胰岛β细胞胰岛素信号转导通路

胰岛β细胞上存在着胰岛素受体(IR)及胰岛素受体底物(IRS),这些蛋白及其下游信号蛋白构成了复杂的信号转导通路,调控胰岛素的分泌,维持β细胞的生长、增殖和存活。其主要途径是磷脂酰肌醇3激酶(PI3K)信号转导途径和钙通道及其相关途径。β细胞IR、IRS基因敲除鼠表现出糖耐量异常或糖尿病症状。对这一信号通路的深入研究有利于进一步阐明糖尿病的发病机制并为糖尿病的治疗提供新思路。     

PI3K-Akt/PKB信号通路与胰岛β细胞功能

磷脂酰肌醇3激酶-蛋白激酶B／Akt（P13K-AkL／PKB）介导β细胞的生存通路近来较受关注。P13K-Akt／PKB信号通路是细胞内重要的信号转导通路，与细胞生长、增殖、分化、凋亡等密切相关。P13K-Akt／PKB信号通路激活通过下游效应分子促进β细胞增殖、生长调节、增强β细胞抗凋亡功能，改善β细胞生存。调节该通路P13K、Akt／PKB及其上下游靶位点，可能为2型糖尿病的防治提供广阔前景。     

胰岛素样生长因子-1促血管平滑肌细胞增殖的信号转导机制

目的：探讨胰岛素样生长因子—l(IGF—1)促血管平滑肌细胞(VSMC)增殖的细胞内信号转导机制及雷帕霉素干预作用。方法：免血管平滑肌细胞分6组处理，以细胞计数、噻唑盐比色法测定细胞增殖能力，Western Blot测定蛋白激酶B(PKB)表达水平，免疫沉淀、特异底物组蛋白H2Bβγ^32P掺人量测定PKB活性。以磷脂酰肌醇3激酶(PI3K)特异性抑制剂渥漫青霉素处理细胞间接反映PI3K作用。结果：IGF—l使细胞增殖增加至2．8—3．8倍，IGF—l对PKB活性的影响呈浓度(1-l00μg／L)依赖性增加及时间(10min一24h)依赖性降低，lμg／L刺激l0min即使PKB活性增至2倍，l00μg／L时增至近60倍，l00μg／L刺激24hPKB活性增加仍达4倍以上。雷帕雷素在浓度为l0—l00nmol／L范围内使PKB活性进行性降低25％-73％，渥漫青霉素和雷帕霉素使VSMC增殖至少降低30％，并完全逆转IGF—1的上述作用。结论：雷帕霉素可抑制IGF—1促VSMC增殖及对生长信号PI3K／PKB的活化。     

PI3K-Akt/PKB信号通路与胰岛β细胞功能

磷脂酰肌醇3激酶-蛋白激酶B/Akt(PI3K-Akt/PKB)介导β细胞的生存通路近来较受关注。PI3K-Akt/PKB信号通路是细胞内重要的信号转导通路,与细胞生长、增殖、分化、凋亡等密切相关。PI3K-Akt/PKB信号通路激活通过下游效应分子促进β细胞增殖、生长调节、增强β细胞抗凋亡功能,改善β细胞生存。调节该通路PI3K、Akt/PKB及其上下游靶位点,可能为2型糖尿病的防治提供广阔前景。     

PI3K/Akt信号转导通路与脑缺血后细胞凋亡

细胞凋亡为脑缺血时细胞死亡的重要形式之一.磷脂酰肌醇-3激酶(phosphoinositide-3 kinase,PI3K)/丝氨酸-苏氨酸蛋白激酶(serine/threonine kinase,Akt)为重要的细胞存活信号通路,c-Jun氨基端激酶(c-jun N-terminal kinase,JNK)为重要的促进细胞凋亡信号通路.这两大通路转导信号的动态平衡维持着生理状态下的细胞生存与凋亡.脑缺血刺激打破了这一生理平衡,导致大量神经细胞凋亡.多种确切的神经保护因素都与增强细胞存活信号的放大或抑制凋亡信号的放大有关,从而维持这2个通路信号的平衡.     

PI-3 K/Akt信号转导通路在神经系统疾病中的研究进展

磷脂酰肌醇-3-激酶/蛋白激酶B (PI-3K/Akt)信号转导通路是细胞内重要的信号转导通路,在细胞的凋亡、存活、增殖以及细胞骨架的变化等活动中发挥重要的生物学功能,其中尤为重要的是它对细胞凋亡、存活的调节作用。细胞凋亡参与许多神经系统疾病的发生与发展过程,近年来的研究发现该通路的激活具有一定的神经保护作用,因此针对PI-3K/Akt/GSK3β信号通路内源性神经保护机制的研究,有望为神经系统疾病的治疗提供新的理论依据。     

胰岛素样生长因子-1的神经保护作用

胰岛素样生长因子-1(IGF-1)是一种多肽类神经营养因子。在生理条件下，IGF-1及其受体广泛分布于中枢神经系统；在病理条件下，IGF-1表达上调，并通过促分裂原活化蛋白激酶和磷脂酰肌醇3-激酶，丝氨酸一苏氨酸蛋白激酶等信号通路，抑制细胞凋亡、调节离子通道活性、抑制一氧化氮毒性等多种途径发挥神经保护作用。     

β-Arrestins在胰岛素/胰岛素样生长因子-1信号转导中的作用

β-Arrestins是G蛋白耦联受体信号转导通路的负调节因子,越来越多的证据表明,β-arrestins也能作用于细胞内的多种信号分子,调节胰岛素/胰岛素样生长因子-1(IGF-1)信号转导通路.在胰岛素的刺激下,β-arrestin 2能够募集蛋白激酶B(Akt)和酪氨酸激酶Src到胰岛素受体,从而调节胰岛素介导的糖代谢效应;而β-arrestin 1则与胰岛素受体底物-1(IRS-1)竞争性结合泛素连接酶Mdm2,从而减少IRS-1的泛素化和降解,促进磷脂酰肌醇3激酶(PI3K)通路的信号转导.在IGF-1介导的信号转导通路中,β-arrestin 1结合并介导了IGF-1受体(IGF-1R)的内吞,促进胞外信号调节激酶活化,正性调节丝裂原活化蛋白激酶通路.此外,β-arrestin 1与IGF-1R相耦联后,能越过信号分子IRS-1而激活PI3K,进而活化Akt,表现出对P13K途径的正性调控作用.     

IKKβ/NF-κB信号通路与骨骼肌胰岛素抵抗

骨骼肌是胰岛素抵抗发生的主要部位.IκB激酶β(IKKβ)/核因子-κB(NF-κB)信号通路通过干扰正常胰岛素信号转导和诱导机体低水平慢性炎性反应,在骨骼肌胰岛素抵抗中发挥重要作用.通过作用于IKKB/NF-κB信号通路达到治疗2型糖尿病的目的,可成为一个新的研究方向.     

Akt与β细胞生存和功能

Akt是在多种组织和细胞表达的一种丝氨酸/苏氨酸激酶,接受磷脂酰肌醇3激酶-Akt-磷酸肌醇依赖性激酶信号通路调节而发生构象变化,显露其磷酸化位点而被激活.研究发现,胰岛中Akt主要表达于β细胞,一方面通过其下游效应子核糖体S6激酶1和细胞周期素依赖激酶/细胞周期素的调节,以及阻断细胞凋亡信号通路来促进β细胞的生存、增殖和分化;另一方面通过调节胰岛素分泌通路末梢的信号分子和葡萄糖代谢等促进β细胞正常功能的维持.因而可能为糖尿病的治疗提供一个新的靶点.     

Dexamethasone inhibits insulin-like growth factor signaling and potentiates myoblast apoptosis

In the critically ill, glucocorticoids induce myopathy, combining profound protein catabolism and mild myotubular death. Insulin-like growth factors (IGFs) inhibit muscle catabolism through activation of phosphatidylinositol 3-kinase (PI3K). Using rat L6 myoblasts, we show that IGF-I also acts through PI3K to inhibit apoptosis induced by hyperosmolar metabolic stress with 300 mM mannitol. We find that the glucocorticoid dexamethasone inhibits this antiapoptotic effect of IGF-I by impairing PI3K signaling. Dexamethasone induces overexpression of the PI3K subunit p85alpha, which, in turn, competes with the complete PI3K heterodimer for binding at insulin receptor substrate-1, inhibiting PI3K activation. Dexamethasone blocks IGF-I-induced phosphorylation of Akt, a PI3K-dependent process. Increased cellular p85alpha abundance, induced by either 10 microM dexamethasone or transient transfection with a plasmid coding for p85alpha, significantly inhibits IGF-I rescue from apoptosis induced by mannitol, as indicated by both loss of cell viability and increased activity of caspase-3 by fluorogenic assay. Conversely, constitutively active PI3K inhibits death induced by mannitol, even in the presence of dexamethasone. These findings may have particular relevance in the pathogenesis of acute steroid myopathy in critical illness, in which catabolic glucocorticoid effects combine with acute metabolic stressors, including sepsis, fasting, and chemical denervation.     

Insulin and insulin-like growth factor resistance in alcoholic neurodegeneration

Background:  Chronic alcohol feeding of adult Long Evans rats causes major central nervous system abnormalities that link neuronal loss and impaired acetylcholine homeostasis to ethanol inhibition of insulin and insulin-like growth factor (IGF) signaling and increased oxidative stress.
Objectives:  We now characterize the integrity of insulin and IGF signaling mechanisms and assess molecular indices of neurodegeneration in the cerebellar vermis and anterior cingulate gyrus of human alcoholics.
Results:  Alcoholic cerebella had increased neuronal loss, gliosis, lipid peroxidation, and DNA damage relative to control. Quantitative RT-PCR studies demonstrated reduced expression of insulin, insulin receptor and IGF-II receptor in the anterior cingulate, and reduced expression of insulin, IGF-I, and their corresponding receptors in the vermis. Competitive equilibrium binding assays revealed significantly reduced specific binding to the insulin, IGF-I, and IGF-II receptors in both the anterior cingulate and vermis of alcoholic brains. These effects of chronic alcohol abuse were associated with significantly reduced expression of choline acetyltransferase, which is needed for acetylcholine biosynthesis.
Conclusions:  The results suggest that alcoholic neurodegeneration in humans is associated with insulin and IGF resistance with attendant impairment of neuronal survival mechanisms and acetylcholine homeostasis.     

Wnt signaling regulates pancreatic beta cell proliferation

There is widespread interest in defining factors and mechanisms that stimulate proliferation of pancreatic islet cells. Wnt signaling is an important regulator of organ growth and cell fates, and genes encoding Wnt-signaling factors are expressed in the pancreas. However, it is unclear whether Wnt signaling regulates pancreatic islet proliferation and differentiation. Here we provide evidence that Wnt signaling stimulates islet beta cell proliferation. The addition of purified Wnt3a protein to cultured beta cells or islets promoted expression of Pitx2, a direct target of Wnt signaling, and Cyclin D2, an essential regulator of beta cell cycle progression, and led to increased beta cell proliferation in vitro. Conditional pancreatic beta cell expression of activated beta-catenin, a crucial Wnt signal transduction protein, produced similar phenotypes in vivo, leading to beta cell expansion, increased insulin production and serum levels, and enhanced glucose handling. Conditional beta cell expression of Axin, a potent negative regulator of Wnt signaling, led to reduced Pitx2 and Cyclin D2 expression by beta cells, resulting in reduced neonatal beta cell expansion and mass and impaired glucose tolerance. Thus, Wnt signaling is both necessary and sufficient for islet beta cell proliferation, and our study provides previously unrecognized evidence of a mechanism governing endocrine pancreas growth and function.     

Role of insulin／insulin-like growth factor I signaling pathway in longevity

The insulin/insulin-like growth factor 1 (IGF-1) signaling pathway is evolutionary conserved in diverse species including C.elegans, saccharomyces cerevisiae, Drosophila melanogaster, rodents and humans, which is involved in many interrelated functions that are necessary for metabolism, growth and reproduction. Interestingly, more and more research has revealed that insulin/IGF-1 signaling pathway plays a pivotal role in the regulation of longevity. Generally, disruption of the power of this pathway will extend longevity in species ranging from C.elegans to humans. The role of insulin/IGF-1 in longevity is probably related to stress resistance. Although the underlying mechanisms of longevity are not fully understood, the Insulin/IGF-1 signaling pathway has attracted substantial attention and it will be a novel target to prevent or postpone age-related diseases and extend life span. In this review, we mainly focus on the similar constitution and role of insulin/IGF-1 signaling pathway in C.elegans, saccharomyces cerevisiae, rodents and humans.     

胰腺导管腺癌组织中WT1,IGF-IR表达与细胞凋亡的关系

目的:研究胰腺导管腺癌组织中WT1,IGF-IR的表达与细胞凋亡关系．方法:应用免疫组化技术检测WT1,IGF-IR在49例胰腺导管腺癌及15例正常胰腺组织中的表达,并应用TUNEL法检测细胞凋亡,计算凋亡指数(AI)．结果:WT1,IGF-IR在正常胰腺组织中的阳性表达率分别为26．67％(4／15)、40．00％(6／15);在胰腺导管腺癌组织中的阳性表达率分别为71．43％(35／49)、77．55％(38／49),两者在癌组织中的表达分别明显高于其在正常胰腺组织中的表达(P<0．05),且在癌组织中的表达呈正相关(r=0．385,P<0．05)．正常胰腺组织及癌组织中的AI分别为0．41±0．13、5．93±4．18,两者比较有显著性差异(P<0．05),癌组织中AI随组织分化程度的升高而升高．IGF-IR表达阳性组的AI显著低于阴性组(4．11±3．68 vs 12．21±5．67,P<0．01)．结论:胰腺导管腺癌组织中IGF-IR的高表达抑制细胞凋亡,WT1,IGF-IR的高表达以及细胞凋亡的减少可能在胰腺导管腺癌的发生发展中起重要作用．     

FLIP switches Fas-mediated glucose signaling in human pancreatic beta cells from apoptosis to cell replication

Type 2 diabetes mellitus results from an inadequate adaptation of the functional pancreatic β cell mass in the face of insulin resistance. Changes in the concentration of glucose play an essential role in the regulation of β cell turnover. In human islets, elevated glucose concentrations impair β cell proliferation and induce β cell apoptosis via up-regulation of the Fas receptor. Recently, it has been shown that the caspase-8 inhibitor FLIP may divert Fas-mediated death signals into those for cell proliferation in lymphatic cells. We observed expression of FLIP in human pancreatic β cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro exposure of islets from nondiabetic organ donors to high glucose levels decreased FLIP expression and increased the percentage of apoptotic terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL)-positive β cells; FLIP was no longer detectable in such TUNEL-positive β cells. Up-regulation of FLIP, by incubation with transforming growth factor β or by transfection with an expression vector coding for FLIP, protected β cells from glucose-induced apoptosis, restored β cell proliferation, and improved β cell function. The beneficial effects of FLIP overexpression were blocked by an antagonistic anti-Fas antibody, indicating their dependence on Fas receptor activation. The present data provide evidence for expression of FLIP in the human β cell and suggest a novel approach to prevent and treat diabetes by switching Fas signaling from apoptosis to proliferation.