激动剂TZD18与脂质代谢的研究进展

噻唑烷二酮（TZD）包括一系列具有2,4-噻唑烷二酮结构的化合物.它们均具有不同的侧链取代基,因而药理特点各有不同.最近发现一种化合物TZD18,一种兼具有改善胰岛素抵抗和降低甘油三酯、胆固醇作用的PPARα/γ的双重激动剂.本文综述了TZD18在脂质代谢方面的研究进展.     

Therapeutic approaches to insulin resistance

Insulin resistance is now acknowledged to be a significant predictor of cardiovascular morbidity and mortality as well as the primary defect in Type 2 diabetes. Such pathologies are set to pose an ever greater socio-economic burden in developed and developing nations, especially in the light of evidence that insulin resistance may be acquired through the (Western) diet. Given the recognition of the central role of insulin resistance in the progression of syndrome X and diabetes, improving insulin sensitivity has become a major clinical focus. The traditional ‘first line of defence’ approach to restoring glycaemic control in diabetes involving dietary and exercise regimens, may now be supplemented with insulin-sensitising pharmacotherapy. This therapeutic modality, which was clinically pioneered with the biguanide metformin, is also today provided by the thiazolidinedione (TZD) class of anti-hyperglycaemic agent, exemplified by rosiglitazone and pioglitazone. More TZD derivatives are to be expected, along with novel, non-TZD ligands of their common therapeutic target: the peroxisome proliferator-activated receptor-γ (PPARγ). In addition, the role of PPARα activation in the regulation of insulin sensitivity is gaining attention. There is also the theoretical prospect at least of creating a therapeutic synergy by co-administering retinoid X receptor (RXR) agonists or so-called rexinoids with these PPAR ligands. Furthermore, interest has been registered in a nutraceutical approach to insulin resistance concerning supranutritional levels of chromium and biotin. While TZDs are currently only licensed for use in established Type 2 diabetes, such insulin-sensitising interventions have the potential to delay or prevent both cardiovascular and diabetic disease progression in insulin resistant individuals.     

The Monascus metabolite monascin against TNF-α-induced insulin resistance via suppressing PPAR-γ phosphorylation in C2C12 myotubes

Chronic inflammation in muscle tissue causes insulin resistance and type-2 diabetes. Peroxisome proliferator-activated receptor (PPAR) ligands are reported to activate the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, including pioglitazone, which belong to the thiazolidinedione (TZD). Monascin (MS), a Monascus metabolite, has been reported to exert anti-inflammatory activity in our recent study. Therefore, the alleviating mechanism of MS on tumor necrosis factor-α (TNF-α; 20 ng/mL) induced insulin resistance in C2C12 cells was investigated in this study. Results showed that MS increased the uptake of 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) in C2C12 myotubes. This result was associated with both PPAR-γ activity and PI3K/Akt pathway caused by MS inhibited p-JNK activity and prevented PPAR-γ phosphorylation. Moreover, we found that MS may act a PPAR-γ agonist to improve insulin sensitivity, and this issue was further confirmed by PPAR-γ antagonist (GW9662). Briefly, MS as pioglitazone, stabilized PPAR-γ structure and diminished PPAR-γ phosphorylation thereby improving insulin resistance.     

Activation of peroxisome proliferator-activated receptor-γ downregulates soluble epoxide hydrolase in cardiomyocytes

1. The antidiabetic agents, thiazolidinediones (TZD), ligands for peroxisome proliferator-activated receptor-γ (PPARγ), have been reported to reduce cardiac hypertrophy. However, the underlying mechanism is still elusive. 2. We previously reported that soluble epoxide hydrolase (sEH) was specifically upregulated by angiotensin-II (AngII), which directly mediated AngII-induced cardiac hypertrophy. In the present study, we examined the role of sEH in PPARγ inhibiting AngII-induced cardiac hypertrophy. 3. The protein level of sEH was elevated in the left ventricle of AngII-infused Sprague-Dawley rats. Administration of the TZD rosiglitazone decreased this induction. In vitro, AngII upregulated the expression of sEH and hypertrophy markers, including atrial natriuretic factor and β-myosin heavy chain, in rat neonatal cardiomyocytes and H9c2 cells, which was attenuated by rosiglitazone and pioglitazone. An elevated level of sEH was also found in the left ventricle of heterozygous PPARγ-deficient mice. The effect of TZD on sEH level could be reversed by treatment with the PPARγ antagonists, GW9662 and BADGE, which suggests PPARγ activation. In elucidating the mechanisms by which PPARγ inhibited AngII-induced sEH expression, we found that rosiglitazone inhibited AngII-induced sEH promoter activity in H9c2 cells. In contrast, the activity of the human sEH 3'UTR was not affected by AngII and TZD. 4. Our results suggest that the protective role of PPARγ activation in AngII-induced cardiac hypertrophy is, at least in part, through downregulating sEH.     

Telmisartan increases localization of glucose transporter 4 to the plasma membrane and increases glucose uptake via peroxisome proliferator-activated receptor γ in 3T3-L1 adipocytes

Angiotensin II is a peptide hormone with strong vasoconstrictive action, and recent reports have shown that Angiotensin II receptor type 1 antagonists (angiotensin II receptor blockers) also improve glucose metabolism. The angiotensin II receptor blocker telmisartan acts as an agonistic ligand of the peroxisome proliferator-activated receptor gamma (PPARγ). In this study, we investigated the effects of telmisartan on glucose uptake and insulin sensitivity in 3T3-L1 adipocytes and compared it with the action of other angiotensin II receptor blockers. Telmisartan treatment dose-dependently increased (from 1 μM) protein expression of PPARγ-regulated molecules such as fatty acid binding protein 4 (FABP4), insulin receptor, and glucose transporter 4 (GLUT4). Telmisartan increased glucose uptake both with and without insulin stimulation in 3T3-L1 adipocytes. Telmisartan increased the up-regulation of phosphorylated insulin receptor, insulin receptor substrate-1 (IRS-1) and Akt by insulin, suggesting that telmisartan increases insulin sensitivity. Furthermore, in the absence of insulin, telmisartan, but not candesartan, increased GLUT4 levels at the plasma membrane. These effects by 10 μM telmisartan were similar potency to those of 1 μM troglitazone, an activator of PPARγ. In addition, up-regulation of glucose uptake by telmisartan was inhibited by a PPARγ antagonist, T0070907 (2-chloro-5-nitro-N-4-pyridinyl-benzamide). These results indicate that telmisartan acts via PPARγ activation in adipose tissue and may be an effective therapy for the metabolic syndrome.