内容提要高血糖诊断的细化是对其危害的进一步认识高糖毒性与氧化应激、肥胖与胰岛素抵抗等—基础研究从循证医学证据看高血糖与心血管事件发病危险的关系高血糖的诊断胰岛素抵抗的个体极早期的变化研究对象：共188例非肥胖NGT 个体（BMI ≤25 ）：19 例肥胖NGT 个体：42例IGT 个体：22例BMI 配对糖尿病个体：105例研究方法：胰岛素敏感性测定：正糖胰岛素钳夹胰岛素分泌速率：对OGTT 过程中的血浆C 肽计算得出2005 年国际糖尿病联盟( IDF) 全球统一代谢综合征定义中心性肥胖＋以下4项中的任意2项华人：腰围≥90厘米（男性）腰围≥80厘米（女性）TG 水平升高: ≥150 mg/dL (1.7mmol/L) HDL-C 水平降低: < 40 mg/dL (1.0mmol/L) 男性< 50mg/dL (1.3mmol/L) 女性( 或者已经接受相应调脂治疗) · 血压升高( 收缩压≥130 或舒张压≥85mm Hg) ( 或者已经、正在接受降压治疗) · 空腹血糖升高(FPG ≥100mg/dL (5.6mmol/L)) ( 或已诊断糖尿病) 如果FPG ≥100mg/dL (5.6mmol/L), 强烈推荐进行OGTT ，但是不必要采用OGTT 来确定是否合并代谢综合征代谢综合征的各种组分内容提要高血糖诊断的细化是对其危害的进一步认识高糖毒性与氧化应激、肥胖与胰岛素抵抗等—基础研究从循证医学证据看高血糖与心血管事件发病危险的关系高血糖—线粒体超氧化物生成过多葡萄糖诱导的反应性氧化产物（ROS) 产自线粒体电子转运系统ROS 通过激活聚（ADP- 核糖基）聚合酶(PARP) 抑制GAPDH 高血糖引起的细胞内氧化应激的后果细胞内氧化应激的结局过度热量摄入/运动减少引起细胞内葡萄糖和游离脂肪酸增高，引发氧化应激β细胞氧化应激→功能降低，发生糖尿病肌肉、脂肪组织氧化应激→胰岛素抵抗内皮细胞氧化应激→内皮功能失调\动脉粥样硬化，发生心血管疾病3者之间的互动加重损害２型糖尿病和动脉粥样硬化的共同土壤炎症致胰岛素抵抗的分子机制胰岛素抵抗的选择性选择性胰岛素抵抗的作用IRS-2 丝氨酸/苏氨酸磷酸化导致B 细胞凋亡由肥胖和代谢综合征的关系 看脂肪细胞、脂毒性的危害关于胰岛素抵抗原因的争论来自脂肪细胞的肽类物质通过复杂的机制影响组织的胰岛素作用脂肪细胞是全身胰岛素抵抗的罪魁祸首细胞内脂肪酸的代谢失调启动肝脏和骨骼肌的胰岛素抵抗应减少这一代谢过程来逆转胰岛素抵抗Banting Lecture 关键的对话：脂肪，大脑和能量平衡的调节评估瘦素抵抗在肥胖中的作用Banting 奖报告主要内容多数肥胖患者存在瘦素抵抗脂联素的作用脂联素具有非常强的抗动脉粥样硬化的作用抑制内皮的炎症反应抑制血管平滑肌细胞的增殖抑制巨噬细胞向泡沫细胞的转化异位脂肪沉积内容提要高血糖诊断的细化是对其危害的进一步认识高糖毒性与氧化应激、肥胖与胰岛素抵抗等—基础研究从循证医学证据看高血糖与心血管事件发病危险的关系欧洲心脏调查（EHS，EURO Heart Survey）EHS 纳入欧洲25个国家，110家医疗中心，共4961例冠心病患者2107例由于急性心血管事件入院接受调查，2854例病情稳定而接受调查除已知糖尿病患者( n=1524) 外，其余均采用FPG 检测,其中1920例接受OGTT 检测糖代谢状况2004年8月底欧洲心脏年会（ESC）首次发布2004年11月正式发表于《欧洲心脏杂志》欧洲心脏调查结果-分组欧洲心脏调查结果-汇总NGT、NEW-DM、IGR 中MS 患病率(>25岁)  ( WHO 标准) 谢谢！脂毒性高脂摄入脂肪细胞功能异常血FFA 升高肝脏TG 增加肝糖异生和肝糖输出增加骨骼肌TG 增加葡萄糖利用下降胰腺TG 沉积，β细胞凋亡胰岛素抵抗β细胞分泌胰岛素异常糖尿病Stratton ,et al. UKPDS 35. BMJ 2000; 321: 405-12 UKPDS（观察性研究）血糖与心肌梗死的关系具有阶段性0 2 0 4 0 6 0 8 0 0 5 6 7 8 9 1 0 1 1 心肌梗死平均HbA1c (%) Incidence per1000 patient-years 心血管死亡危险与餐后血糖具有线性曲线关系Tuomilehto J. Diabetes Care. 2003 Mar; 26 (3) : 688-96. 4 3 2 1 0 4 3 2 1 0 样本人数( x1,000) 	 0	2	4	6	8	10	12	14	16 OGTT 2 -hour 血糖( mmol/L) 相对危险DECODE 研究The Euro Heart Survey on diabetes and the heart，European Heart Journal (2004) 25, 1880–1890 n=5377 未确诊CAD (75) 已确诊糖尿病(341) 4961 调查设计The Euro Heart Survey on diabetes and the heart，European Heart Journal (2004) 25, 1880–1890 997 997 860 门诊患者( n=2,854) 总数( n=4961) 急性入院( n=2,107) 1920 923 OGTT 1517 520 仅测FPG 1524 664 已诊断DM 不满足调查设计要求n=416 n=2107 n=2854 The Euro Heart Survey on diabetes and the heart，European Heart Journal (2004) 25, 1880–1890 The Euro Heart Survey on diabetes and the heart，European Heart Journal (2004) 25, 1880–1890 30.01 28.82 77.3 71.39 68.9 63.65 1994年全国糖尿病协作组% 2 Overnutrition and decreased physical activity lead to increased glucose and FFA loads in cells. Their transformation in energy is accompanied by increased free radicals generation (oxidative stress). The muscle cells and adipocytes can protect themselves from this condition, producing a resistance to the action of insulin, aiming to reduce glucose and FFA penetration in the cells. cells and endothelium are insulin-independent tissues. Glucose and FFA overload in these cells and cause oxidative stress, which in turn induces a dysfunction of both B cells and endothelium. Endothelial dysfunction may lead to the development of cardiovascular disease, B cell dysfunction is characterized by an alteration of insulin secretion. This last condition is worsened by the concomitant insulin resistance, which is a condition that requires increased insulin secretion to maintain plasma glycemia in a normal range. -cell dysfunction is particularly characterized by a decreased first-phase insulin secretion, which in turn produces the clinical picture of IGT. This last situation is clinically characterized by increased postprandial hyperglycemia. Postprandial hyperglycemia induces oxidative stress. The persistence of such condition produces an exhaustion of cells, leading to the overt diabetes. Oxidative stress produced both during IGT and overt diabetes may contribute to the development of cardiovascular disease. Moreover, the cluster of the risk factors that accompanies the insulin resistance also contribute to produce cardiovascular disease. Fig. 3. Potential mechanisms that trigger IRS-2 degradation and apoptosis of pancreatic b cells. IRS-2 expression in b cells is vital for normal b-cell growth, survival, and turnover. Chronic hyperglycemia by means of mTOR activation and hyperlipidemia by means of fatty acyl-CoA–mediated activation of the novel class of PKC isoforms can lead to increased serine/threonine phosphorylation of IRS-2 that then leads to its ubiquitination and subsequent proteosomal degradation. In addition, certain cytokines, including IL-1b and TNF-a, activate IkKb and Jnk/p38 kinases [by means of TNF-receptor associated factor (TRAF) signaling complexes] and/or PKCd, which in turn also leads to IRS-2 serine/ threonine phosphorylation. Other local inflammatory responses can activate IkKb, and other metabolic stresses (e.g., increased ROS and ceramide generation, or chronically elevated [Ca2t]) can activate PKC isoforms and/or Jnk/p38 kinases, which can reduce IRS-2 levels by a similar mechanism. Other cytokines (including IL-6 and IFN-g) can induce expression of SOCS-1 and SOCS-3, which can then bind to IRS-2, leading to its ubiquitination and subsequent proteosomal degradation. This multipronged assault could significantly lower IRS-2 levels in the b cell. The resultant increase in bcell apoptosis is thought to be a key factor contributing to the loss of b-cell mass in type 2 diabetes. ERK 细胞外信号调节激酶JAKJanus 蛋白酪氨酸激酶PI 磷脂酰肌醇STAT3 信号传递与转录激活因子3, 使瘦素信号转到加强 ERK 细胞外信号调节激酶过度表达的SOCS3 可与胰岛素受体结合或整合IRS 也可以通过两者一起拮抗胰岛素的作用游离脂肪酸能诱导SOCS3 的过度表达PI3 K 信号系统是下丘脑胰岛素和瘦素作用的一个主要介质胰岛素诱导了胰岛素受体底物( IRS)2 的酪氨酸磷酸化作用, 并激活大鼠下丘脑IRS2 关联的PI3 K NADPH ，还原型烟酰胺腺嘌呤二核苷酸磷酸, 还原型辅酶ⅡNAD ，二磷酸吡啶核苷酸, 辅酶Ⅰa-glycerol-P, a- 磷酸甘油２型糖尿病和动脉粥样硬化是炎症的两个平行的结果，但一旦出现高血糖，或与之相干的肥胖等合并症，可以进一步加剧炎症过程。观点左：“I will review evidence to suggest that adipose tissue produces circulating factors, either hormones or adipose cytokines, that affect insulin sensitivity in other tissues, such as muscle and liver,”said Mitchell Lazar, MD, PhD, Director of the Institute for Diabetes, Obesity and Metabolism at the University of Pennsylvania, Philadelphia. “There has been a major paradigm shift in the past decade with the idea that adipose tissue has a humoral effect on the rest of the body,”Dr. Lazar continued. “The idea has gone from almost heretical to almost completely accepted. Recent research has shown that a number of factors are involved, including leptin and adiponectin, which are produced by fat tissue, resistin, which may be produced by fat tissue or immune cells, as well as factors that are