1、胰岛素及其类似物在慢性肾功能不全患者中的应用Insulin & its Analogin CKD with DM,2,胰岛,胰岛是分散在胰腺腺泡之间的细胞团。正常人有200万个胰岛。细胞占胰岛细胞总数的20%，分泌胰高血糖素；细胞约占胰岛细胞总数的75%，分泌胰岛素。 D细胞分泌生长抑素，PP细胞分泌胰多肽.,3,Proinsulin Structure,4,Time,0600,1000,1400,1800,2200,0200,0600,800,600,400,200,Insulin secretion (pmol/min),正常人胰岛素分泌模式,Polonsky KS et al. N En
2、gl J Med 1996;334:777,0,Insulin Secretion,Insulin分泌有2种Basal insulin（基础胰岛素）：每天持续不断释放以应付体內肝糖不断的释放。正常人每天约24U。Prandial insulin（餐时胰岛素）：进食后，与血糖同步上升。正常人每天约24U。Phase 1：正常人在进食后細胞会在3至10分钟释放出胰岛素的第一个波峰1st peak，先遣部队作用：抑制肝糖输出刺激Phase 2 insulin的释放Phase 2：在phase 1結束后約15秒，跟着出現第二波峰2nd peak 直至血糖恢复正常为止，持续約12小時。援军主要是降低餐后
3、血糖,2型糖尿病的病理生理: 胰岛素分泌缺陷,FPG 8 mmol/l,FPG 18 mmol/l,正常人,0.40,1.00,0.80,0.60,平均胰岛素 (nmol/l),0.20,0,30,0,30,60,90,120,150,180,210,240,时间 (分钟),Coates PA et al. Diabetes Res Clin Pract 1994;26:177,2型糖尿病患者,7,第一时相胰岛素分泌缺失是T2DM的重要特征,Stefano Del Prato. et al. Diabetes 51:S109-S116, 2002,8,2型糖尿病早期相胰岛素分泌受损,正常早期相
4、分泌,糖尿病早期相缺失,常规胰岛素早期相延迟,9,何时开始胰岛素治疗？,10,何时是胰岛素治疗的最佳时机？,100,75,50,25,0,-10,-6,-2,2,0,6,10,14,-12,诊断时间（年）,残存细胞功能 (% ),2型糖尿病Phase I,口服单药治疗,2型糖尿病Phase II,口服联合治疗,Phase III,胰岛素,HbA1C not at target: 7.0%,Based on data of UKPDS 16. UKPDS Group. Diabetes. 1995;44:1249-1258.,11,传统序贯疗法总是不能达标,6,7,8,9,10,HbA1c(%)
5、,序贯疗法,Adapted from Campbell IW. Br J Cardiol 2000; 7: 625-631,目标 HbA1c 6.5%,12,改进的强化治疗,6,7,8,9,10,HbA1c(%),Adapted from Campbell IW. Br J Cardiol 2000; 7: 625-631,Conservative approach,序贯疗法,目标 HbA1c 6.5%,13,2型糖尿病也存在蜜月期！,Erol Cerasi: 1997年 13例新诊糖尿病用胰岛素泵静脉注射胰岛素两周后，有9例不用任何抗糖尿病药物能维持血糖正常达9-50个月。他把这称之为2型糖
6、尿病的蜜月期. 在2型糖尿病血糖水平的良好控制使胰岛素分泌功能得到极大的改善，甚至恢复了第一时相胰岛素分泌功能。1型2型糖尿病之间并不像以前人们所认为的那样大的区别，在病因和临床表现上它们更像是居于一个疾病谱的两端。两者都有蜜月期，但是2型糖尿病的蜜月期更长.,Ilkova H, et al. Diabetes Care. 1997 20:1353-6.,14,国内相关研究,国内李延兵、翁建平报告在新诊断的2型糖尿病，2周的胰岛素强化控制血糖后，六月缓解率约70%，1-2年缓解率40%,Li Y et al.Diabetes Care ,2004,27:2597-602.Neda Rasoul
7、i,et al.J.C.E.M 2004. 89: 6331-6335,胰岛素治疗具体方案,胰岛素的种类,胰岛素按来源可分为： 动物胰岛素 人胰岛素 人胰岛素类似物。动物胰岛素主要来源于猪和牛的胰脏，其结构组成与人胰岛素有差别。（牛3个氨基酸；猪1个氨基酸不同）人胰岛素是通过基因工程由酵母菌（诺和灵）或大肠杆菌（优泌林）合成，结构与人体内的胰岛素一致。人胰岛素类似物是通过将人胰岛素的结构略有改变，以求达到超短效或超长效等目的。,胰岛素的种类,按作用时间和效应分类：短效胰岛素中效胰岛素长效胰岛素超短效人胰岛素类似物超长效人胰岛素类似物预混胰岛素,18,胰岛素制剂及其作用时间,19,胰岛素强化治疗
8、常见方案 类型 早餐前 中餐前 晚餐前 睡前注射胰岛素方案1 RI RI RI NPH方案2 RI RI RIUL方案3 RIUL RI RIUL方案4 RI RI RI ULCSII RI RI RI ,强化治疗胰岛素初始剂量的确定,1型糖尿病人按0.50.8u/Kg体重； 2型糖尿病人按0.30.8u/Kg体重 。,DM胰岛素治疗方案(一),基础餐前, 4次/d强化疗法,常规,NPH,早 R 25-30%午 R 15-20%晚 R 20-30%睡前 N 25%,（二）胰岛素的常规治疗,1.每日一次注射: 每日需20单位以下的病人,早餐前一次注射PZI,或NPH, 或预混胰岛素(诺和灵30R
9、或50R);或睡前注射NPH。 2.每日二次注射:适合每日需要量20单位以上病人。早餐前注射一天量的1/22/3,晚餐前注射一天量的1/31/2;多用预混胰岛素, 如:诺和灵30R或50R; 起始剂量：0.30.8U/Kg体重,24,预混型 (70/30）/bid,70/30（瓶装或笔芯）,早餐前30分 30R或50R=1/22/3日剂量晚餐前30分 30R或50R=1/31/2日剂量,25,影响胰岛素剂量的因素,个体差异极大、没有固定公式糖尿病的分型体重、腰围，肥胖情况糖尿病病程同一病人受饮食、运动、情绪、睡眠影响大！有无应激存在肾功能情况既往口服降糖药情况及是否曾经接受胰岛素治疗合并用药情
10、况：皮质激素、生长激素、葡萄糖注射液,26,Q1： 一滴5%GS滴到血糖仪，如果能够测出来大概是多少？A. 5mmol/L B. 20mmol/LC. 50mmol/L D. 200mmol/L,27,5%GS5g/100ml=5000mg/dl18278mmol/L 配制5.6mmol/L的溶液20ul的5%GS加入1ml蒸馏水,胰岛素的剂量调整,Capillary glucose monitoringCorrectional insulin For blood glucose 22.2, give 12 units,过山车式血糖控制“Roller-coaster” glucose,2.8,
11、8,13,18,16U,16 U,16 U,10U/晚,调整后理想血糖控制,2.8,8,13,18,10U,10 U,10 U,16U/晚,31,DCCT,5.5,6.0,6.5,7.0,7.5,8.0,8.5,9.0,9.5,10.0,慢性并发症,低血糖,HbA1c (%),10.5,DCCT, N Engl J Med 1993;329:97786.,32,胰岛素类似物,目前短效胰岛素治疗的问题,皮下注射起效时间慢作用时间偏长早期餐后高血糖和随后的下一餐前的低血糖危险升高餐前30分钟注射胰岛素，不方便，依从性差,34,超短效胰岛素类似物,目前的胰岛素均为含锌的六聚体,首先在皮下分解为单体才
12、能被吸收。胰岛素B链第28位氨基酸脯氨酸是形成六聚体的关键位点。采用基因技术将其替换成其他氨基酸(如天门冬氨酸或赖氨酸)不能形成六聚体，单体胰岛素很快被吸收, 清除也快,起效快、作用时间短,35,诺和锐,商品名：诺和锐TM、Aspart通用名: 门冬胰岛素由门冬氨酸替代人胰岛素B28的脯氨酸而成,36,Pro,-Asp,诺和锐,37,人胰岛素,六聚体,单体,38,诺和锐,40-50 min,80-120 min,39,超短效胰岛素与短效胰岛素对比:,0 2 4 6 8 10小时,血浆胰岛素浓度,40,诺和锐30的组成,30,%,30,%,NPH,预混人胰岛素30/70,30%,鱼精蛋白结合的结
13、晶门冬胰岛素,可溶性门冬胰岛素,预混混悬液:,30%,可溶性人胰岛素,诺和锐 30,41,诺和锐30药代动力学,Jacobsen L et al. Eur J Clin Pharm 2000;56:399403,快速达峰，快速回落，餐前即刻注射。,42,诺和锐30药代动力学,McSorley PT et al. Clin Ther 2002;24(4):530539,血浆胰岛素水平,120,80,60,40,20,0,100,全天时间,18:00,22:00,08:00,13:00,18:00,诺和锐 30,预混人胰岛素30,*,*,43,超长效胰岛素类似物,44,Long-acting In
14、sulin Analogs,Insulin glargine（Lantus）甘精胰岛素（来得时）利用胰岛素在等电点( isoelectric point ) 有結晶沉淀析出的特性，將正电荷加入胰岛素制剂中使呈偏酸性( pH4，注射部位較疼痛 )，皮下注射后会沉淀於皮下组织( pH7.4 )，約24小時缓慢而平稳释放。,45,46,Long-acting Insulin Analogs,Insulin Detemir (Levemir) 使胰岛素与水溶性脂肪酸（Myristic acid）結合，皮下注射及被人体吸收后，在组织及血液中有98与白蛋白albumin結合。在血中稳定地释放，而产生缓慢且
15、延长的效果。沒有波峰且能維持24小時，所以能提供血中稳定而不波动的基础胰岛素浓度。 可溶于中性环境（不同于Insulin glargine），不会形成結晶，但仍不建议和其他insulin混合。pH 7.27.6，注射時无灼热感。,47,48,特殊情况下胰岛素的应用,肾功能不全时胰岛素的应用,胰岛素的排泄,Approximately 3040% of the bodys insulin is removed by the kidneys.,Insulin Metabolism in CKD, Insulin has a MW of 6000 and is filtered at theglome
16、rulus Insulin is metabolized by proximal tubular cells into aminoacids Less than 1% of filtered insulin appears in the urineContribution of renal metabolism is augmented when exogenous insulin is administered,Mechanism of Insulin Resistance in CKD,Uremic toxins Hyperparathyroidism Anemia Vitamin D d
17、efeciency Inactivity,53,Insulin requirements in DM with renal diseaseInsulin requirements show a biphasic course in patientswith diabetes and renal disease.In the beginning glucose deteriorates because of insulin resistance,therefore more insulin is needed to achieve glycemic control. In advanced re
18、nal failure with creatinine clearance below 50 ml/min, the need for insulin is lower or even the cessation of insulin may be necessary. With the institution of hemodialysis the need for insulin changes because the insulin sensitivity and liver metabolism improve,Risk of Hypoglycemia in CKD,Decreased
19、 clearance of insulin Impaired gluconeogenesis by the kidney Poor intake,不同胰岛素在肾功能不全时的药代动力学改变,The pharmacokinetics of various insulin preparationshave not been well studied in patients with varyingdegrees of renal dysfunction, and there are no absolute guidelines defining appropriate dosing adjustme
20、nt of insulin that should be made based on the level of GFR.,Rapidly acting analogues like lispro and aspart are active within minutes and peak in about 1 h, may not only facilitate the correction of hyperglycemia but also decrease the risk of late hypoglycemic episodes. Long-acting analogues, such
21、as glargine, provide a peak-less, continuous insulin release over 24 h that approximates a normal basal pattern and their role in CKD is under evaluation.Some suggest thatshould be avoided, while other support that such agents should be used.,RENAL FAILURE,With increasing doses, duration of action o
22、f regular insulin increases. This increases the risk for late-postprandial hypoglycemia Nosek et al (2003): Aspart unlike regular human insulin does not show a significant prolongation in its duration of action with higher doses.,Kinetics of Insulin Aspart were comparable among diabetes with various
23、 degrees of renal dysfunction.,62,胰岛素剂量的调整,Use of Insulin in CKD No dose adjustment with GFR 50ml/min Reduce dose to 75% with GFR 10 to 50m/min Reduce dose to 50% when GFR 10ml/min,64,肾功能不全者不同治疗阶段的血糖控制,CKD patient on peritoneal dialysisThe objective of is to maintain euglycemia during the dwell time
24、, to prevent postprandial or post-PD hyperglycemia, and to avoid delayed hypoglycemia. However, controversy exists about the route of insulin administration. Subcutaneous (SC) and intraperitoneal (IP) insulin therapy are both acceptable in PD.,IP Insulin use in Peritoneal Dialysis,Advantages: Provid
25、es continuous infusion Eliminates need for injections Physiologic Route: absorbed into portal vein decrease fluctuations of blood glucose decrease hyperinsulinemia decrease insulin antibodies Disadvantages: Source of bacterial contamination increase in insulin requirement and Variable absorption Fib
26、roblastic proliferation and hepatic steatosis,腹膜透析液引起的假性高血糖,EXTRANEAL (icodextrin淀粉类多醣)，此药物为长时间（8-16小时）的腹膜透析液，与4.25% dextrose腹膜透析液比较，EXTRANEAL可以改善长时间的超过滤率和肌酐、尿素氮的廓清。 EXTRANEAL造成假性高血糖的原因 FDA2005年公告非肠道麦芽糖maltose（会代谢变成麦芽糖）、非肠道半乳糖、木醛糖 ，使用血糖仪（GDH- PQQ测定方法）无法辨别葡萄糖与麦芽糖的差异，因而产生假性高血糖。EXTRANEAL会释放出麦芽糖（matose。
27、假性高血糖可能过量使用胰岛素导致低血糖，因此出现不可逆的脑部病变甚至死亡。,Patient requiring maintenance hemodialysisPatients undergoing HD frequently become hypoglycemic. These events have become more frequent with the current use of glucose-free bicarbonate dialysis solution. Post-dialysis hypoglycemia manifests with non-specific sym
28、ptoms like headache, weakness and easy fatigability. Hypoglycemia can be prevented by decreasing the morning insulin dose, food intake prior to dialysis, or by addition of glucose to the dialysis fluid.,Post-transplant diabetes mellitus PTDM is a form of type 2 diabetes mellitus, develop from increa
29、sed insulin resistance due to corticosteroid use, impaired insulin production because of use of calcineurin inhibitors. Improved appetite and weight gain following renal transplantation may also contribute. 1. reduce steroid use or to replace them with less diabetogenic steroids such as deflazacort
30、2. A healthy allograft kidney clears insulin and hypoglycemic drugs normally.,HbA 1c Pseudo-low HbA 1c decreased RBC survival (Red cell turnover is high) such as hemolysis, transfusions ,treatment with fe, B12, folate, erythropoietin Pseudo-high A1c values Red cell turnover is low such as fe, B12 an
31、d folate deficiency，Uremia cause pseudo-elevation of HbA 1c are the presence of carbamylated hemoglobin and acidosis. Measurement of glycated albumin provides a better estimate of glycemic control in these patients.,EPO treatment- Pseudo-low HbA 1c,类固醇性糖尿病或糖尿病使用皮质激素,血糖变化特点1、典型的口服强的松导致的血糖变化：早餐后、中餐前后、晚餐前后高血糖，夜间逐渐下降，清晨空腹正常！2、地塞米松、氢化可的松、甲基强的松龙对血糖的影响持续全天。,对策1、三餐前短效，早中多，夜间少！或预混早多晚少！2、同普通糖尿病，剂量大！,76,Thank you,谢 谢！,
