胰岛素受体底物-2与胰岛素抵抗

所谓胰岛素抵抗是指正常剂量的胰岛素低于正常生物学效应的一种状态.胰岛素在体内发挥其生理作用的过程,有以下几步:(1)胰岛素与靶细胞上的胰岛素受体特异性结合;(2)胰岛素与其受体结合后发生一系列生化反应,使其生物信号得以转导和放大;(3)产生一系列生物效应.在上述过程中任何一个或数个环节的异常均可导致胰岛素抵抗.     

肝胰岛素抵抗的研究进展

胰岛素受体底物蛋白-2信号转导异常（影响因素如：蛋白和脂类磷酸酶、脂源性细胞因子、过氧化物酶体增生物激活受体等）、游离脂肪酸、胰淀素等均可导致胰岛素抑制内源性葡萄糖生成的能力减弱和肝糖原合成减少,一旦高分泌量的胰岛素无法代偿,即出现空腹血糖升高,表现为胰岛素抵抗。减轻肝胰岛素抵抗,作为治疗2型糖尿病是很有前景的。     

胰岛素受体底物-2与胰岛素抵抗

所谓胰岛素抵抗是指正常剂量的胰岛素低于正常生物学效应的一种状态。胰岛素在体内发挥其生理作用的过程,有以下几步：（1）胰岛素与靶细胞上的胰岛素受体特异性结合;（2）胰岛素与其受体结合后发生一系列生化反应,使其生物信号得以转导和放大;（3）产生一系列生物效应。在上述过程中任何一个或数个环节的异常均可导致胰岛素抵抗。     

高胰岛素血症诱导胰岛素抵抗与血糖浓度增加有关

目的 探讨高浓度胰岛素和高浓度葡萄糖共同作用对原代培养老鼠脂肪细胞的糖转运活动、细胞内胰岛素信号肽及葡萄糖转运子4（GLUT4）易位的影响。方法 分离的老鼠脂肪细胞在胰岛素（10^4μU/ml)和不同浓度葡萄糖（5、10、15、25mM)培养基中孵育24h,然后测定糖的转运活动;用Western blot方法测定这些细胞内胰岛素受体底物（IRS）1／2、肌醇磷脂－3－激酶85亚单位（p85)、蛋白激酶B（PKB）和GLUT4的蛋白表达。结果 胰岛素和不同高浓度葡萄糖培养24h,以一种剂量依赖的方式诱导糖摄取率的减少,抑制了IRS蛋白表达,而不影响p85、PKB和GLUT4的表达,但抑制了GLUT4易位至质膜;胰岛素加正常或不同高浓度葡萄糖治疗,均抑制了IRS2蛋白表达。结论 慢性胰岛素治疗诱导的胰岛素抵抗与周围环境中葡萄糖浓度增加有关,可能影响了胰岛素受体底物蛋白表达以及GLUT4易位等。     

糖皮质激素诱导胰岛素抵抗的分子机理

目的：探讨糖皮质激素以原代培养老鼠脂肪细胞的糖转运活动及胰岛素信号肽的信号,方法：分离的老鼠脂肪细胞在5mmol浓度葡萄糖加塞米松0．3μmol分别孵育2h,8h,16h,和24h,然后测定糖的转运活动;Western blotting测定细胞内胰岛素受体底物（IRS）1／2、肌醇磷脂－3－激酶85亚单位（p85)和蛋白激酶B（PKB）的蛋白表达。结果：地塞米松治疗抑制了基础的和胰岛素刺激的葡萄糖转运活动,产生最大抑制作用时间分别为2h和24h ,对IRS1的3蛋白表达的抑制作用与培养的时间长短成正比,同时,它也削弱了P85和PKB的蛋白表达,但对IRS2呈现上高作用。结论：糖皮质激素可以抑制葡萄糖的转运活动,诱导胰岛素抵抗。其机理可能与改变胰岛信号肽的表达等因素有关。     

酒精对高脂喂养大鼠肝脏胰岛素抵抗的影响

目的探讨长期高脂饮食状态下不同剂量酒精摄入对大鼠胰岛素抵抗的影响及可能机制。方法清洁级Wistar大鼠,随机分为正常对照、高脂对照、高脂+5%、10%、20%、30%、40%酒精共7组。13w后,断头取血,测空腹血糖(FPG)及血胰岛素(FINS)浓度,计算胰岛素抵抗指数(homeostasis model assessment,HOMA-IR)及HOMA-β功能指数(HOMAβ-cellindex,HBCI)。RT-PCR法测定肝脏胰岛素受体底物-1(IRS-1),磷脂酰肌醇3激酶(PI-3K)、葡萄糖转运体-2(GLUT-2)的mRNA表达水平。Westernblotting测定肝脏PI-3K(p85α)、GLUT-2的蛋白表达水平。结果高脂对照组与正常对照组比,血胰岛素、HOMA-IR、HBCI明显升高(P0.05),肝脏胰岛素信号传导关键分子没有显著差异。与高脂对照组比,高脂+酒精组空腹血糖、胰岛素抵抗指数明显升高(P0.05),血胰岛素、胰岛β细胞功能指数明显下降(P0.05);肝脏胰岛素信号传导关键分子mRNA、蛋白表达水平随酒精剂量的增加而逐渐下降。结论长期高脂饮食联合酒精摄入导致胰岛素抵抗;同时抑制肝脏胰岛素信号传导关键分子表达水平,在高剂量酒精组更明显,这可能是其导致胰岛素抵抗的分子机制。     

PCOS患者IRS-2及酪氨酸磷酸化的表达

目的 研究多囊卵巢综合征患者脂肪组织胰岛素受体底物-2蛋白的表达及其酪氨酸磷酸化,探讨其在多囊卵巢综合征产生胰岛素抵抗中的作用.方法 采用放射免疫法检测多囊卵巢综合征胰岛素抵抗组(24例)、多囊卵巢综合征非胰岛素抵抗组(15例)及对照组(20例)血清空腹胰岛素的浓度;葡萄糖氧化酶法测定血浆空腹血糖;稳态模型计算胰岛素抵抗指数;Western blot方法检测胰岛素受体底物-2蛋白的表达,应用免疫沉淀及增强化学发光法检测酪氨酸磷酸化程度.结果 ①多囊卵巢综合征胰岛素抵抗组患者血清空腹胰岛素及胰岛素抵抗指数均显著高于多囊卵巢综合征非胰岛素抵抗组与对照组(F=66.25,P＜0.01;F=97.31,P＜0.01);多囊卵巢综合征非胰岛素抵抗组患者血清空腹胰岛素及胰岛素抵抗指数亦显著高于对照组(均P＜0.05);②多囊卵巢综合征胰岛素抵抗组、多囊卵巢综合征非胰岛素抵抗组及对照组3组相比较,胰岛素受体底物-2蛋白表达无显著性差别;③多囊卵巢综合征胰岛素抵抗组胰岛素受体底物-2蛋白质酪氨酸磷酸化程度显著降低(F=48.12,P＜0.05).结论 多囊卵巢综合征患者脂肪组织胰岛素受体底物-2蛋白质酪氨酸磷酸化程度降低,可能是其产生胰岛素抵抗的机制之一.     

糖皮质激素加重高糖诱导的胰岛素抵抗

目的 探讨糖皮质激素和高浓度糖（高糖）共同作用诱导胰岛素抵抗的分子机理。方法 分离的大鼠脂肪细胞在5.25mM葡萄糖或加地塞米松（Dex）0.3μM培养基中孵育24h，然后测定葡萄糖的转运率，胰岛素受体底物（IRS）1／2的酪氨酸磷酸化、IRS1／2及蛋白激酶B（PKB）的蛋白表达。结果 高糖抑制了这些细胞的糖摄取率、IRS1酪氨酸磷酸化及蛋白表达，Dex加重高糖的以上抑制作用；高糖增加IRS2蛋白表达，Dex部分对抗高糖的此作用及抑制IRS2酪氨酸磷酸化。结论 高糖能诱导胰岛素抵抗，Dex加重高糖的此作用。其作用机制与影响胰岛素信号蛋白磷酸化及蛋白表达等因素有关。     

TLR4与胰岛素抵抗研究进展

Toll样受体家族(Toll-like receptors,TLRs)是哺乳动物体内唯一可以将细胞外抗原识别信息向细胞内传递并引发炎症反应的跨膜蛋白,在已发现的11种TLR中,TLR4是研究热点之一.TLR4与炎症有着密不可分的关系,胰岛素抵抗早期即处于一种慢性炎症状态,治疗胰岛素抵抗对预防Ⅱ型糖尿病有重要作用[1]. 1 TLR4的调节作用 存在于Kupffer细胞(肝巨噬细胞)和其他巨噬细胞的脂联素刺激TLR4信号通路,激活下游腺苷酸活化蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK),白介素10(interleukin-10,IL-10)和血红素氧-1,其中巨噬细胞内的AMPK可抑制脂多糖诱导核因子κB抑制蛋白(inhibitor of KB,IκB)和激活cAMP应答元件结合蛋白(cAMP response element blinding protein,CREB).活性核受体转录因子糖皮质激素受体(glucocorticoid receptor,GR)、过氧化物酶体增殖物激活受体γ(peroxisome proliferators-activated receptorγ,PPARγ)和肝脏X受体α(liver Xreceptorα,LXRα)均会干扰TLR4基因转录和TLR4介导的炎症反应.     

胰岛素抵抗可引发中老年人常见慢性病

什么是胰岛素抵抗及胰岛素抵抗综合征在骨骼肌、脂肪和肝脏细胞表面,广泛分布对胰岛素有高度亲和力的胰岛素受体。生理状态下,胰岛素只有与胰岛素受体结合,才能发挥降糖作用。在糖尿病患者中,90%以上是由于胰岛素受体被非特异性的有害酸     

Assessment of insulin secretion in relation to insulin resistance

PURPOSE OF REVIEW: In healthy individuals, upregulation of insulin secretion compensates for insulin resistance so that normal glucose tolerance is maintained. Thus insulin secretion should be evaluated in relation to insulin sensitivity, as failure to account for insulin resistance may prevent the detection of beta-cell defects. Numerous studies have considered this problem, but how insulin secretion is regulated by insulin sensitivity and how insulin secretion should be quantitatively expressed to account for sensitivity are issues still under debate. This review will discuss these concepts and the aspects that should be considered for an appropriate solution to the problem. RECENT FINDINGS: While the historical paradigm of a specific hyperbolic relationship between some particular insulin secretion and insulin sensitivity indices has recently been confirmed, it has been suggested that this paradigm is not applicable to all the indices. It has also been suggested that for some relevant insulin secretion indices this relationship may not exist. Thus, the classical insulin secretion index that accounts for sensitivity, the so-called disposition index, should be used cautiously, as it presupposes a hyperbolic relationship. Furthermore, it has been pointed out that the assessment of this relationship requires independency of the indices. SUMMARY: The assessment of insulin secretion in relation to insulin sensitivity is important in the study of glycemic control but requires appropriate methods and cautious interpretations. Blind application of principles that are valid for specific insulin secretion and sensitivity indices may produce false results.     

胰岛素分泌不足与胰岛素抵抗的临床诊断

现今认为胰岛素分泌不足 (ｉｎｓｕｌｉｎｈｙｐｏ -ｓｅｃｒｅ ｔｉｏｎ ,ＩＨ)与胰岛素抵抗 (ｉｎｓｕｌｉｎｒｅｓｉｓｔａｎｃｅ ,ＩＲ)是糖尿病的两大病因 ,保护胰岛素分泌功能、减轻胰岛素抵抗状态是现代糖尿病治疗的两大关键和原则。临床上除了少见的 ,已明确的许多单基因突变所致的特殊类型糖尿病外 ,占临床糖尿病绝大多数的是 2型及 1型糖尿病 ,其与多基因遗传和生活环境联合影响有关 ,均存在胰岛素生理作用低下 (即ＩＲ)和胰岛素分泌相对或绝对不足 ,只是在病型、病程各阶段其因果关系和构成比例有所不同。所有种类的口服降糖药物…     

Vitamin D, glucose, insulin, and insulin sensitivity

This review examines available evidence of links between abnormalities of glucose and insulin metabolism and vitamin D deficiency. Possible mechanisms of action of vitamin D include stimulation of insulin secretion and effects on insulin sensitivity. Sun exposure usually implies greater outdoor physical activity, which in itself may have beneficial effects on insulin sensitivity, unrelated to serum 25-hydroxyvitamin D concentrations. The observed associations in humans among vitamin D, insulin, and glucose metabolism have not yet been confirmed by intervention studies and, hence, a causal association has not been established. Clinical trials are needed to determine whether vitamin D treatment of vitamin D-deficient individuals is able to prevent or treat diabetes mellitus.     

The use of human insulin in cases of insulin allergy

The authors treated 14 insulin-allergic diabetic patients in 1985-87. Previous short-term therapy with conventional insulins could be verified in 12 cases. The "presensitizing" effect of this transient treatment seems highly probable. Five of the 14 patients were allergic to all animal insulins incl. monospecies porcine monocomponent (MC) preparations. Surprisingly, all these patients proved to be allergic to biosynthetic human insulin (Huminsulin Normal and Huminsulin Basal) preparations too, but two of them could be treated with semisynthetic human insulins (Actrapid HM and Monotard HM). Another patient was able to receive Monotard HM exclusively. The remaining two patients proved to be allergic to all human insulins used. One of them was desensitized but the insulin therapy had to be supplemented with steroid drugs for two years. The fifth patient continued the oral treatment but her metabolism is poorly controlled. These results show that some diabetics with allergy to animal insulins are allergic to human insulins as well. As a prevention, transient therapy with conventional preparations should be avoided. If, however, there is an absolute indication for it (e.g. gestational diabetes or surgical intervention), it should be carried out with human insulin, or, if that is not available, with monospecies porcine MC insulin.