小檗碱激活PAK1/PDK1缓解胰岛素抵抗治疗糖尿病脑病的作用

目的： 观察小檗碱对糖尿病模型大鼠胰岛素抵抗及PAK1/PDK1通路的作用,并探讨其改善糖尿病脑病的作用。方法： 将100只Wistar大鼠构建糖尿病模型后分为正常组（control,Con）、糖尿病组（diabetes mellitus,DM）、小檗碱组（berberine,BBr）、二甲双胍组（metformin,Met）、石杉碱甲组（huperzine A,Hup）5组。期间监测每组大鼠体质量、饥饿血糖值、空腹胰岛素水平并计算胰岛素抵抗指数。HE染色观察神经元结构改变,刚果红染色检测Aβ42的生成,Western-blot法检测p-PAK1/PAK1与p-PDK1/PDK1的蛋白表达水平。结果： 与Con比较,DM组大鼠体质量降低,饥饿血糖值、空腹胰岛素水平及胰岛素抵抗指数增加;与DM组比较,BBr组大鼠体质量增加,饥饿血糖值、空腹胰岛素水平及胰岛素抵抗指数降低,其作用与Met组相当。与Con组比较,DM组大鼠海马神经元结构紊乱、Aβ42明显增加以及PAK-1/PDK-1信号通路显著抑制;与DM组比较,BBr组、Met组及Hup组大鼠海马神经元结构改善,Aβ42生成减少且PAK-1/PDK-1信号通路被明显激活。结论： 小檗碱一方面可直接通过降低饥饿血糖值、空腹胰岛素水平改善外周胰岛素抵抗,另一方面也可通过激活PAK1/PDK1信号通路改善中枢胰岛素抵抗从而改善糖尿病脑病。     

小檗碱抑制核因子NF-kBp65的核转位改善高糖诱导的3T3-L1细胞胰岛素抵抗的分子机制

目的：观察小檗碱对高糖诱导的3T3-L1脂肪细胞胰岛素抵抗模型核因子NF-kBp65表达及转位的影响，探讨小檗碱改善胰岛素抵抗的分子生物学机制。方法：以25mmol·L^-1葡萄糖加0．6nmol·L^-1胰岛素诱导3T3-L1脂肪细胞产生胰岛素抵抗，以小檗碱进行干预，同时阿司匹林作为阳性对照，以2-脱氧-[3H]-D-葡萄糖摄入法推算葡萄糖的转运率，用Westernblot检测3T3-L1脂肪细胞总NF-kBp65蛋白及核NF-kBp65蛋白的表达，激光扫描共聚焦（CLSM）对NF-kBp65蛋白进行定位显示。结果：25mmol·L^-1葡萄糖加0．6nmol·L^-1胰岛素作用18h后使3T3L1脂肪细胞胰岛素刺激的葡萄糖转运率抑制60％，Westernblot显示核NF-kBP65蛋白表达明显增加，CLSM显示NF-kBp65核转位增加；同时加入小檗碱或阿司匹林则可逆转上述效应。但高糖、小檗碱阿司匹林对3T3-L1脂肪细胞总NF-kBp65蛋白的表达无明显影响。结论：小檗碱可以改善高糖诱导的胰岛素抵抗，其分子机制可能与小檗碱抑制NF-kBp65的核转位有关。     

基于网络药理学和分子对接探讨复方风湿宁片治疗类风湿关节炎的作用机制

目的 采用网络药理学联合分子对接技术探讨复方风湿宁片治疗类风湿性关节炎的作用机制。方法 通过TCMSP、BATMAN-TCM、Swiss TargetPrediction数据库及文献报道收集复方风湿宁片的活性化学成分靶点，并使用GeneCards数据库检索类风湿关节炎的疾病靶点，将两者取交集，并通过绘制“复方风湿宁片–活性成分–靶点–通路–类风湿关节炎”网络图。对复方风湿宁片中的活性成分与类风湿关节炎靶点进行分子对接。结果 通过网络药理学分析得到复方风湿宁片中有34种活性化学成分，对应1 059个靶点，与类风湿关节炎靶点交集356个。通过KEGG富集分析发现复方风湿宁片主要可能在肿瘤坏死因子（TNF）信号通路、白细胞介素-17（IL-17）信号通路、Th17细胞分化、T细胞受体信号通路、Toll样受体（TLR）信号通路、核因子κB（NF-κB）信号通路、Th1和Th2细胞分化、Janus激酶（JAK）-信号传导和转录激活蛋白3（STAT3）信号通路、B细胞受体信号通路和类风湿性关节炎等通路上发挥治疗作用。蛋白激酶B（Akt1）、前列腺素内过氧化物酶2（PTGS2）、丝裂原活化蛋白激酶1（MAPK1）、TNF、丝裂原活化蛋白激酶8（MAPK8）、白细胞介素-6（IL-6）和κB抑制因子激酶β（IKBKB）关键靶点与血根碱、珊瑚菜素、氧基白屈菜季铵碱、二氢白屈菜红碱、槲皮素、木犀草素、山奈酚、香叶木素、异鼠李素的结合较好。结论 复方风湿宁片治疗类风湿关节炎的作用机制可能主要在免疫调控及抑制炎症方面发挥多靶点、多通路治疗类风湿关节炎作用。     

小檗碱及其主要Ⅰ相代谢产物改善人肝癌Hep G2细胞胰岛素抵抗作用及机制初探

目的探讨小檗碱及其4个主要的Ⅰ相代谢产物改善胰岛素抵抗的作用及相关分子机制。方法首先本研究采用高浓度葡萄糖刺激人肝癌HepG2细胞建立胰岛素抵抗模型。采用葡萄糖氧化酶法和2-NBDG法检测小檗碱及其代谢产物在胰岛素抵抗的HepG2细胞中葡萄糖摄取的情况;分别采用蛋白质免疫印迹法和实时-PCR技术检测小檗碱及其活性代谢产物对于葡萄糖转运及糖异生关键蛋白GLUT1、GLUT2和PEPCK表达的变化;采用蛋白质免疫印迹考察小檗碱及其代谢产物对PI3K/Akt信号通路的影响。结果与空白对照组相比,高浓度葡萄糖刺激HepG2细胞后,葡萄糖摄取显著降低,提示本研究条件可以建立体外胰岛素抵抗模型。小檗碱及其代谢产物M1,M2和M3可以显著增加葡萄糖摄取(P<0.05)。本研究进一步发现,在高糖诱导的胰岛素抵抗的HepG2细胞中,BBR,M1和M2不影响GLUT1的表达,而BBR和M1明显上调GLUT2的膜上蛋白表达(P<0.05);同时,BBR,M1和M2抑制PEPCK的mRNA表达(P<0.05)。此外,BBR和M2上调PI3K和Akt蛋白磷酸化的水平(P<0.05)。结论小檗碱及其代谢产物M1,M2和M3在体外可以明显改善胰岛素抵抗。其中,小檗碱和M1可以通过促进葡萄糖转运缓解胰岛素抵抗,而小檗碱和M2可能通过PI3K/Akt通路调控糖异生进而发挥缓解胰岛素抵抗的作用。     

异槲皮苷调控PTP1B改善胰岛素抵抗的网络药理学研究及体外实验验证

目的 采用网络药理学法及分子对接技术探析异槲皮苷改善胰岛素抵抗的分子机制,并通过体外实验研究异槲皮苷对胰岛素抵抗的干预作用及机制。方法 利用PubChem、PharmMapper、GEO、CTD、GeneCards、OMIM等多个数据库筛选异槲皮苷活性成分及胰岛素抵抗相关靶点;采用Cytoscape软件将异槲皮苷治疗胰岛素抵抗的潜在靶点构建蛋白质相互作用（PPI）网络,并根据度值筛选核心靶点。利用基因本体（GO）与京都基因与基因组百科全书（KEGG）富集分析寻找与靶点蛋白相关的生物学通路,采用AutoDock Tools软件模拟分子对接,预测异槲皮苷与关键靶点的结合度。体外实验采用异槲皮苷干预蛋白酪氨酸磷酸酶1B（PTP1B）质粒转染HepG2细胞,检测不同浓度异槲皮苷干预后PTP1B的活性;构建PTP1B质粒转染HepG2胰岛素抵抗细胞模型,给予异槲皮苷（40μmol/L）干预,葡萄糖氧化酶法、qRT-PCR、Western Blotting法检测PTP1B等相关因子的表达。结果 网络药理学筛选得到异槲皮苷改善胰岛素抵抗的交集靶点21个,富集到GO条目2 761个,主要涉及胰岛素受体信号通路、糖原生物合成过程的调控等,富集到KEGG通路89条,涉及包括胰岛素信号通路、胰岛素抵抗、磷脂酰肌醇-3-羟激酶（PI3K）-蛋白激酶B（Akt）信号通路、磷酸腺苷活化的蛋白激酶（AMPK）信号通路等。分子对接结果显示,异槲皮苷与靶点PTP1B、磷酸肌醇依赖性蛋白激酶1（PDPK1）、胰岛素受体（INSR）、糖原合酶激酶3β（GSK3β）、AKT2均有一定的结合活性。体外实验结果显示,异槲皮苷能有效抑制PTP1B活性,降低PTP1B过表达HepG2胰岛素抵抗细胞中PTP1B、GSK3β的表达,升高胰岛素受体底物1（IRS-1）、葡萄糖转运蛋白-1（GLUT-1）等因子的表达,改善细胞胰岛素抵抗。结论 异槲皮苷可能通过抑制PTP1B调控PI3K/Akt信号通路因子活性改善胰岛素抵抗。     

炎性因子NF—κB在2型糖尿病发病及治疗中的作用

研究表明潜在的慢性亚临床炎性反应是胰岛素抵抗和2型糖尿病的发病机制。核因子-κB（nuclear factorkappaB,NF-κB）是炎症信号通路的关键因子。NF-κB激活介导了许多炎症因子水平升高,从而引起胰岛素抵抗和胰岛β细胞功能损伤,最后导致2型糖尿病发生。许多药物正是通过直接或间接激活NF-κB改善糖尿病。     

小檗碱抑制核因子NF-кB p65的核转位改善高糖诱导的3T3-L1细胞胰岛素抵抗的分子机制

目的:观察小檗碱对高糖诱导的3T3-L1脂肪细胞胰岛素抵抗模型核因子NF-кB p65表达及转位的影响,探讨小檗碱改善胰岛素抵抗的分子生物学机制.方法:以25mmol·L-1葡萄糖加0.6nml·L-1胰岛素诱导3T3-L1脂肪细胞产生胰岛素抵抗,以小檗碱进行干预,同时阿司匹林作为阳性对照,以2-脱氧-[3H]-D-葡萄糖摄入法推算葡萄糖的转运率,用Western blot检测3T3-L1脂肪细胞总NF-кB p65蛋白及核NF-кB p65蛋白的表达,激光扫描共聚焦(CLSM)对NF-кB p65蛋白进行定位显示.结果:25mmol·L-1葡萄糖加0.6nmol·L-1胰岛素作用18h后使3T3-L1脂肪细胞胰岛素刺激的葡萄糖转运率抑制60%, Western blot显示核NF-кB p65蛋白表达明显增加, CLSM显示NF-кB p65核转位增加;同时加入小檗碱或阿司匹林则可逆转上述效应.但高糖、小檗碱、阿司匹林对3T3-L1脂肪细胞总NF-кB p65蛋白的表达无明显影响.结论:小檗碱可以改善高糖诱导的胰岛素抵抗,其分子机制可能与小檗碱抑制NF-кB p65的核转位有关.     

马鞭草苷对口腔扁平苔藓免疫反应的抑制作用及机制

目的 探讨马鞭草苷对口腔扁平苔藓（OLP）免疫反应的抑制作用及机制。方法 用脂多糖（LPS）体外刺激角质形成细胞系HaCaT细胞构建OLP炎症模型,CCK-8法检测细胞活力;实时荧光定量聚合酶链式反应（PCR）法检测细胞中肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）的基因表达变化;蛋白质印迹法检测细胞中核因子-κB p65（NF-κB p65）和p-NF-κB p65蛋白的表达变化。结果 在HaCaT细胞中,LPS刺激抑制细胞活力,并诱导TNF-α、IL-1β和IL-6基因的表达上调,以及NF-κB p65和p-NF-κB p65蛋白的表达上调;20 mg/L马鞭草苷作用24 h可减轻LPS诱导的HaCaT细胞损伤、抑制炎症因子的表达和NF-κB p65信号通路的活化;同时,经G蛋白偶联受体18（GRP18）抑制剂O1918预处理后,马鞭草苷的保护作用显著减弱。结论 马鞭草苷可以通过激活GPR18受体抑制NF-κB信号通路的活化,进而降低炎症因子的表达和减轻OLP口腔黏膜炎症反应。     

消渴饮水方对链脲佐菌素联合高脂高糖诱导的糖尿病肾病小鼠的保护作用

目的：研究消渴饮水方（XEC）对实验性2型糖尿病（T2DM）小鼠糖脂代谢及肾病损伤的保护作用及机制。方法：采用链脲佐菌素联合高脂高糖饲料诱导C57BL/6小鼠为T2DM动物模型,分为模型（DM）组、二甲双胍（MET）组、消渴灵片（XKLP）组、消渴饮水方低（XEC-L）、中（XEC-M）、高（XEC-H）剂量组,并以健康小鼠为正常（NC）组,给药6周。每周测空腹血糖,第6周进行口服葡萄糖耐量实验,检测糖化血红蛋白、空腹胰岛素、尿素氮等生化指标;HE染色观察胰腺病理改变,HE、PAS和Masson染色观察肾脏病理改变;蛋白质印迹（Western blot）检测肝脏组织胰岛素受体α（InsRα）、胰岛素受体底物1（IRS-1）、磷酸脂酰激醇-3激酶（PI3K）、蛋白激酶B （AKT）、腺苷酸化蛋白激酶（AMPK）和磷酸化AMPK （p-AMPK）水平,肾脏组织晚期糖基化终末产物受体（RAGE）、核因子-κB （NF-κB）、c-Jun氨基末端激酶（JNK）和磷酸化JNK （p-JNK）水平。结果：XEC显著改善T2DM小鼠的胰岛素抵抗、糖耐量降低和糖脂代谢紊乱（P<0.01）,以及受损的肾功能（P<0.05）。在组织病理分析中,XEC减轻T2DM小鼠胰腺、肾小球和肾小管的结构病变。Western blot分析表明,XEC-H显著上调InsRα、IRS-1、PI3K、AKT的表达和p-AMPK/AMPK比值,降低RAGE、NF-κB的水平和p-JNK/JNK比值（P<0.05）。结论：XEC能够改善T2DM小鼠的糖脂代谢紊乱,在预防治疗糖尿病肾病方面显示出比MET和XKLP更优异的效果。其作用机制可能是通过上调InsRα/IRS-1/PI3K/AKT信号通路,促进AMPK磷酸化及下调肾脏AGE/RAGE和JNK/NF-κB信号通路,实现对糖尿病及肾病的预防和治疗作用。     

miRNA介导的TLR4炎症信号通路在辐射损伤中的研究进展

放疗是目前全球公认的治疗各种肿瘤的主要手段之一，但放疗过程中产生的各类射线会对辐射周围的正常组织造成炎症性损害，因此探寻有效治疗靶点以改善辐射造成的炎症性损伤，提高放疗疗效是当务之急。研究发现，微小RNA （microRNA，miRNA）作为一种新型的炎症调节因子，主要通过TLR4介导的NF-κB信号通路来调控辐射诱发的炎症反应。因此，miRNA与TLR4形成的交互网络系统有望成为防辐射损伤药物研发的筛选靶点。本文从TLR4介导的炎症相关信号通路对辐射的调控作用、miRNA对辐射的调控作用、miRNA对辐射中TLR4/NF-κB信号通路调控的炎症反应的靶向作用及靶向miRNA-TLR4改善辐射后炎症反应的治疗策略4个方面进行综述，以期找到miRNA靶向调控TLR4介导的NF-κB信号通路的有效靶点，为辐射损伤的防治研究提供新的思路。     

肉桂醛防治糖尿病的药理作用研究进展

糖尿病是人类最常见的代谢疾病之一，目前尚缺乏根治的药物。肉桂醛是从肉桂、决明子树皮中提取的醛类化合物。肉桂醛能够通过调节过氧化物酶体增殖物激活受体（PPAR）、蛋白激酶B2（Akt2）信号通路提高胰岛素敏感性，通过激活核转录因子红系2相关因子2（Nrf2）信号通路、调节胰岛素受体底物1（IRS1）/磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）信号通路抗氧化反应，促进胰岛素分泌，减轻胰岛素抵抗，抑制炎症反应，调节肠道菌群多种途径发挥防治糖尿病的作用。探讨了肉桂醛防治糖尿病的作用机制，为肉桂醛的临床应用提供依据。     

Improvement of insulin resistance by removal of systemic hydrogen peroxide by PEGylated catalase in obese mice

Insulin resistance, a condition in which insulin action is impaired, is one of the characteristic features of type 2 diabetes. Excessive amounts of reactive oxygen species (ROS) interfere with the insulin signaling pathway, which leads to the progression of insulin resistance. To examine whether removal of systemic hydrogen peroxide is effective in improving insulin resistance, polyethylene glycol-conjugated catalase (PEG-catalase), a derivative with a long circulation half-life, was repeatedly injected into leptin-deficient ob/ob or high fat diet-induced obese mice for 16 or 10 consecutive weeks, respectively. Although ob/ob mice gradually gained weight with time irrespective of the treatment, repeated intraperitoneal injections of PEG-catalase significantly reduced glucose levels in the fed state. Glucose and insulin tolerance tests also showed PEG-catalase significantly improved glucose tolerance and insulin sensitivity in ob/ob mice, respectively. Similar but less marked results were obtained in the diet-induced obese mice. Treatment of 3T3-L1 adipocytes with glucose oxidase (GO) increased lipid hydroperoxide formation and reduced insulin-stimulated Akt phosphorylation. Addition of catalase or PEG-catalase significantly inhibited the GO-induced changes in adipocytes. These findings indicate that systemic removal of hydrogen peroxide by PEG-catalase activates the insulin signaling pathway and improves insulin resistance in obese mice.     

Causal effects of synthetic chemicals on mitochondrial deficits and diabetes pandemic

It is generally accepted that mitochondrial deficits cause many common age-associated diseases including type 2 diabetes. However, it has not been understood what causes mitochondrial damages and how to interrupt the development of the diseases in patients. Recent epidemiologic studies demonstrated a positive correlation between serum concentrations of environmental pollutants and insulin resistance/diabetes. Emerging data strongly suggest that some synthetic pollutants disturb the signaling pathway critical for energy homeostasis and insulin action. The synthetic chemicals are possibly involved in pathogenesis of insulin resistance and diabetes as mitochondria-disturbing agents. In this review, we present a molecular scheme to address the contribution of environmental synthetic chemicals to this metabolic catastrophe. Efforts to identify synthetic chemicals with mitochondria-damaging activities may open a new era to develop effective therapeutic interventions against the worldwide-spreading metabolic disorder.     

Sarsasapogenin improves adipose tissue inflammation and ameliorates insulin resistance in high-fat diet-fed C57BL/6J mice

Insulin resistance is a major cause of type 2 diabetes and metabolic syndrome.Macrophage infiltration into obese adipose tissue promotes inflammatory responses that contribute to the pathogenesis of insulin resistance.Suppression of adipose tissue inflammatory responses is postulated to increase insulin sensitivity in obese patients and animals.Sarsasapogenin(ZGY)is one of the metabolites of timosaponin AIII in the gut,which has been shown to exert anti-inflammatory action.In this study,we investigated the effects of ZGY treatment on obesity-induced insulin resistance in mice.We showed that pretreatment with ZGY(80 mg·kg^?1·d^?1,ig,for 18 days)significantly inhibited acute adipose tissue inflammatory responses in LPS-treated mice.In high-fat diet(HFD)-fed obese mice,oral administration of ZGY(80 mg·kg^?1·d^?1,for 6 weeks)ameliorated insulin resistance and alleviated inflammation in adipose tissues by reducing the infiltration of macrophages.Furthermore,we demonstrated that ZGY not only directly inhibited inflammatory responses in macrophages and adipocytes,but also interrupts the crosstalk between macrophages and adipocytes in vitro,improving adipocyte insulin resistance.The insulin-sensitizing and anti-inflammatory effects of ZGY may result from inactivation of the IKK/NF-κB and JNK inflammatory signaling pathways in adipocytes.Collectively,our findings suggest that ZGY ameliorates insulin resistance and alleviates the adipose inflammatory state in HFD mice,suggesting that ZGY may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.     

TiO2 nanoparticles induce insulin resistance in liver-derived cells both directly and via macrophage activation

Abstract

Upon exposure, TiO₂ nanoparticles (NPs) have been recovered in internal organs such as the liver, and are proposed to cause cellular/organ dysfunction, particularly in the liver and lungs. We hypothesized that despite being considered “inert” as bulk material, TiO₂ NPs may impair insulin responses in liver-derived cells, either indirectly by inflammatory activation of macrophages, and/or by directly interfering with insulin signaling. Using qRT-PCR and conditioned medium (CM) approaches, we show that exposure to TiO₂ NPs activates macrophages' expression of TNF-α, IL-6, IL-8, IL-1α and IL-1β and the resulting CM induces insulin resistance in Fao cells. Furthermore, direct exposure of Fao cells to TiO₂ results in activation of the stress kinases JNK and p38MAP kinase, and in induction of insulin resistance at the signaling and metabolic levels. Collectively, our findings provide a proof-of-concept for the ability of man-made NPs to induce insulin resistance in liver-derived cells, an endocrine abnormality underlying some of the most common human diseases.     

Plausible anti-inflammatory mechanism of resveratrol and caffeic acid against chronic stress-induced insulin resistance in mice

Stress is associated with many diseases and dysfunctions, such as depression, cardiovascular alterations, immunological function disorder, inflammation, obesity, and insulin resistance. Stress-induced inflammation is associated with the genesis of insulin resistance. Stress activates hypothalamic pituitary adrenal axis, Renin Angiotensin System pathway, and sympatho-adrenal system, all of which are involved in the production of cytokines, causing the negative downregulation of insulin signaling either by phosphorylating serine residues of IRS or by inhibiting the activity of Akt leading to insulin resistance. In this study, male LACA mice (20–30 g) were subjected to 2 h of chronic restraint stress daily for 30 days at variable time. Resveratrol, caffeic acid, glibenclamide, and their combinations were administered 45 min prior to restraint stress daily for 30 days and their anti-inflammatory effect was examined on CRS-induced behavioral, biochemical, and metabolic alterations. Induction of stress in mice was evident by increased corticosterone and decreased bodyweight. Chronic restraint stress for 30 days developed insulin resistance characterized by hyperglycemia, hyperinsulinemia, increased glycosylated haemoglobin (HbA1c), and homeostasis model assessment of insulin resistance index, hyperlipidemia, increased inflammatory cytokines, and TNF-α. Treatment with resveratrol, caffeic acid, and their combinations has attenuated stress-induced insulin resistance by reducing inflammation.     

Effect of obesity on insulin signaling through JAK2 in rat aorta

Pathway specific resistance to insulin signaling through PI 3-kinase/Akt/eNOS associated with a normal or hyper-activated MAP kinase signaling in vascular tissues has recently been proposed as a candidate link between cardiovascular disease and insulin resistance. Growth stimulatory pathways other than ERK/MAP kinase, such as JAK/STAT have not yet been investigated in vessels of animal models of insulin resistance. Here we have examined whether insulin is able to activate JAK2/STAT pathway in rat aorta and also the regulation of this pathway in an animal model of obesity/insulin resistance. Our results demonstrate that insulin activates JAK2 tyrosine kinase activity in rat aorta in parallel with the activation of STAT3 and STAT5a/b. Moreover, it is shown that, in obese animals, JAK2/STAT and MAP kinase pathways are hyper-activated in response to insulin, which occurs in association with a reduced activation of PI 3-kinase/Akt pathway in aorta. The results of the present study suggest that, besides ERK/MAP kinase pathway, another potentially pro-atherogenic pathway, JAK2/STAT is hyper-activated in vessels in a state of insulin resistance and this phenomenon, in association with the inhibition of the PI 3-kinase/Akt pathway, may play an important role in the pathogenesis of cardiovascular diseases.     

Insulin sensitizers may prevent metabolic inflammation

The relative decreased response of peripheral tissues to insulin (insulin resistance) is a key metabolic disturbance that predisposes a large percentage of individuals to the development of type 2 diabetes and to cardiovascular disease. As detailed in an extensive literature over the last two decades, insulin resistance co-exists in varying degrees with a variety of other key risk factors, including dyslipidemia, hypertension, and vascular inflammation, that contribute to poor cardiovascular outcomes of individuals with type 2 diabetes and metabolic syndrome. Whereas insulin resistance is generally thought of as pathology unto itself, this commentary suggests that insulin resistance is a physiological compensation to inappropriate oxidative metabolism that induces a metabolic inflammatory response. Via signaling of this inflammatory response, the protective compensation to excessive oxidative metabolism dampens metabolism by reducing insulin action, fatty acid oxidation, and eventually mitochondrial function and numbers. Such a scenario could explain the coexistence of these phenomena with obesity and reduced mitochondrial function. Recent evidence suggests that thiazolidinediones exert pharmacology through modifications of mitochondrial metabolism, preventing the metabolic inflammation and allowing the up regulation of mitochondrial biogenesis. A further understanding of these mechanisms, which are likely to involve key redox signaling events emanating from mitochondrial biochemistry, is needed to fuel new therapeutic advances for the treatment of metabolic syndrome.     

Cellular mechanism of nutritionally induced insulin resistance: the desert rodent Psammomys obesus and other animals in which insulin resistance leads to detrimental outcome

Animal species with genetic or nutritionally induced insulin resistance, diabetes and obesity (diabesity) may be divided into two broad groups: those with resilient pancreatic beta-cells, e.g. ob/ob mice and fa/fa rats, capable of long-lasting compensatory insulin over-secretion, and those with labile beta-cells in which the secretion pressure leads to irreversible beta-cell degranulation, e.g. db/db mice, Macaca mulatta primates, ZDF diabetic rats. Prominent in this group is the Israeli desert gerbil Psammomys obesus (sand rat), which features low insulin receptor density in liver and muscle. On a diet of relatively high energy, the capacity of insulin to activate the receptor tyrosine kinase (TK) is reduced, in the face of hyperinsulinemia. With the following hyperglycemia, the rising insulin resistance imposes a vicious cycle of insulinemia and glycemia, accentuating the TK activation failure and the beta-cell failure. Among various factors affecting the insulin signaling pathway, multisite phosphorylation, including serine and threonine on the receptor beta-subunit, due to overexpression of certain protein kinase C isoforms, seems to be responsible for the inhibition of the critical step of TK phosphorylation activity. The compromised TK activation is reversible by diet restriction which restores to normal the glycemia and insulinemia. The beta-cell response to long-lasting stimulation and the receptor malfunction in diabesity have implications for a similar etiology in human insulin resistance syndrome and type 2 diabetes, particularly in populations emerging from a food scarce environment into nutritional affluence, inappropriate to the human metabolic capacity. It is suggested that the "thrifty gene" is characterized by a low threshold for insulin secretion and low capacity for insulin clearance. Thus, nutritionally-induced hyperinsulinemia is potentiated and becomes the primary phenotypic expression of the thrifty gene, linked to the insulin receptor signaling pathway malfunction.