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1、糖尿病发病机理与治疗药物进展,南京中医药大学国家规范化中药药理实验室 朱荃,Aphorism,We have two ends with a common link; With one we sit, with one we think. Success depends on which we use; Heads we win, tails we lose! -Author unknown,荷兰50岁以上糖尿病的病死率,前言,我國的發病情況,中國80年代1%,目前升到3.6-5%，其中60歲以上達6%，發病人數也由80年代的6百萬目前增加到3千萬。老年糖尿病患者中90%以上為2型糖尿病.截今
2、為止，該病尚無根治的辦法.近年來許多國家崇尚自然療法，中醫藥日益受到青睞.,胰岛素的发现,C.H. Best. Bantings and Bests experiments were crudely conducted and did not substantiate Bantings idea, which was physiologically incorrect. But their apparently favourable results encouraged greater efforts, which culminated in the winter of 1921-22 in
3、the discovery of insulin by a team of researchers that included Macleod, Banting, J.B. Collip and Best.,人类第一次用胰腺提取物治疗糖尿病-多伦多大学年轻学者Banting, Sir Frederick Grant 等,在狗实验成功的基础上完成的night of 31 Oct 1920,胰岛素的发现者们,结 构,胰岛素的空间构型,胰岛细胞分泌胰岛素,Islets of Langerhans, specialized cells located in human pancreas that se
4、crete insulin, glucagon, and gastrin.Pancreas,胰岛素的药理作用,糖代谢 增加葡萄糖的 转运 氧化和酵解 促进糖原的合成与贮存， 抑制糖原分解和异生,胰岛素受体与葡萄糖,葡萄糖的氧化与酵解,胰岛素的药理作用,脂肪代谢 增加脂肪酸的转运，促进脂肪合成抑制其分解，减少游离脂肪酸和酮体的生成,胰岛素的药理作用,蛋白质代谢 增加氨基酸的转运和蛋白质的合成 抑制蛋白质的分解,胰岛素的药理作用,胰岛素的药理作用,胰岛素的药理作用,胰岛素的药理作用,一、二型糖尿病对葡萄糖的利用,Resistin, Obesity, and Insulin Resistance T
5、he Emerging Role of the Adipocyte as an Endocrine Organ,Why has the incidence of type 2 diabetes increased so rapidly?,Considerable epidemiologic evidence points to excess caloric intake and physical inactivity as the major reasons. A chronic imbalance between energy expenditure and energy intake ca
6、uses obesity, which is one of the most potent risk factors for insulin resistance and type 2 diabetes.,Adipocyte- the pathways responsible for energy balance,Recent studies have transformed our thinking about the adipocyte. It is no longer regarded as a passive depot for storing excess energy in the
7、 form of triglyceride, but as a cell that actively regulates the pathways responsible for energy balance and whose activity is controlled by a complex network of hormonal and neuronal signals (Figure 1). Indeed, the adipocyte secretes chemical messengers that include leptin, tumor necrosis factor ,
8、angiotensinogen, and adiponectin.2,leptin is secreted by triglyceride-laden adipocytes, travels through the circulation, crosses the bloodbrain barrier, and reaches the hypothalamus, where it modulates a host of neuroendocrine and autonomic nervous system activities, resulting in decreased food inta
9、ke and increased energy expenditure. Resistin, as well as tumor necrosis factor , adiponectin, free fatty acids, and possibly other factors released by adipocytes, act in peripheral tissues to influence sensitivity to insulin and other cellular and metabolic processes involved in the use and partiti
10、oning of substrates.,Resistin,New adipocyte hormone Mouse resistin contains 114 amino acids and circulates as a homodimer of two peptides joined by a disulfide bridge.4 Resistin may be an important link between increased fat mass and insulin resistance. secreted by adipocytes and acts at distant sit
11、es. The obese mice that serum levels of resistin are markedly increased and are decreased by rosiglitazone and other thiazolidinediones that increase sensitivity to insulin point to resistin as a mediator of insulin resistance.,Many questions remain,Since energy metabolism differs in mice and humans
12、, is the physiology of resistin in mice relevant to that in humans? Will resistin antagonists be effective for the treatment of type 2 diabetes, and if so, will they be better or worse than thiazolidinediones? A more complete understanding of how adipocytes regulate energy balance awaits the discove
13、ry of other proteins produced by these cells and the elucidation of the complex signaling network of which molecules like resistin are a part.,体内过程,口服无效 易被消化酶破坏 注射给药 皮下注射吸收快 代谢快t 为9-10分钟，作用可维持数小时 在肝肾内灭活 中长效制剂为混悬剂,Diabetes, Insulin Secretion, and the Pancreatic Beta-Cell Mitochondrion,Zhang et al. re
14、cently provided compelling evidence that a mitochondrial anion carrier called uncoupling protein 2 is a critical modulator of insulin secretion and that an increase in this protein may cause beta-cell dysfunction.1,The steps that link changes in glucose levels to insulin secretion are well character
15、ized (Figure 1A). Following its entry into the beta cell, glucose is phosphorylated by glucokinase. This rate-limiting enzymatic step constitutes a glucose sensor, since it allows rapid and precise adjustments to be made in response to changes in extracellular glucose levels. Further products of glu
16、cose metabolism enter the mitochondrial respiratory chain, which uses them to generate adenosine triphosphate (ATP). The increase in ATP inhibits ATP-sensitive potassium channels, which in turn stimulates insulin secretion. The hypoglycemic effect of sulfonylureas, which are widely used in the treatment of type 2 diabetes, is due to the inhibition of these channels. In the process of generating ATP, control of the coupling between oxygen consumption and ATP synthesis is essential, since it modulates ATP levels.,
