糖尿病的胰岛素治疗 北京大学人民医院 高蕾莉

历史

如果时光将你载回到1920年。你可能会对当时的科技留下深刻的印象——科技正成为生活的一部分，早期模式的汽车、无线电、电影、电话、直升飞机、空调、医学科学，甚至识别鉴定系统和标识同位素。 可是，你如果患了糖尿病怎么办？尽管世界已经开始了飞机旅行，但你仍不得不接受无望的治疗，直到最终慢慢地死亡。 自从1921年，那年二位加拿大人：班丁.费雷克和贝斯特.奎里发现了胰岛素的存在。从此改变了整个世界——更不要说上百万人的生活前景。

糖尿病的胰岛素治疗

什么是胰岛素？ 胰岛素是人体自身胰腺分泌的唯一能降低血糖的物质。

胰岛素的合成与分泌 C肽 ß 细胞最初生成胰岛素原，后经分泌小泡运送到细胞膜，由胞吐作用经细胞膜释放入血。释放过程中脱去一段C肽，形成A、B链结构的胰岛素。 血液中内生胰岛素和C肽的比例是对等的。 B链 胰岛素原 A链 C肽 B链

胰岛素的结构 胰岛素的两个肽链分别为21个氨基酸组成的A链和30个氨基酸组成的B链，氨基酸排列有种属差异。 猪胰岛素与人胰岛素仅在B链第30位氨基酸上有所不同，牛胰岛素在A链上还有两个氨基酸不同。 人胰岛素的一级结构

胰岛素的研发史 自18世纪至今，在诸多研究者不断进取的努力下，胰岛素的研究经历了五个阶段：  发现胰岛素  得到胰岛素  了解胰岛素  合成胰岛素  改造胰岛素

胰岛素对糖尿病的基本治疗益处： 降低血糖——良好的代谢控制。降低高血糖的中毒作用，降低β细胞负荷——预防延缓大、小血管并发症发送率。 维持儿童及青少年正常生长发育。 急救，降低糖尿病的急症病死率。

胰岛素的治疗机理： 抑制肝糖产生、输出 促进葡萄糖载体GIut4合成、位移 抑制脂肪分解 全局校正糖尿病代谢紊乱 由于上述作用，胰岛素治疗亦改善胰岛素抵抗 在肾小管促进水、盐的重吸收。

注射胰岛素的重要性： 胰岛素是人体必不可少的物质，没有它血糖局高不下。 人体内有多种升高血糖的激素，但只有胰岛素一种物质是能够降血糖的。 当人体不能正常地分泌和利用胰岛素时，一定要通过注射外源性胰岛素控制血糖

胰岛素制剂

人胰岛素是利用基因重组技术，从叫酵母细胞中生产出来的。和人体分泌的胰岛素结构完全相同，且具单组分纯度，无动物及大肠杆菌污染。胰岛素原样物＜1 ppm。中性酸碱度。不良反应和胰岛素抵抗最低。具备有最完备的剂型，满足糖尿病病人的不同需求。

glargin lispro detemir aspart B 1 21 30 精氨酸 甘氨酸 glargin 32 天门冬氨酸 A 1 B 1 21 30 28 27 27 28 lispro A 1 B 1 21 30 肉豆蔻酸 赖氨酸 detemir A 1 B 1 21 30 天门冬氨酸 脯氨酸 aspart

什么人应该使用胰岛素？ 1型糖尿病 2型糖尿病有以下情况： 妊娠糖尿病或糖尿病妊娠 口服药控制不佳 有糖尿病慢性并发症 肝、肾功能不全 消瘦、体重在理想体重的90％以下 非酮症性高渗性昏迷，乳酸性酸中毒，酮症酸中毒。 合并感染、创伤、大手术等应激状态。 妊娠糖尿病或糖尿病妊娠

胰岛素治疗的副反应 最严重者为严重的低血糖反应，老年非感知性低血糖反应最危险。 过敏反应、全身性皮肤反应偶见：局部红肿、皮疹、过敏性休克。 注射部位皮下脂肪萎缩。 体重增加。 水肿。

1. R－短效人胰岛素 酸碱度：中性 纯度： 单组分 使用： 一天注射二次或更多 性状： 无色澄清溶液 纯度： 单组分 使用： 一天注射二次或更多 性状： 无色澄清溶液 制剂： 瓶装 40单位/毫升×10毫升/支 笔芯 100单位/毫升×3毫升/支 注射方法：皮下注射、肌肉注射、静脉注射

作用时间： 起初作用时间：半小时 最大作用时间：1至3小时 维持作用时间：8小时

2. N－中效人胰岛素 低精蛋白锌人胰岛素。每天单独注射两次（部分病人一次）或与R混合使用。 酸碱度：中性 纯度： 单组分 纯度： 单组分 性状： 摇均后呈白色均匀混悬液 制剂种类：瓶装40单位/毫升×10毫升/支 笔芯100单位/毫升×3毫升/支 注射方法：仅供皮下注射

作用时间： 起初作用时间：1.5小时 最大作用时间：4至12小时 维持作用时间：24小时

3. 30R－预混型人胰岛素 30％短效中性可溶性人胰岛素与70％中效低精精蛋白锌人胰岛素预先混合。 酸碱度： 中性 纯度： 单组分 纯度： 单组分 使用： 一天注射两次 性状： 无色澄清溶液 制剂种类：瓶装40单位/毫升×10毫升/支 笔芯100单位/毫升×3毫升/支 注射方法：仅供皮下注射

作用时间： 起初作用时间：半小时 最大作用时间：2至8小时 维持作用时间：24小时

4. 50R－预混型人胰岛素 50％短效中性可溶性人胰岛素与50％中效低精精蛋白锌人胰岛素预先混合。 酸碱度： 中性 纯度： 单组分 纯度： 单组分 使用： 一天注射两次 性状： 摇均后呈白色均匀混悬液 制剂种类：瓶装40单位/毫升×10毫升/支 笔芯100单位/毫升×3毫升/支 注射方法：仅供皮下注射

作用时间： 起初作用时间：半小时 最大作用时间：2至8小时 维持作用时间：24小时

糖尿病的胰岛素治疗

Recommended therapy for T1DM 1) use multiple dose insulin injections (3–4 injections per day basal and prandial insulin) or CSII therapy; 2) matching prandial insulin to carbohydrate intake, premeal blood glucose, and anticipated activity; 3) for many patients (especially if hypoglycemia is a problem), use insulin analogs.

1型糖尿病人胰岛素治疗方案 基础—餐前加強疗法,每日注射4次 诺和灵R(瓶装,笔芯) 诺和灵N(瓶装,笔芯)

2型糖尿病出现口服药继发失效时的胰岛素使用 胰岛素补充治疗 VS 常规胰岛素替代治疗

口服降糖药原发失效 指发生在开始治疗的第一个月内糖尿病未能得到控制。 由于残存的β细胞在OHA作用下仍不能产生足够的胰岛素。

口服降糖药继发失效 指开始治疗控制有效一年以上，以后发生控制失效达3个月以上。 原因: -肝葡萄糖输出（26.1％） -胰岛素抵抗（17.3％） β细胞功能恶化（12.6％） 原因不明（44％）

口服降糖药物失效 －糖尿病进展的结果 每年大约有10％的2型糖尿病患者出现继发失效。 糖尿病病程为5年时，50％ 2型糖尿病需用胰岛素。 糖尿病病程为15年时，60％ 2型糖尿病需用胰岛素。 β细胞功能衰竭后，任何口服降糖药物均无法维持血糖控制。

胰岛素治疗对2型糖尿病患者 的积极作用 矫正胰岛素不足 改善胰岛素敏感性 改善内源性胰岛素分泌 抑制夜间过高的肝脏葡萄糖输出 降低葡萄糖对β细胞的毒性作用

2型糖尿病患者胰岛素治疗 理想的胰岛素治疗方案 良好的血糖控制 最小的体重增加 低血糖危险最小 胰岛素用量尽可能少 没有顺应性问题

胰岛素和口服降糖药联合应用的理论基础 口药主要和辅助的作用仍然得到发挥。 内源胰岛素仍可直接进入肝脏起作用。 节省外源性胰岛素。 降低医源性高胰岛素血症。 减少胰岛素的副作用如体重增加、HT、心血管并发症等。 低血糖危险性减低。

UKPDS 研究中  细胞功能的渐进恶化 -细胞的功能 (% ) 年限 100 80 60 40 20 10 9 8 7 6 10 9 8 7 6 5 4 3 2 1 1 2 3 4 5 6 Adapted from UK Prospective Diabetes Study (UKPDS) Group. Diabetes. 1995; 44:1249-1258.

多数的2型糖尿病患者都将通过 胰岛素的治疗来达到良好的血糖控制 随着糖尿病病程的进展 多数的2型糖尿病患者都将通过 胰岛素的治疗来达到良好的血糖控制

2型糖尿病中个体化治疗 的策略

2型糖尿病胰岛素治疗的进阶方案 OHA联合治疗，血糖控制无法达标 第1阶段 白天OHA＋睡前胰岛素 血糖控制无法达标 第3阶段 每天多次胰岛素（MDI）

2型糖尿病胰岛素治疗的第1阶段 白天OHA ＋ 睡前胰岛素 Slide 6-39 Starting With Basal Insulin INSULIN TACTICS Starting With Basal Insulin Combination Oral Agents + Evening Basal Insulin The next group of slides explores the synergistic or complementary effects of this type of combination. Different strategies for combining oral agents with basal insulin are discussed.

OHA与胰岛素联合治疗的协同或补充作用 磺脲类及苯甲酸衍生物（胰岛素分泌激动剂）： 二甲双胍（Metformin）： 增加肝脏内源性胰岛素水平并且增强饮食介导的胰岛素释放 二甲双胍（Metformin）： 在肝脏增加胰岛素的敏感性并且减少肝糖输出 噻唑烷二酮（胰岛素增敏剂）： 在外周组织增强胰岛素的作用并且增加外周组织对葡萄糖的摄取 -糖苷酶抑制剂 ： 延缓餐后葡萄糖的吸收 Slide 6-40 INSULIN TACTICS Combination Oral Agents + Insulin Synergistic or Complementary Effects The oral agents can be divided into two general categories: those augmenting the supply of insulin by increasing the secretion of insulin into the portal circulation and those enhancing the effectiveness of insulin. Injected insulin, in turn, increases insulin in the systemic circulation. Because the mechanisms of action for these classes of oral agents differ, they may have complementary or additive effects and can help meet the individualized needs of patients. The sulfonylureas are oral agents that augment the supply of portal insulin. They increase hepatic levels of endogenous insulin and enhance meal-mediated insulin release. Metformin and the glitazones are oral agents that enhance the effectiveness of insulin. Metformin improves insulin sensitivity at the liver and reduces hepatic glucose production. The glitazones improve insulin action in peripheral tissues and enhance glucose uptake. The a-glucosidase inhibitors have a different mechanism of action, decreasing postprandial glucose absorption by inhibiting digestion of complex carbohydrates and disaccharides, thereby retarding gastrointestinal glucose absorption.

针对应用OHA治疗血糖控制仍无法达标的患者 2型糖尿病胰岛素治疗的第1阶段 （白天OHA＋睡前胰岛素） 针对应用OHA治疗血糖控制仍无法达标的患者 ◆ 维持原OHA治疗方案 ◆ 睡前 (22:00), NPH (H), 0.1u ~0.2u/kg （或晚餐时应用70/30预混胰岛素）

2型糖尿病胰岛素治疗的第2阶段 每天二次胰岛素 （70/30预混胰岛素）

2型糖尿病胰岛素治疗的第2阶段 （每天二次胰岛素） 针对应用白天OHA＋睡前胰岛素治疗 血糖控制仍无法达标的患者 ◆ 停用先前OHA ◆ 每天二次胰岛素治疗方案 （70/30预混胰岛素）

每天二次胰岛素方案 胰岛素的作用 Regular NPH B L S HS B Slide 6-23 INSULIN TACTICS Twice-daily Split-mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years. In some cases, premixed 70/30 insulin is used for this purpose. Patient profiles of insulin levels resulting from this method, as shown in this figure, do not come close to matching the normal endogenous secretory pattern, shown in the shaded background. Patients with type 1 diabetes using this “split- mixed” regimen rarely achieve reasonably good glycemic control by present standards, since they lack endogenous insulin to supplement the partially adequate profile of injected insulin. Type 2 diabetes patients who have substantial endogenous insulin may fare much better with this regimen, but may experience late morning or nocturnal hypoglycemia because of excessive levels of insulin at these times. Berger M, Jorgens V, Mühlhauser I. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes. Diabetes Care. 1999;22(suppl 3):C71-C75; Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews. 1995;3:308-334. B L S HS B

每天二次胰岛素治疗方案 单独饮食控制 每天二次胰岛素治疗6个月 血浆葡萄糖 血胰岛素水平 70/30预混胰岛素 70/30预混胰岛素 1000 70/30预混胰岛素 70/30预混胰岛素 400 800 300 600 pmol/L mg/dL 200 400 Slide 6-49 INSULIN TACTICS Advancing With Multiple Daily Injections NPH + Regular, Twice Daily Henry et al studied a group of 14 patients with type 2 diabetes to determine whether tight glycemic control can be obtained using conventional split-dose insulin therapy in an outpatient setting by aggressively titrating insulin therapy. Patients received conventional subcutaneous NPH and regular insulin before breakfast and supper for 6 months, with dose adjustments based on an algorithm built on frequent blood glucose measurements (4-6 times a day). The total dose of required exogenous insulin was 86 ± 13 U at 1 month and 100 ± 24 U at 6 months. Hypoglycemic events at 1 month were infrequent, with mean 4.1 ± 0.3 events/patient/month. These events were mild in nature and progressively decreased to 1.3 ± 0.5 events/patient/month by 6 months. At study completion, the average weight gain was >9% (8.7 ± 1.9 kg) of the pretreatment body weight. Weight gain was inversely related to the rate of pretreatment glucose disposal and was directly correlated with mean day-long serum insulin level and total exogenous insulin dose. One month after initiating intensive insulin therapy, day-long glycemia had improved to within normal range and remained at this level through month 6 of therapy. The HbA1c, which was 7.7% ± 0.3% at baseline, decreased to 5.1% ± 0.2% at 6 months. All postprandial glucose excursions before treatment were similar and virtually identical before and after insulin treatment. These glycemic peaks indicate that the primary contributor to improved overall glycemia is the reduction in FPG levels. Henry RR, Gumbiner B, Ditzler T, Wallace P, Lyon R, Glauber HS. Intensive conventional insulin therapy for type II diabetes. Diabetes Care. 1993;16:21-31. 100 200 0600 1200 1800 2400 0600 0600 1200 1800 2400 0600 B L S B L S Henry, et al. Diabetes Care. 1993;16:21-31.

2型糖尿病胰岛素治疗的第3阶段 （每天多次胰岛素） 针对应用二次胰岛素治疗 血糖控制仍无法达标的患者 ◆ 应用每天三次或四次胰岛素治疗方案 ◆ 三短一中 或二短二中（早晨70/30预混胰岛素， 晚餐短效胰岛素，睡前中效胰岛素）

每天多次胰岛素治疗方案 (MDI) 二短二中 三短一中 短效 短效 NPH NPH 胰岛素的作用 胰岛素的作用 B L S HS B B L Slide 6-24 INSULIN TACTICS Multiple Daily Injections (MDI) NPH + Regular Another strategy, shown in this slide, consists of two injections of NPH (or lente) insulin daily plus two or three injections of regular insulin with meals. The second injection of NPH is given at bedtime, to confer less risk of nocturnal hypoglycemia while providing enough insulin to control overnight fasting glucose levels. This is often called a multiple daily injection (MDI) regimen. It is widely used for type 1 diabetes patients but is also appropriate for type 2 diabetes patients whose endogenous levels are declining. The match of insulin levels to endogenous needs is better with this approach than with twice-daily NPH and regular, but still not very good. B L S HS B B L S HS B

每天多次胰岛素治疗方案（三短一中） 正常对照 OHA治疗 三短一中胰岛素治疗8周 血浆葡萄糖 血胰岛素水平 R R R N R R R N 300 300 250 200 200 pmol/L mg/dL 150 Slide 6-50 INSULIN TACTICS Advancing With Multiple Daily Injections Bedtime NPH + Mealtime Regular In a randomized crossover study of 8 weeks of oral hypoglycemic agents followed by 8 weeks of 2- or 4-dose insulin regimens, blood glucose and free insulin were measured in 10 type 2 diabetes patients and 10 nondiabetic control subjects. During the first 8 weeks, diabetic patients received oral hypoglycemic agents and then were randomized to receive either 2 or 4 daily insulin injections for the next 8 weeks. Twenty-four hour glycemic profiles were obtained during both treatment periods. The patients were instructed on diet and encouraged to maintain normal physical activities during the course of the study. Mean blood glucose and free-insulin profiles show that patients taking the oral agents had higher blood glucose and lower postprandial insulin concentrations than those receiving insulin. When patients received the daily 4-dose regimen of preprandial regular insulin and intermediate-acting NPH insulin at 10:00 PM, glycemic control improved. The mean HbA1c was 8.8% during treatment with oral therapy compared with 5.6% on the 4-dose insulin regimen. Lindström TH, Arnqvist HJ, von Schenck HH. Effect of conventional and intensified insulin therapy on free-insulin profiles and glycemic control in NIDDM. Diabetes Care. 1992;15:27-34. 100 100 50 0800 1200 1600 2000 2400 0400 0800 0800 1200 1600 2000 2400 0400 0800 B L S HS B L S HS Lindström, et al. Diabetes Care. 1992;15:27-34.

当前在2型糖尿病 患者中进行胰岛素治疗的 指南 Slide 6-57 Practical Guidelines for Insulin Therapy in Type 2 Diabetes Today! For physicians managing patients with type 2 diabetes, practical guidelines for pharmacologic interventions are particularly important in view of the fact that there have been major changes in the pharmacotherapy of type 2 diabetes over the past 5 years. In addition, a number of new classes of antidiabetic drugs have recently been approved for use in the United States, and there is a move to start pharmacotherapy earlier in the course of the disease in order to address the dual defect of type 2 diabetes: insulin deficiency and insulin resistance. There is also an emerging paradigm shift, with increasing use of combination therapy involving lower doses of insulin secretagogues plus an insulin sensitizer, doing so almost from the outset of a patient’s treatment regimen. This concept of treatment is embraced by the community of diabetes experts, who also view insulin therapy as an early strategy to supplement the oral therapy in reaching their glycemic target. ADA：Clinical Practice Recommendations 2001,Diabetes Care 2001;24(suppl 1)

联合治疗方案 适用一般2型糖尿病患者 适用明显胰岛素抵抗的2型糖尿病患者 假如仍然无法达到HbA1c < 7％的血糖控制目标 早期联合应用胰岛素分泌激动剂及胰岛素增敏剂 可根据简便及效价比原则制订临床治疗方案 小剂量联合应用磺脲类及双胍类口服降糖药 亚最大剂量磺脲类联合双胍类口服降糖药（双胍逐渐加量） 适用明显胰岛素抵抗的2型糖尿病患者 联合应用双胍类及胰岛素增敏剂 假如仍然无法达到HbA1c < 7％的血糖控制目标 尝试进行三种OHA联合治疗方案: No 或者 增加睡前胰岛素治疗 Slide 6-58 PRACTICAL GUIDELINES Combination Therapy Regimens For the usual patient with type 2 diabetes, the recommendation is for early use of combination therapy involving an insulin secretagogue and an insulin sensitizer. The simplest and most cost-effective approach consists of either a once-daily, low-dose or eventually full-dose sulfonylurea in combination with increasing doses of metformin. For patients with type 2 diabetes who show marked insulin resistance, a combination of metformin + glitazone can be recommended. If the target HbA1c < 7% is not achieved, triple oral therapy can be attempted, or basal insulin can be added while continuing oral therapy.

继续保持原有OHA剂量（或最终适当减量），同时增加睡前胰岛素（6－10U） < 130%标准体重,NPH (睡前) > 130%标准体重,70/30 预混胰岛素 (晚餐) 每周根据血糖情况逐渐增加胰岛素剂量 假如 FBG >180 mg/dL，则增加 4 U 假如 FBG >140 mg/dL，则增加 2 U 争取达到血糖控制目标（FBG <120 mg/dL，HbA1c <7％) ，假如仍然无法达标，则停用OHA开始每天二次直至每天多次胰岛素治疗 Slide 6-59 PRACTICAL GUIDELINES Starting Basal Insulin The most critical approach to the management of type 2 diabetes patients with persistent hyperglycemia despite combination oral therapy is to use a simple, straightforward strategy that will facilitate initiation of insulin therapy. The increasing use of insulin pens will certainly simplify the administration of insulin, and its use can be demonstrated to patients in “real time” during their visit to the physician’s office. It is very important that patients continue the oral agents at the same dosage and eventually reduce this dose when appropriate. Conservatively, a single insulin dose of around 10 U of NPH given at bedtime or 70/30 insulin given at the evening meal is a standard initial approach to treatment. Basal insulin glargine has the potential to facilitate and extend the use of this insulin strategy because of its long duration of action, peakless flat profile, more predictable response, and reduced risk of hypoglycemia. Insulin glargine is given once daily at bedtime, but based on its insulin kinetics, it could theoretically be given at any time. The insulin dose should be adjusted according to the fasting SMBG level. The insulin dose can be increased on a weekly basis as needed. It should be increased by 4 U if the fasting blood glucose (FBG) is greater than 140 mg/dL, and by 2 U if the FBG is 120 to 140 mg/dL. The treat- to-target level is usually an FBG < 120 mg/dL.

注意事项 (1) 需增加胰岛素量： 高热 甲亢 肢端肥大症 酮症酸中毒 严重感染或外伤 重大手术 孕妇，尤为妊娠中、后期 青春期儿童

注意事项 (2) 需减少胰岛素量： 胰岛素在肾脏的代谢及排泄减少：肝、肾损、甲减 可致低血糖的疾病：肾上腺皮质功能和垂体功能低下、腹泻、胃麻痹、肠梗阻、呕吐、食物吸收减退 1型糖尿病哺乳期 老年人 (易发生低血糖)

注意事项 (3) 联合应用药物 升高血糖的药物：糖皮质激素、ACTH、胰升血糖素、雌激素、口服避孕药、甲状腺素、肾上腺素、噻嗪类利尿剂、苯妥英纳、吸烟(拮抗儿茶酚胺、皮肤吸收下降) 协同降血糖：口服降糖药、同化类固醇、雄激素、单胺氧化酶抑制剂、非甾体消炎痛药

注意事项 (4) 联合应用药物 血中胰岛素增加：氯喹、奎尼丁、奎宁等延缓降介 改变糖代谢、血糖上升：钙通道阻滞剂、可乐定、二氮嗪、GH、肝素、α受体拮抗剂、大麻、吗啡、尼古丁、β受体阻滞剂(普萘洛尔可阻止肾上腺素升高血糖的反应) 降低血糖：(ACEI、溴隐停、氯贝特、酮康唑、锂、甲苯咪唑、茶碱、大量酒精、奥曲肽)

谢谢！