胰岛素受体的病理生理学

受体必须满足下列功能特征,才能作为激素生物作用的媒介:激素与受体的结合必须迅速,可以饱和及可逆;对激素有特异性,并且与激素结合的相对亲和力与激素的相对生物学效能相平行,激素的亲和力常数在生理浓度范围;激素与受体结合后应该激发可以测得的生物学反应。脂肪细抱、肝细胞及肌肉内的胰岛素受体都满足这些标准。IM-9培养的人淋巴细胞及人红细胞似乎也有胰岛素的特异受体,但胰岛素对它们未发现已知的生物作用。胰岛素受体的证实及特征1.定位大量研究表明胰岛素对细胞的作用是通过细胞质膜的特异受体而实现的。Pasten等首先用抗胰岛素血清消除胰岛素作用的方法,间接证明这一点。Kono及Cuatrecasas等用各种酶改变脂肪细胞表     

胰岛素受体底物与信号转导

胰岛素受体底物 (IRS)家族包括 4种异构体蛋白 ,是多种信号转导受体的共同底物 ,其中通过与胰岛素受体 (IR)及胰岛素样生长因子 1(IGF 1)受体结合而介导的信号转导系统与糖代谢及生长发育 ,胰腺功能密切相关。IRS异构体具有组织特异性及不同亚细胞定位 ,共同介导胰岛素和IGF 1信号转导网络 ,发挥胰岛素和IGF 1的多向性细胞信号转导效应。蛋白激酶C等因素通过抑制IRS的酪氨酸磷酸化影响胰岛素和IGF 1的信号转导效应并与糖尿病的发生有关     

脑内胰岛素研究进展

近年来胰岛素在中枢神经系统的生物效应越来越受到神经科学工作者重视，本文就胰岛素与胰岛素样生长因子的分子结构、生理作用、脑内胰岛素的来源和脑内胰岛素受体的存在，胰岛素在神经细胞培养、周围神经和中枢神经系统损伤后促进再生和保护作用，以及胰岛素在中枢神经系统损伤后作用的实验研究等方面进行综述。     

胰岛素受体与VEGF

胰岛素受体与胰岛素结合后发生自身磷酸化并磷酸化底物,启动受体后信号传导途径,在胰岛素促代谢、促细胞生长繁殖作用中起重要作用。血管内皮生长因子(VEGF)参与肿瘤发生与发展、缺血性血管病变、糖尿病小血管异常增生等多种病理生理过程,受缺氧、多种生长因子、高胰岛素水平等多种因素的调控。胰岛素受体及其底物作为VEGF的调控因素之一可通过多种途径影响VEGF的表达。     

胰岛素样生长因子I受体与细胞凋亡信号转导

胰岛素样生长因子Ⅰ 受体 (IGF ⅠR)是一种跨膜受体 ,属于酪氨酸激酶受体家族 ,与胰岛素受体有高度的同源性。在接受其相应的配体刺激后 ,IGF ⅠR可以激活包括IRS 1,IRS 2 ,shc和PI3 激酶等多种胞内亚单位 ,产生级联信号转导反应 ,通过启动相关的信号转导通路来发挥抗细胞凋亡的生物学作用。     

胰岛素样生长因子Ⅰ受体与细胞凋亡信号转导

胰岛素样生长因子Ⅰ受体(IGF-ⅠR)是一种跨膜受体,属于酪氨酸激酶受体家族,与胰岛素受体有高度的同源性.在接受其相应的配体刺激后,IGF-ⅠR可以激活包括IRS-1,IRS*2,shc和PI3-激酶等多种胞内亚单位,产生级联信号转导反应,通过启动相关的信号转导通路来发挥抗细胞凋亡的生物学作用.     

胰岛素样生长因子家族与肺癌

胰岛素样生长因子 (IGFs)家族与多种肿瘤的发生发展关系密切。本文综述了IGFs和胰岛素样生长因子受体 (IGFRs)以及胰岛素样生长因子结合蛋白 (IGFBPs)在肺癌发生发展、增殖、侵袭、转移和凋亡中所起的作用及其作用机制 ,为肺癌的预防、治疗、预后提供新的思路     

结构反常的胰岛素导致糖尿病

胰岛素抗性患者的症状为对内源性分泌或外源性给予的胰岛素不能产生正常反应,因此即使血内胰岛素水平很高,仍有严重糖尿。过去发现大多数患者的病因是靶细胞不正常,或循环中有胰岛素拮抗物或反调节激素的存在。靶细胞不正常包括外周细胞膜上姨岛素受体减少,或激素与受体作用后反应减弱等细胞缺损;循环内拮抗物质包括抗胰岛素的抗体以及抗受体的抗体。本文报告一例糖尿病患者属于新的病因,患者对内源性分泌的胰岛素有抗性,但对外源性给予的胰岛素没有抗性,饥俄时血内葡萄塘与胰岛素水平都比正常的高,血内不含胰岛素或其受体的抗体。从患者胰腺中分出胰岛素,试验在大鼠脂细胞内兴     

糖尿病与胰岛素受体酪氨酸激酶区突变有关

大多数非胰岛素依赖型糖尿病人对胰岛素的生物作用具有拮抗,这是引起糖尿病的主要因素之一。胰岛素作用的第一步是与其受体结合,因此,胰岛素受体的功能缺损便成为糖尿病患者产生胰岛素拮抗的原因。当胰岛素与受体的细胞外区域结合时,受体便开始进行自磷酸化,与受体的细胞内区域有关的酪氨酸激酶被活化,从而激发靶细胞中的生物     

胰岛素信号通路与动脉粥样硬化

动脉粥样硬化(atherosclerosis,AS)性血管病变是导致2型糖尿病患者致残、致死的主要原因之一.最终大部分糖尿病患者死于AS相关并发症.胰岛素分泌不足和胰岛素抵抗是2型糖尿病的主要病理生理特征.胰岛素受体广泛分布于全身各个器官和组织,胰岛素受体信号通路的激活对维持细胞正常生理功能有重要的作用.     

Newer insulin analogues and inhaled insulin

Diabetes is a metabolic disease with high prevalence worldwide. Exogenous insulin is used in the management of this condition. The development of human insulin has provided tighter control of glycaemia in diabetic patients. Insulin analogues like insulin lispro and aspart were developed to closely match its profile with physiological secretion. The newer additions to this armamentarium are insulin glulisine, insulin detemir and albulin. Insulin glulisine is a short acting analogue with a rapid onset of action. The antiapoptotic property, mediated through insulin substrate receptor-2 has a favourable protective action on beta cells. Insulin detemir is a long acting analogue, soluble at neutral pH, which reversibly binds to albumin in plasma, prolonging its action. Its lower affinity for insulin receptors necessitates higher doses compared to human insulin. The reduction in body weight is an additional advantage of detemir. A major concern about all newer insulin analogues is their altered mitogenic properties and resultant risk of carcinogenicity on long term use. Albulin is a latest addition of insulin analogue which is under various in vitro and in vivo studies. Inhaled insulin in powder form (Exubera) is recently approved by FDA and appears promising.     

Spontaneous insulin fluctuations and the preabsorptive insulin response to food ingestion in humans

Insulin secretion occurs in response to cephalic stimulation by foods; in humans, the response is quite variable and its importance in meal situations is difficult to assess. Insulinemia also varies spontaneously in the absence of food stimulation. In the present work, a comparative study of spontaneous and food-associated insulinemia changes was performed. Spontaneous preprandial fluctuations of glycemia and insulinemia were recorded and the presence of significant oscillations or trends was investigated. Premeal changes in insulinemia then served as a basis for evaluating the preabsorptive insulin response (PIR) during food ingestion. A sinewave fitted to preprandial insulin oscillations did not appear satisfactory as a basis for the assessment of the PIR. Significant PIRs were then defined in terms of deviation from a confidence interval (mean of the preprandial values +/- 2 SD). Significant PIRs were more frequent when the food presented was more palatable. Individual differences in responsiveness appeared. The physiological significance of a PIR over a background of spontaneous fluctuations is discussed.     

Validity and use of a non-parallel insulin assay for pharmacokinetic studies of the rapid-acting insulin analogue, insulin aspart

A radioimmunoassay (RIA) for insulin was validated for reliable measurement of the human insulin analogue, insulin aspart, by correction of non-linear measurements. Specificity was equivalent for several species of insulin, except insulin aspart. A non-linear hyperbolic model fitted insulin aspart with a correction formula for non-linearity of: z = 1,503y/ (1,398 - y), where y denotes measured concentration and z denotes true concentration. Matrix-effects were insignificant for human, porcine, and canine heparin-plasma and for human and porcine serum. The coefficient of variation was below 15% for 80-800 pmol/L human and porcine insulin and for 80-600 pmol/L insulin aspart. The limit of detection for insulin aspart was 11.5 pmol/L with a lower limit of quantification of 17.5 pmol/ L. Dilution of serum with Pharmacia dilution media introduced no significant error. In conclusion, this paper demonstrates that a non-parallel radioimmunoassay can be used to estimate accurate concentrations of insulin aspart.     

Goblet cell-targeting nanoparticles for oral insulin delivery and the influence of mucus on insulin transport

The present study was to demonstrate the effects of goblet cell-targeting nanoparticles on the oral absorption of insulin in vitro, ex vivo and in vivo, and identify the targeting mechanism as well as the influence of mucus. The insulin loaded nanoparticles were prepared using trimethyl chitosan chloride (TMC) modified with a CSKSSDYQC (CSK) targeting peptide. Compared with unmodified nanoparticles, the CSK peptide modification could facilitate the uptake of nanoparticles in villi, enhance the permeation of drugs across the epithelium, meanwhile, induce a significantly higher internalization of drugs via clathrin and caveolae mediated endocytosis on goblet cell-like HT29-MTX cells. In transport studies across Caco-2/HT29-MTX co-cultured cell monolayer (simulating intestinal epithelium), the CSK peptide modification also showed enhanced transport ability, even if the targeting recognition was partially affected by mucus. Moreover, it was found the existence of mucus was propitious to the transport of insulin from both modified and unmodified nanoparticles. In the pharmacological and pharmacokinetic studies in diabetic rats, the orally administrated CSK peptide modified nanoparticles produced a better hypoglycemic effect with a 1.5-fold higher relative bioavailability compared with unmodified ones. In conclusion, CSK peptide modified TMC nanoparticles showed sufficient effectiveness as goblet cell-targeting nanocarriers for oral delivery of insulin.