Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by a paucity of adipose (fat) tissue which is evident at birth and is accompanied by a severe resistance to insulin, leading to hyperinsulinaemia, hyperglycaemia and enlarged fatty liver. We have developed a mouse model that mimics these features of CGL: the syndrome occurs in transgenic mice expressing a truncated version of a nuclear protein known as nSREBP-1c (for sterol-regulatory-element-binding protein-1c) under the control of the adipose-specific aP2 enhancer. Adipose tissue from these mice was markedly deficient in messenger RNAs encoding several fat-specific proteins, including leptin, a fat-derived hormone that regulates food intake and energy metabolism. Here we show that insulin resistance in our lipodystrophic mice can be overcome by a continuous systemic infusion of low doses of recombinant leptin, an effect that is not mimicked by chronic food restriction. Our results support the idea that leptin modulates insulin sensitivity and glucose disposal independently of its effect on food intake, and that leptin deficiency accounts for the insulin resistance found in CGL.     

Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance

Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.     

同型半胱氨酸、超敏C反应蛋白与2型糖尿病合并高血压、冠心病关系的研究

目的探讨血浆同型半胱氨酸、超敏C反应蛋白水平与2型糖尿病合并高血压、冠心病的关系。方法将113例2型糖尿病患者依病情分为3组,即单纯2型糖尿病组45例（A组）。2型糖尿病合并高血压组38例（B组）,2型糖尿病合并冠心病组30例（c组）,以38例体检健康者为对照组。测定各组空腹同型半胱氨酸、超敏C反应蛋白水平。结果与正常对照组相比．3组2型糖尿病患者的平均同型半胱氨酸、超敏c反应蛋白水平升高,差异有统计学意义（P〈0．05）;2型糖尿病患者3组中,B组同型半胱氨酸、超敏C反应蛋白水平高于A组,差异有统计学意义（p〈0．05）;c组同型半胱氨酸、超敏C反应蛋白水平高于B组,且差异有统计学意义（P〈0．01）;同型半胱氨酸和超敏C反应蛋白水平无相关性。结论2型糖尿病合并高血压、冠心病时,同型半胱氨酸、超敏c反应蛋白水平显著升高;高同型半胱氨酸、超敏C反应蛋白是2型糖尿病发生血管病变的重要危险因素。     

HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus

Over half of the inherited predisposition to insulin-dependent diabetes mellitus maps to the region of chromosome 6 that contains the highly polymorphic HLA class II genes which determine immune responsiveness. Analysis of DNA sequences from diabetics indicates that alleles of HLA-DQ beta determine both disease susceptibility and resistance, and that the structure of the DQ molecule, in particular residue 57 of the beta-chain, specifies the autoimmune response against the insulin-producing islet cells.     

Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes

In obesity and type 2 diabetes, expression of the GLUT4 glucose transporter is decreased selectively in adipocytes. Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4(-/-)) mice show insulin resistance secondarily in muscle and liver. Here we show, using DNA arrays, that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4(-/-) mice. We show that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity and type 2 diabetes. RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance. Conversely, genetic deletion of Rbp4 enhances insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalizes serum RBP4 levels and improves insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impairs insulin signalling in muscle. Thus, RBP4 is an adipocyte-derived 'signal' that may contribute to the pathogenesis of type 2 diabetes. Lowering RBP4 could be a new strategy for treating type 2 diabetes.     

运动对2型糖尿病胰岛素抵抗相关因子的影响研究

通过分析运动对2型糖尿病胰岛素抵抗的相关因子的影响,发现2型糖尿病主要是胰岛素抵抗和胰岛素分泌受损所导致.因此,只要了解胰腺β细胞的胰岛素抵抗程度,就可以加以弥补,使葡萄糖耐受性维持正常.     

胰岛素治疗糖尿病常见的护理问题与对策

目的探讨胰岛素治疗糖尿病常见护理问题及对策。方法对148例使用胰岛素治疗糖尿病住院患者加强常见护理问题的观察及处理。结果148例糖尿病患者在使用胰岛素治疗过程中未出现不良反应。结论加强对使用胰岛素治疗糖尿病患者常见问题的观察护理是保证糖尿病患者治疗成功的关键。     

胰岛素治疗糖尿病常见的护理问题与对策

目的 探讨胰岛素治疗糖尿病常见护理问题及对策.方法 对148例使用胰岛素治疗糖尿病住院患者加强常见护理问题的观察及处理.结果 148例糖尿病患者在使用胰岛素治疗过程中未出现不良反应.结论 加强对使用胰岛素治疗糖尿病患者常见问题的观察护理是保证糖尿病患者治疗成功的关键.     

血糖控制良好的2型糖尿病患者血清VEGF—A及其受体VEGFR1和VEGFR2含量检测

研究目的：探讨血糖控制良好的2型糖尿病患者血管内皮生长因子-A（VEGF—A）及其受体VEGFR1和VEGFR2含量及其临床意义。研究方法：本文以31例血糖得到良好控制且没有明显大血管或微血管病变的2型糖尿病患者作为研究对象（实验组）,30位健康志愿者为对照组,同期检测患者及健康志愿者的空腹血糖、血脂、糖化血红蛋白水平,及血清VEGF—A、VEGFR1和VEGFR2含量,并加以比较和统计学分析。重要结论：研究结果表明,血糖控制良好的2型糖尿病患者血清中的VEGF-A及其受体VEGFR1和VEGFR2的含量和健康志愿者基本一致,两者无统计学意义,这可能显示血糖水平的合理控制能延缓血管并发症的产生。同时,2型糖尿病患者的血清VEGFR2含量和高密度脂蛋白胆固醇水平之间存在负相关,而血清VEGF-A、VEGFR2含量和甘油三脂水平之间存在正相关,这也表明糖尿病患者的血脂紊乱可能参与了血管生成的调节。     

伊贝沙坦对高血压合并糖尿病患者早期肾功能损害的干预研究

目的探讨高血压(EH)和糖尿病(DM)早期肾功能损害的测定指标,观察伊贝沙坦对EH和DM患者早期肾损害的影响.方法将60例EH合并DM患者按病程分为A组(病程＜3年),B组(病程3～5年),C组(病程＞5年)三组,分别测量三组患者的尿β2微球蛋白(β2-mG)、微量白蛋白(Alb)水平,同时与50名健康人作对照;将60例患者按入选顺序,随机分为伊贝沙坦组和依那普利组,观察治疗前后尿β2-mG、Alb的变化.结果EH合并DM患者尿β2-mG、Alb明显高于正常人(P＜.05或P＜0.01).尿β2-mG、Alb水平随糖尿病病程升高,其升高顺序为C组＞B组＞A组,伊贝沙坦与依那普利均有降低患者尿β2-mG、Alb的作用,但伊贝沙坦优于依那普利(P＜0.05).结论尿β1-mG、Alb是诊断EH和DM患者早期肾损害的敏感指标,伊贝沙坦有明显的改善EH和DM患者的早期肾功能作用.     

伊贝沙坦对高血压合并糖尿病患者早期肾功能损害的干预研究

目的探讨高血压(EH)和糖尿病(DM)早期肾功能损害的测定指标,观察伊贝沙坦对EH和DM患者早期肾损害的影响.方法将60例EH合并DM患者按病程分为A组(病程＜3年),B组(病程3～5年),C组(病程＞5年)三组,分别测量三组患者的尿β2微球蛋白(β2-mG)、微量白蛋白(Alb)水平,同时与50名健康人作对照;将60例患者按入选顺序,随机分为伊贝沙坦组和依那普利组,观察治疗前后尿β2-mG、Alb的变化.结果EH合并DM患者尿β2-mG、Alb明显高于正常人(P＜.05或P＜0.01).尿β2-mG、Alb水平随糖尿病病程升高,其升高顺序为C组＞B组＞A组,伊贝沙坦与依那普利均有降低患者尿β2-mG、Alb的作用,但伊贝沙坦优于依那普利(P＜0.05).结论尿β1-mG、Alb是诊断EH和DM患者早期肾损害的敏感指标,伊贝沙坦有明显的改善EH和DM患者的早期肾功能作用.     

Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis

Cystic fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Initially, Cl- conductance in the sweat duct was discovered to be impaired in CF, a finding that has been extended to all CFTR-expressing cells. Subsequent cloning of the gene showed that CFTR functions as a cyclic-AMP-regulated Cl- channel; and some CF-causing mutations inhibit CFTR Cl- channel activity. The identification of additional CF-causing mutants with normal Cl- channel activity indicates, however, that other CFTR-dependent processes contribute to the disease. Indeed, CFTR regulates other transporters, including Cl(-)-coupled HCO3- transport. Alkaline fluids are secreted by normal tissues, whereas acidic fluids are secreted by mutant CFTR-expressing tissues, indicating the importance of this activity. HCO3- and pH affect mucin viscosity and bacterial binding. We have examined Cl(-)-coupled HCO3- transport by CFTR mutants that retain substantial or normal Cl- channel activity. Here we show that mutants reported to be associated with CF with pancreatic insufficiency do not support HCO3- transport, and those associated with pancreatic sufficiency show reduced HCO3- transport. Our findings demonstrate the importance of HCO3- transport in the function of secretory epithelia and in CF.     

伊贝沙坦对高血压合并糖尿病患者早期肾功能损害的干预研究

目的探讨高血压(EH)和糖尿病(DM)早期肾功能损害的测定指标,观察伊贝沙坦对EH和DM患者早期肾损害的影响。方法将60例EH合并DM患者按病程分为A组(病程<3年),B组(病程3～5年),C组(病程>5年)三组,分别测量三组患者的尿β2微球蛋白(β2-mG)、微量白蛋白(Alb)水平,同时与50名健康人作对照;将60例患者按入选顺序,随机分为伊贝沙坦组和依那普利组,观察治疗前后尿β2-mG、Alb的变化。结果EH合并DM患者尿β2-mG、Alb明显高于正常人P(<0.05或P<0.01)。尿β2-m G、Alb水平随糖尿病病程升高,其升高顺序为C组>B组>A组,伊贝沙坦与依那普利均有降低患者尿β2-mG、Alb的作用,但伊贝沙坦优于依那普利P(<0.05)。结论尿β2-mG、Alb是诊断EH和DM患者早期肾损害的敏感指标,伊贝沙坦有明显的改善EH和D M患者的早期肾功能作用。     

Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport

The ATP-binding cassette (ABC) superfamily of transport systems now includes over thirty proteins that share extensive sequence similarity and domain organization. This superfamily includes the well characterized periplasmic binding protein-dependent uptake systems of prokaryotes, bacterial exporters, and eukaryotic proteins including the P-glycoprotein associated with multidrug resistance in tumours (MDR), the STE6 gene product that mediates export of yeast a-factor mating pheromone, pfMDR that is implicated in chloroquine resistance of the malarial parasite, and the product of the cystic fibrosis gene (CFTR). Here we present a tertiary structure model of the ATP-binding cassettes characteristic of this class of transport system, based on similarities between the predicted secondary structures of members of this family and the previously determined structure of adenylate kinase. This model has implications for both the molecular basis of transport and cystic fibrosis and provides a framework for further experimentation.     

A central role for JNK in obesity and insulin resistance

Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus, yet the molecular mechanisms of this association are poorly understood. The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes. Here we show that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics.     

彩色多普勒超声检测糖尿病、高血压病肾动脉血流的意义

目的:应用彩色Doppler超声观察糖尿病及高血压病患者肾血流变化对生化指标的影响.方法:应用彩色Doppler超声检测50例正常人及50例糖尿病、高血压患者的肾脏,测量肾动脉最大血流速度(Vmax)、平均血流速度(Vmean)、搏动指数(PI)、阻力指数(RI),并检测血肌酐(CR).结果:高血压病组及2型糖尿病组RI均较正常组增高,而Vmax则明显减低,且高血压病组及糖尿病组肾内血管管壁增厚、内径变细,彩色血流信号稀疏.结论:应用彩色Doppler超声检测高血压病及糖尿病肾血流参数变化对肾脏的损害能为临床及时诊断和治疗提供一种更敏感、更准确、更快捷的方法.     

冠心病合并2型糖尿病女性患者冠状动脉造影特点分析

目的分析冠心病合并2型糖尿病女性患者冠状动脉造影特点及临床危险因素,探讨糖尿病对冠状动脉病变的作用机制。方法将2005年11月～2008年11月在我院经冠状动脉造影确诊为冠心病的女性患者168例,按有无2型糖尿病（DM）分为糖尿病组（DM组）和非糖尿病组（nonDM组）,对其冠状动脉造影资料、危险因素进行分析研究。结果冠状动脉病变特点：冠状动脉受累血管及严重程度DM组比nonDM组显著高（P〈0．01）。临床危险因素：收缩压、舒张压、空腹血糖（FBG）、餐后2h血糖（2hBG）、糖化血红蛋白（GHbA。C）、总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL—C）、载脂蛋白B（ApoB）DM组比nonDM组高（P〈0．05）,且与冠状动脉狭窄程度呈正相关（P〈0．05）。高密度脂蛋白胆固醇（HDL—C）、载脂蛋白A1（Apo A1）DM组比nonDM组显著低（P〈0．01）,且与冠状动脉狭窄程度呈负相关（P〈0．05）。两组年龄、体重指数（BMI）差异无显著性（P〉0．05）。结论冠心病合并2型糖尿病女性患者冠状动脉病变程度重,除糖尿病外,常与高血压、高血脂等危险因素同时存在。     

末稍微量血糖GDM筛查516例分析

目的：探讨糖筛查试验异常对母儿预后的影响。方法：将50g糖筛查异常而葡萄糖耐量试验正常即单纯糖筛查异常108例列为观察组，50g糖筛查正常402例列为对照组，对照观察两组的母儿并发症。结果：观察组母儿并发症：羊水过多、感染、手术产、巨大儿、新生儿重度窒息、病理性黄疽发生高于对照组。结论：对单纯糖访查异常应予监测及治疗，以改善母儿预后。