胰岛素及口服降糖药 胰岛素 口服降糖药 : 磺酰脲类, 双胍类, 胰岛素增敏 剂,α- 糖苷酶抑制剂, 促胰岛素释放药物
糖尿病
糖尿病 糖尿病分型 1 胰岛素依赖型糖尿病 (1 型 ) 胰岛素绝对缺乏青幼年起病较急病毒感染自身免疫病多食 多尿 多饮 体重减轻症状明显
糖尿病 2 非胰岛素依赖型糖尿病 (2 型 ) 胰岛素相对不足中老年起病缓慢隐匿常有肥胖 高血压 高血脂等早期胰岛素增加后期胰岛功能逐渐减退靶组织对胰岛素敏感性降低
高血糖为主要标志 糖尿病 糖尿病并发症 1 酮症酸中毒高渗昏迷 2 微血管 ( 眼等 ) 微血管瘤基底膜增厚 3 大血管并发症 ( 冠脉等 ) 动脉粥样硬化 4 肾脏病变肾小球硬化 5 神经病变肢端感觉异常 6 肝脏病变脂肪肝
胰岛素 分子量为 58kD 的酸性蛋白 药用胰岛素多从猪 牛胰腺中提取杂质多 通过重组 DNA 技术利用大肠杆菌合成
胰岛素
胰岛素的发现 The Nobel Prize in Physiology or Medicine 1923 "for the discovery of insulin" Frederick Grant Banting University of Toronto Toronto, Canada John James Richard Macleod
Glory Enough For All: History of Insulin Credit( 荣誉 )for the discovery of insulin is given to Banting and Best, who extracted( 提取 )the active principle ( 活性物质 ) from the pancreas and demonstrated its therapeutic ( 治疗的 )effects in diabetic ( 糖尿病的 ) dogs and human subjects in 1921 and 1922. However, many investigators had paved the way for the discovery, including E.L. Scott, who in 1911 had extracted an active principle from the pancreas with acid ethanol( 酸性乙醇 ). Paulesco (1921) also demonstrated the presence of a pancreatic material that was capable of producing hypoglycemia ( 低血糖 ) in animals. Probably of greatest earlier import( 意义 )was the demonstration by von Mering and Minkowski in 1889 that pancreatectomized( 胰腺切除 )dogs exhibited a syndrome( 综合征 )similar to diabetes mellitus( 糖尿病, 三多一少 ) in man, with polyuria( 多尿 ), polyphagia ( 多食 ), wasting ( 消瘦 ), ketosis ( 酮症 ), poor wound healing, and infection. They also demonstrated that deprivation( 去除 )of the exocrine( 外分泌 )function of the pancreas by ligation( 结扎 ) of the pancreatic duct did not cause diabetes, despite marked atrophy( 萎缩 ) of the gland. The suggestion was made that diabetes occurred in the absence of a factor from the pancreas.
Glory Enough For All- History of Insulin Banting approached ( 探讨, 处理 ) the problem with two working hypotheses( 假设 ): (1) the islet tissue secreted insulin, and (2) previous difficulties in isolating the active principle had been due in many instances to the proteolytic( 蛋白水解 )destruction of insulin by the digestive enzymes of the pancreas during the course of extraction. He devised elegantly simple approaches to circumvent the difficulty. Banting tied the pancreatic ducts so that the acinar tissue( 腺泡组织 ) degenerated( 退化 )and left the islet tissue undisturbed, and from the remaining tissue extracted the active principle in relatively high concentration. He also used fetal( 胚胎 )pancreas as starting material, tissue with functional islets but lacking proteolytic digestive activity. Later on, normal pancreas was used as a commercial source when it was rediscovered that acid alcohol not only extract insulin but also prevented proteolytic destruction.
Glory Enough For All- History of Insulin The first patient to receive the active extracts prepared by Banting and Best was Leonard Thompson, aged 14. He appeared at the Toronto General Hospital with a blood glucose of 500 mg/dl, and he was excreting ( 排出 )3 to 5 liters of urine per day. Despite rigid control of diet (450 kcal per day), he continued to excrete large quantities of glucose, and, without insulin, the most likely course was death after a few months. Extracts were first administered on January 11, 1922, and they induced a reduction in the concentration and excretion of blood glucose. Daily injections were then begun, and there was immediate improvement. The excretion of glucose was reduced from over 100 to as little as 7.5 g per day. Furthermore, the boy became brighter, looked better and said he felt stronger. Here was as dramatic an interruption of a fatal metabolic disorder as one will find in the annals ( 编年史, 年鉴 ) of the history of medical science.
胰岛素 Insulin 生理及药理作用 影响三大代谢 1 糖代谢降低血糖促进糖原合成, 增加葡萄糖转运及氧化 酵解, 抑制糖原分解及异生 2 脂肪代谢促进脂肪转运 合成 抑制分解减少游离脂肪酸及酮体生成 3 蛋白质代谢促进氨基酸转运, 促进蛋白合成抑制分解
胰岛素的作用
胰岛素 临床应用糖尿病分型并发症及胰岛素抵抗 1 胰岛素依赖型糖尿病 (1 型 ) 胰岛素替代治疗 2 非胰岛素依赖型糖尿病 (2 型 ) 经饮食或口服降糖药未能控制者 3 糖尿病并发各种严重并发症如酮症酸中毒 4 糖尿病合并感染创伤手术妊娠分娩
体内过程 口服无效皮下 肌肉或静脉注射 制剂 胰岛素 短效正规胰岛素 regular insulin 中效低精蛋白或珠蛋白锌胰岛素长效精蛋白锌胰岛素持续皮下胰岛素输注 与碱性蛋白结合使 ph 提高接近体液 ph 加微量锌使之稳定
胰岛素
Insulin pen Insulin jet Insulin pump
不良反应 胰岛素 1* 低血糖 * 急性低血糖反应饥饿感出汗心悸休克昏迷慢性低血糖反应头痛精神 运动障碍 2 过敏牛胰岛素最多见人工胰岛素少 3 胰岛素抵抗急性抵抗感染 手术 创伤时慢性抵抗抗胰岛素抗体或受体因素 4 脂肪萎缩
口服降糖药
磺酰脲类甲苯磺丁脲 (D 860 ) 格列本脲 ( 优降糖 ) 格列齐特 ( 达美康,gliclazide) 作用及机制 口服降糖药 1 阻滞胰岛 beta 细胞的 ATP 敏感钾通道阻止钾外流, 使细胞膜去极化 ; 增强电压依赖性钙通道, 使钙内流促进胰岛素释放 2 抑制胰高血糖素分泌 3 改善胰岛素受体及受体后缺陷增加靶细胞敏感性
口服降糖药
口服降糖药 磺酰脲类体内过程血浆蛋白结合率高肝脏代谢临床应用 2 型糖尿病且单用饮食控制无效者不良反应 1 低血糖老人 肝肾功能不全者 2 胃肠道反应 3 粒细胞减少 4 中枢神经系统 5 体重增加
口服降糖药 磺酰脲类药物相互作用 1 与保泰松 水杨酸 吲多美辛 双香豆素等竞争结合血浆蛋白 2 氯丙嗪 糖皮质激素 噻嗪类利尿药可诱导肝药酶而降低其降糖作用
口服降糖药 双胍类甲福明 ( 二甲双胍,metformin) 作用与应用减少食物吸收及抑制葡萄糖异生 加速无氧糖酵解 促进葡萄糖摄取用于 2 型糖尿病尤其肥胖者可与磺酰脲类合用 ( 苯乙双胍因亦导致乳酸血症 酮血症等严重不良反应, 严格控制应用 ) 不良反应胃肠道恶心腹泻厌食血乳酸增高肝肾功能及心肺功能不良者应避免使用
口服降糖药 胰岛素增敏剂噻唑烷酮类药物 ( 也称格列酮类 ) 罗格列酮 (rasiglitazone) 托格列酮 (troglitazone) 吡格列酮 (pioglitazone) 药理作用 改善骨骼肌 脂肪和肝脏的胰岛素抵抗, 降低血糖 改善脂肪代谢紊乱 防治血管并发症 改善胰岛 B 细胞功能
口服降糖药 作用机制 竞争性激活细胞核过氧化物酶增殖体激活物受体 γ(ppar-γ), 激活胰岛素调节的影响碳水化合物及脂肪代谢的基因, 从而增加外周组织对胰岛素的敏感性 临床应用 胰岛素抵抗,II 型糖尿病 不良反应 低血糖发生率低
其他适用于 2 型糖尿病降血糖药物 α- 葡萄糖苷酶抑制剂 : 阿卡波糖 (acabose) 竞争小肠水解碳水化合物的酶减慢水解产生葡萄糖的速度并减慢其吸收从而降低血糖主要不良反应为胃肠道反应餐时血糖调节剂 : 瑞格列奈 (repaglinide) 与胰岛素受体结合模仿生理性胰岛素释放促使 β 细胞上的 ATP 敏感 K 通道关闭而促进胰岛素分泌