2型糖尿病患者血清睫状神经营养因子水平的变化及其临床意义

目的 探讨血清睫状神经营养因子（CNTF）水平与T2DM及肥胖的相关性与临床意义.方法 选择44名糖耐量正常（NGT组）者和44例新诊断T2 DM（T2 DM组）患者按BMI各自分为超重（Ob）和正常体重（Nob）亚组.ELISA法测定血清CNTF水平.结果 T2DM组血清CNTF的浓度较NGT组降低（P＜0.05）.相关分析显示,T2DM组中CNTF与TC、HbA1c、FPG、HOMA-IR呈负相关.HOMA-IR是血清CNTF的独立相关因素.结论 T2DM患者CNTF水平降低,与TC、HbA1c、FPG、HOMA-IR呈负相关,HOMA-IR是CNTF.独立相关因素.     

血管紧张素转换酶2与糖尿病肾病

睫状神经营养因子(CNTF)属1型细胞因子超家族,结构与白细胞介素6相似。近年来发现其不仅对神经系统有重要作用,对代谢系统也有影响。CNTF可作用于中枢神经系统和外周肝脏、脂肪组织等,抑制食欲、增加能量消耗、减轻体重,尤其对瘦素抵抗型肥胖者的作用更明显;并可调节血糖和血脂代谢,改善胰岛素水平;对改善糖尿病神经病变和视网膜病变等糖尿病慢性并发症有一定疗效。     

睫状神经营养因子及受体的研究进展

睫状神经营养因子（ＣＮＴＦ）自７０年代发现以来倍受重视，其对神经细胞的生长、分化具有明显的营养作用。有关ＣＮＴＦ及其受体的组织分布、蛋白质和基因的分子结构、生物学活性、表达调节等的研究取得了新的进展并展现了临床应用前景。     

硫氢化钠对糖尿病视神经病变大鼠氧化应激及血浆睫状神经营养因子水平的影响

目的探讨外源性硫化氢(H_2S)供体硫氢化钠(Na HS)对糖尿病(DM)大鼠视神经病变(DON)的防治作用及其对氧化应激睫状神经营养因子(CNTF)的影响。方法在50只SD大鼠随机抽取10只作为对照组,另40只建立DON模型,对32只造模成功大鼠以随机数字表法随机分为DM模型组和Na HS处理组,各16只。Na HS处理组通过玻璃体腔注射Na HS生理盐水溶液(剂量为100μmol/kg体重),对照组和DM模型组注射等量生理盐水,1次/d,共8 w。对三组大鼠的视神经髓鞘切片行劳克坚牢蓝染色,观察三组切片中视神经髓鞘结构的组织病理学改变,并比较髓鞘所占比率的差异,以紫外分光光度法测定血浆中的H_2S水平,分别采用试剂盒检测血浆中氧化应激指标活性氧(ROS)、丙二醛(MDA)和超氧化物歧化酶(SOD)水平,酶联免疫法(ELISA)试剂盒检测血浆CNTF水平。结果 8 w后三组大鼠血浆中H_2S水平比较差异显著,且Na HS处理组高于DM模型组和对照组(P0.05);显微镜下可见DM模型组与Na HS处理组大鼠的视神经髓鞘结构出现明显溃变,Na HS处理组溃变程度较DM模型组明显减轻,两组髓鞘比率显著低于对照组,而Na HS处理组高于糖尿病模型组(P0.05);DM模型组和Na HS处理组大鼠的ROS和MDA水平显著高于对照组,而Na HS处理组水平低于DM模型组(P0.05);DM模型组和Na HS处理组大鼠的SOD水平及CNTF水平均低于对照组,而Na HS处理组水平高于DM模型组(P0.05)。结论玻璃体腔注射Na HS可作为外源性H_2S供体,提高体内的H_2S水平,而H2S可以防治DON,其机制可能与改善氧化应激损伤,提高血浆中CNTF水平有关。     

睫状神经营养因子与七叶皂苷钠联合应用对大鼠脊髓牵拉伤后细胞凋亡的影响

目的 探讨睫状神经营养因子(CNTF)与七叶皂苷钠(SE)联合应用对脊髓牵拉损伤的保护作用.方法 72只大鼠随机分为模型对照组、CNTF治疗组及CNTF+SE治疗组,牵拉致伤T10-12脊髓建立脊髓牵拉损伤模型.CNTF组经尾静脉注入CNTF20μl;CNTF+SE组除同法应用CNTF外,术后次日始腹腔内注射七叶皂苷钠1.5 mg·kg-1·d-1,连续应用7 d;模型对照组以相同方法给予等量生理盐水.伤后1 d、3 d、7 d、14 d进行BBB行为学评分,每组6只,然后处死动物取脊髓分别作HE染色、免疫组化及TUNEL,观察神经细胞结构的变化,并检测bcl-2、Bax阳性细胞及凋亡细胞.结果 (1)bcl-2:实验组7 d达高峰,CNTF组为(44.27±5.93)%,CNTF+SE组(46.26±6.01)%,模型对照组为(27.46±5.65)%,差异有统计学意义(P＜0.05);(2)bax:实验组3d达高峰,CNTF组为(39.15±5.91)%,CNTF+SE组(32.63±5.34)%,模型对照组为(46.69±7.52)%,差异有统计学意义(P＜0.05).(3)各时间点治疗组细胞凋亡指数较模型对照组低.结论 睫状神经营养因子与七叶皂苷钠对大鼠脊髓牵拉造成的损伤有保护作用,二者联合应用具有协同作用.     

2型糖尿病患者血清脑源性神经营养因子的变化及其临床意义

目的 探讨T2DM患者血清脑源性神经营养因子（BDNF）与APN、瘦素（LP）、胰岛素抵抗指数（HOMA-IR）和ISI的相关性. 方法 选取T2DM组102例和健康对照（NC）组97名,将T2DM组进一步分为体重正常（N-OB）亚组53例和超重（OB）亚组49例.采用RT-PCR检测BDNF表达水平.对T2DM组BDNF表达水平的相关因素行Pearson相关性及多因素线性回归分析. 结果 OB亚组BMI、TG、APN、LP和BDNF较N-OB亚组、NC组低（P＜0.05或P＜0.01）.多因素线性回归分析显示,仅LP进入回归方程. 结论 T2DM患者BDNF表达水平降低,与LP呈正相关.     

中老年2型糖尿病血清瘦素水平与超重或肥胖、血糖、胰岛素的关系

目的 研究中老年2型糖尿病（T2DM）肥胖与非肥胖患者血清瘦素与肥胖、血糖、胰岛素抵抗（IR）之间的关系。方法对样本人群进行体检并测定血清瘦素、空腹C肽（FCP）、空腹胰岛素（FINS）及血糖（FPG）等生化指标并对结果进行统计分析。结果 （1）T2DM组无论男女血清瘦素水平均显著高于对照组（P〈0．01），且女性组显著高于男性组（P〈0．01）；（2）T2DM超重或肥胖组血清瘦素水平显著高于非肥胖组且与腹型肥胖密切相关；（3）T2DMIR组血清瘦素水平显著高于胰岛素敏感组（P〈0．01），并与FINS、C肽呈正相关；（4）T2DM肥胖组血清瘦素水平与收缩压（SBP）、舒张压（DBP）、糖化血红蛋白（HbAlc）、甘油三酯（TG）呈正相关。结论 T2DM血清瘦素水平与超重或肥胖、IR、长期的血压、TG及血糖的平均水平关系密切。减肥，改善瘦素抵抗，增加机体对瘦素的敏感性对治疗T2DM可能提供帮助。     

2型糖尿病胰岛素抵抗与瘦素及糖尿病肾病的关系

为探讨 2型糖尿病患者胰岛素抵抗与瘦素和糖尿病肾病(DN)的关系 ,我们对 2 0 0 1年 7月以来在本院门诊治疗和住院的 112例 2型糖尿病患者观察了胰岛素敏感指数 (IAI)、瘦素 (L PT)和尿白蛋白排泄率 (UAER)。现报告如下。临床资料 :112例 2型糖尿病患者均按 WHO标准确诊 ,男 6 0例 ,女 5 2例 ;年龄 4 0～ 6 5岁 ;病程 1～ 6年。根据本院正常值将 112例 2型糖尿病患者分为 :1A组 :即 IAI异常组、胰岛素抵抗 (IR)组。男 30例 ,女 2 8例 ;年龄 4 0～ 6 5岁。 2 B组 :即 IAI正常组、非胰岛素抵抗 (NIR)组。男 30例 ,女 2 4例 ;年龄 4…     

老年2型糖尿病患者并发抑郁症与脑源性神经营养因子的相关性

目的 研究老年2型糖尿病并发抑郁症与脑源性神经营养因子（BDNF）的相关性,探讨老年糖尿病抑郁症的发病机制.方法 将2008年3月至2009年12月收治的241例年龄≥65岁的老年2型糖尿病患者根据流行病学研究中心抑郁量表（CES-D）和患者健康问卷抑郁量表（PHQ-9）问卷得分,分为糖尿病非抑郁组（NDDM组）187例和糖尿病抑郁组（DDM组）54例;以年龄和性别相匹配的52名健康体检者为健康对照组（NC组）.采用聚合酶链反应-限制性片段长度多态性分析（PCR-RFLP）法检测BDNF基因Val66Met多态性,酶联免疫吸附试验（ELISA）法测定血清中的BDNF水平.组间数据比较采用独立样本t检验、单因素方差分析和SNK法.结果 本研究中老年2型糖尿病患者抑郁症患病率为22.4%,其中男性为17.7%,女性为27.1%.与NDDM组相比,DDM组女性较多、并发症较多、血糖控制较差、体质指数较高、丧偶比例较高（均P＜0.05）.NDDM和DDM组年龄、病程间差异无统计学意义（P＞0.05）.NC、NDDM、DDM组BDNF Val66Met基因型构成相比差异有统计学意义（x^2=10.970,P＜0.05）,3组Met（A）等位基因频率分别为38.4%、38.8%和53.7%,3组差异有统计学意义（x^2=8.145,P＜0.05）.BDNF Val/Val、Val/Met、Met/Met组的PHQ-9问卷得分分别为3.2±0.9、3.9±1.2和8.1±2.7,差异有统计学意义（F=6.520,P＜0.01）.NC、NDDM、DDM组血清BDNF水平分别为：（86±10）、（80±9）和（77±10）ng/L,3组间比较差异有统计学意义（F=28.450,P＜0.01）.多元回归分析发现,女性、丧偶、并发症多、血糖控制差、体质指数高、BDNF Val66Met基因多态性是老年2型糖尿病患者并发抑郁症的危险因素.结论 并发抑郁症的老年2型糖尿病患者血清BDNF水平下降.BDNF Val66Met基因多态性在老年糖尿病并发抑郁症发病机制中具有一定作用,与抑郁程度有关.     

2型糖尿病患者肥胖与胰岛素抵抗的关系

目的观察照2型糖尿病患者肥胖和胰岛素抵抗的关系.方法对正常对照组20例,肥胖2型糖尿病患者41例,非肥胖2型糖尿病患者17例,分别检测体重指数（BMI）、腰围、臀围、空腹血糖（FBG）、胰岛素（INS）,计算腰臀比（WHR）和胰岛素敏感指数（ISI）,并进行对比分析.结果肥胖2型糖尿病患者较非肥胖者FBG、BMI、WHR均显著升高（P＜0.05）,但ISI显著降低（P＜0.01）.结论肥胖的2型糖尿病患者存在更为严重的胰岛素抵抗.     

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

Aims/hypothesis Decreased levels of brain-derived neurotrophic factor (BDNF) have been implicated in the pathogenesis of Alzheimer’s disease and depression. These disorders are associated with type 2 diabetes, and animal models suggest that BDNF plays a role in insulin resistance. We therefore explored whether BDNF plays a role in human glucose metabolism. Subjects and methods We included (Study 1) 233 humans divided into four groups depending on presence or absence of type 2 diabetes and presence or absence of obesity; and (Study 2) seven healthy volunteers who underwent both a hyperglycaemic and a hyperinsulinaemic–euglycaemic clamp. Results Plasma levels of BDNF in Study 1 were decreased in humans with type 2 diabetes independently of obesity. Plasma BDNF was inversely associated with fasting plasma glucose, but not with insulin. No association was found between the BDNF G196A (Val66Met) polymorphism and diabetes or obesity. In Study 2 an output of BDNF from the human brain was detected at basal conditions. This output was inhibited when blood glucose levels were elevated. In contrast, when plasma insulin was increased while maintaining normal blood glucose, the cerebral output of BDNF was not inhibited, indicating that high levels of glucose, but not insulin, inhibit the output of BDNF from the human brain. Conclusions/interpretation Low levels of BDNF accompany impaired glucose metabolism. Decreased BDNF may be a pathogenetic factor involved not only in dementia and depression, but also in type 2 diabetes, potentially explaining the clustering of these conditions in epidemiological studies.     

Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance

Aims/hypothesis  

Ciliary neurotrophic factor (CNTF) improves metabolic variables of obese animals with characteristics of type 2 diabetes, mainly by reducing insulin resistance. We evaluated whether CNTF was able to improve other metabolic variables in mouse models of type 2 diabetes, such as beta cell mass and insulin clearance, and whether CNTF has any effect on non-obese mice with characteristics of type 2 diabetes.     

Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance

Receptor subunits for the neurocytokine ciliary neurotrophic factor (CNTF) share sequence similarity with the receptor for leptin, an adipocyte-derived cytokine involved in body weight homeostasis. We report here that CNTF and leptin activate a similar pattern of STAT factors in neuronal cells, and that mRNAs for CNTF receptor subunits, similarly to the mRNA of leptin receptor, are localized in mouse hypothalamic nuclei involved in the regulation of energy balance. Systemic administration of CNTF or leptin led to rapid induction of the tis-11 primary response gene in the arcuate nucleus, suggesting that both cytokines can signal to hypothalamic satiety centers. Consistent with this idea, CNTF treatment of ob/ob mice, which lack functional leptin, was found to reduce the adiposity, hyperphagia, and hyperinsulinemia associated with leptin deficiency. Unlike leptin, CNTF also reduced obesity-related phenotypes in db/db mice, which lack functional leptin receptor, and in mice with diet-induced obesity, which are partially resistant to the actions of leptin. The identification of a cytokine-mediated anti-obesity mechanism that acts independently of the leptin system may help to develop strategies for the treatment of obesity associated with leptin resistance.     

Ciliary neurotrophic factor is an endogenous pyrogen.

Fever is initiated by the action of polypeptide cytokines called endogenous pyrogens, which are produced by the host during inflammation, trauma, or infection and which elevate the thermoregulatory set point in the hypothalamus. Ciliary neurotrophic factor (CNTF) supports the differentiation and survival of central and peripheral neurons. We describe the activity of CNTF as intrinsically pyrogenic in the rabbit. CNTF induced a monophasic fever which rose rapidly (within the first 12 min) following intravenous injection; CNTF fever was blocked by pretreatment with indomethacin. The fever induced by CNTF was not due to contaminating endotoxins. Increasing doses of CNTF resulted in prolongation of the fever, suggesting the subsequent induction of additional endogenous pyrogenic activity. After passive transfer of plasma obtained during CNTF-induced fever, endogenous pyrogen activity was not present in the circulation; CNTF also did not induce the endogenous pyrogens interleukin 1, tumor necrosis factor, or interleukin 6 in vitro. Nevertheless, a second endogenous pyrogen may originate within the central nervous system following the systemic injection of CNTF. Of the four endogenous pyrogens described to date (interleukin 1, tumor necrosis factor, interferon, and interleukin 6), CNTF, like interleukin 6, utilizes the cell-surface gp 130 signal-transduction apparatus.     

Ciliary neurotrophic factor promotes survival of neonatal rat islets via the BCL-2 anti-apoptotic pathway

Ciliary neurotrophic factor (CNTF) belongs to the cytokine family and increases neuron differentiation and/or survival. Pancreatic islets are richly innervated and express receptors for nerve growth factors (NGFs) and may undergo neurotypic responses. CNTF is found in pancreatic islets and exerts paracrine effects in neighboring cells. The aim of this study was to investigate possible effects of CNTF on neonatal rat pancreatic islet differentiation and/or survival. For this purpose, we isolated pancreatic islets from neonatal rats (1-2 days old) by the collagenase method and cultured for 3 days in RPMI medium with (CNTF) or without (CTL) 1 nM CNTF. Thereafter, glucose-stimulated insulin secretion (RIA), general metabolism by (NAD(P)H production; MTS), glucose metabolism ((14)CO(2) production), gene (RT-PCR), protein expression (western blotting), caspase-3 activity (Asp-Glu-Val-Asp (DEVD)), and apoptosis (DNA fragmentation) were analyzed. Our results showed that CNTF-treated islets demonstrated reduced glucose-induced insulin secretion. CNTF treatment did not affect glucose metabolism, as well as the expression of mRNAs and proteins that are crucial for the secretory process. Conversely, CNTF significantly increased mRNA and protein levels related to cell survival, such as Cx36, PAX4, and BCL-2, reduced caspase-3 activity, and islet cells apoptosis, suggesting that CNTF does not affect islet cell differentiation and, instead, acts as a survival factor reducing apoptosis by increasing the expression of the anti-apoptotic BCL-2 protein and decreasing caspase-3 activity.     

转录因子7样2与2型糖尿病

转录因子7样2(TCF7L2)基因是2型糖尿病最重要的易感基因之一,其基因变异体与2型糖尿病有强相关性,是目前2型糖尿病多因子遗传学领域中最引人注目的基因之一.这一结果在许多人种中都得以证实,而在我国关于该基因的研究刚刚起步.TCF7L2基因位于染色体10q25,共编码619个氨基酸,其产物是Wnt信号通路中一种转录因子.该因子通过对胰高血糖素样肽-1(GLP-1)水平调节,在糖代谢中起重要作用.另外,该信号通路与胰腺和胰岛的正常发育密切相关.