胰島素及其類似物在慢性腎功能不全患者中的應(yīng)用

1、胰島素及其類似物在慢性腎功能不全患者中的應(yīng)用Insulin & its Analogin CKD with DM,2,,胰島,胰島是分散在胰腺腺泡之間的細(xì)胞團。正常人有200萬個胰島。α細(xì)胞占胰島細(xì)胞總數(shù)的20%，分泌胰高血糖素；β細(xì)胞約占胰島細(xì)胞總數(shù)的75%，分泌胰島素。 D細(xì)胞分泌生長抑素，PP細(xì)胞分泌胰多肽.,3,Proinsulin Structure,4,,,,,,,,,,,Time,,0600,1000,14

2、00,1800,2200,0200,0600,800,600,400,200,Insulin secretion (pmol/min),,正常人胰島素分泌模式,Polonsky KS et al. N Engl J Med 1996;334:777,0,,,,,,,,,,,,,Insulin Secretion,Insulin分泌有2種Basal insulin（基礎(chǔ)胰島素）：每天持續(xù)不斷釋放以應(yīng)付體內(nèi)肝糖不斷的釋放。正常人每天約24

3、U。Prandial insulin（餐時胰島素）：進食后，與血糖同步上升。正常人每天約24U。Phase 1：正常人在進食后β細(xì)胞會在3至10分鐘釋放出胰島素的第一個波峰「1st peak」，先遣部隊作用：抑制肝糖輸出刺激Phase 2 insulin的釋放Phase 2：在phase 1結(jié)束后約15秒，跟著出現(xiàn)第二波峰「2nd peak」 直至血糖恢復(fù)正常為止，持續(xù)約1～2小時。援軍主要是降低餐后血糖,,,

4、,,,,,,,,2型糖尿病的病理生理: 胰島素分泌缺陷,FPG <8 mmol/l,FPG <12 mmol/l,FPG 12–15 mmol/l,FPG >18 mmol/l,正常人,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

5、,,,,,,,,,,,,,,,,,,,,,,,,0.40,1.00,0.80,0.60,平均胰島素 (nmol/l),0.20,0,–30,0,30,60,90,120,150,180,210,240,時間 (分鐘),Coates PA et al. Diabetes Res Clin Pract 1994;26:177,2型糖尿病患者,,,,,,7,第一時相胰島素分泌缺失是T2DM的重要特征,Stefano Del Prato. et

6、 al. Diabetes 51:S109-S116, 2002,8,2型糖尿病早期相胰島素分泌受損,正常早期相分泌,糖尿病早期相缺失,常規(guī)胰島素早期相延遲,9,何時開始胰島素治療？,10,,,,何時是胰島素治療的最佳時機？,,,,,,,,,,,100,,75,,50,,25,0,-10,-6,-2,2,0,6,10,14,-12,,,,,,,,,診斷時間（年）,殘存β細(xì)胞功能 (% β),2型糖尿病Phase I,,口服單藥治療,

7、2型糖尿病Phase II,,口服聯(lián)合治療,Phase III,,胰島素,HbA1C not at target: ?7.0%,Based on data of UKPDS 16. UKPDS Group. Diabetes. 1995;44:1249-1258.,,,11,傳統(tǒng)序貫療法總是不能達標(biāo),,,,,6,7,8,9,10,HbA1c(%),,,,序貫療法,Adapted from Campbell IW. Br J Car

8、diol 2000; 7: 625-631,,目標(biāo) HbA1c ?6.5%,12,改進的強化治療,,,,,,,,,,,,,,6,7,8,9,10,HbA1c(%),,,,Adapted from Campbell IW. Br J Cardiol 2000; 7: 625-631,Conservative approach,,,序貫療法,,目標(biāo) HbA1c ?6.5%,13,2型糖尿病也存在蜜月期！,Erol Cerasi: 1997

9、年 13例新診糖尿病用胰島素泵靜脈注射胰島素兩周后，有9例不用任何抗糖尿病藥物能維持血糖正常達9-50個月。他把這稱之為2型糖尿病的‘蜜月期’. 在2型糖尿病血糖水平的良好控制使胰島素分泌功能得到極大的改善，甚至恢復(fù)了第一時相胰島素分泌功能。1型2型糖尿病之間并不像以前人們所認(rèn)為的那樣大的區(qū)別，在病因和臨床表現(xiàn)上它們更像是居于一個‘疾病譜’的兩端。兩者都有蜜月期，但是2型糖尿病的‘蜜月期’更長.,Ilkova H, et al

10、. Diabetes Care. 1997 20:1353-6.,14,國內(nèi)相關(guān)研究,國內(nèi)李延兵、翁建平報告在新診斷的2型糖尿病，2周的胰島素強化控制血糖后，六月緩解率約70%，1-2年緩解率>40%,Li Y et al.Diabetes Care ,2004,27:2597-602.Neda Rasouli,et al.J.C.E.M 2004. 89: 6331-6335,胰島素治療具體方案,胰島素的種類,胰島素按來源可分

11、為： ? 動物胰島素 ?人胰島素 ?人胰島素類似物。動物胰島素主要來源于豬和牛的胰臟，其結(jié)構(gòu)組成與人胰島素有差別。（牛3個氨基酸；豬1個氨基酸不同）人胰島素是通過基因工程由酵母菌（諾和靈）或大腸桿菌（優(yōu)泌林）合成，結(jié)構(gòu)與人體內(nèi)的胰島素一致。人胰島素類似物是通過將人胰島素的結(jié)構(gòu)略有改變，以求達到超短效或超長效等目的。,胰島素的種類,按作用時間和效應(yīng)分類：短效胰島素中效胰島素長效胰島素超短效

12、人胰島素類似物超長效人胰島素類似物預(yù)混胰島素,18,,胰島素制劑及其作用時間,19,,胰島素強化治療常見方案──────────────────── 類型 早餐前 中餐前 晚餐前 睡前────────────────────注射胰島素方案1 RI RI RI NPH方案2

13、 RI RI RI＋UL方案3 RI＋UL RI RI＋UL方案4 RI RI RI ULCSII RI RI RI ────────────────────

14、,強化治療胰島素初始劑量的確定,1型糖尿病人按0.5～0.8u/Kg體重； 2型糖尿病人按0.3～0.8u/Kg體重 。,DM胰島素治療方案(一),基礎(chǔ)＋餐前, 4次/d——強化療法,,,常規(guī),,NPH,早 R 25-30%午 R 15-20%晚 R 20-30%睡前 N 25%,,（二）胰島素的常規(guī)治療,1.每日一次注射: 每日需20單位以下的病人,早餐前一次注射PZI,或N

15、PH, 或預(yù)混胰島素(諾和靈30R或50R);或睡前注射NPH。 2.每日二次注射:適合每日需要量20單位以上病人。早餐前注射一天量的1/2～2/3,晚餐前注射一天量的1/3～1/2;多用預(yù)混胰島素, 如:諾和靈30R或50R; 起始劑量：0.3～0.8U/Kg體重,24,預(yù)混型 (70/30）/bid,,70/30（瓶裝或筆芯）,早餐前30分 30R或50R=1/2~2/3日劑量晚餐前30分 30R或50R=1/3～1

16、/2日劑量,,25,影響胰島素劑量的因素,個體差異極大、沒有固定公式糖尿病的分型體重、腰圍，肥胖情況糖尿病病程同一病人受飲食、運動、情緒、睡眠影響大！有無應(yīng)激存在腎功能情況既往口服降糖藥情況及是否曾經(jīng)接受胰島素治療合并用藥情況：皮質(zhì)激素、生長激素、葡萄糖注射液,26,Q1： 一滴5%GS滴到血糖儀，如果能夠測出來大概是多少？A. 5mmol/L B. 20mmol/LC. 50mmol/L

17、D. 200mmol/L,27,5%GS＝5g/100ml=5000mg/dl÷18＝278mmol/L 配制5.6mmol/L的溶液20ul的5%GS加入1ml蒸餾水,胰島素的劑量調(diào)整,Capillary glucose monitoringCorrectional insulin For blood glucose 22.2, give 12 units,過山車式血糖控制“Roller-coaster”

18、 glucose,,,,,,,,,2.8,8,13,18,16U,16 U,,,,16 U,10U/晚,·,·,·,·,·,·,調(diào)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

19、,8.5,9.0,9.5,10.0,,,,,,,,,,,,,,,,,,,,,,,,慢性并發(fā)癥,,低血糖,HbA1c (%),10.5,DCCT, N Engl J Med 1993;329:977–86.,32,胰島素類似物,目前短效胰島素治療的問題,皮下注射起效時間慢作用時間偏長早期餐后高血糖和隨后的下一餐前的低血糖危險升高餐前30分鐘注射胰島素，不方便，依從性差,34,超短效胰島素類似物,目前的胰島素均為含鋅的六聚體,首先在皮

20、下分解為單體才能被吸收。胰島素B鏈第28位氨基酸脯氨酸是形成六聚體的關(guān)鍵位點。采用基因技術(shù)將其替換成其他氨基酸(如天門冬氨酸或賴氨酸)不能形成六聚體，單體胰島素很快被吸收, 清除也快,起效快、作用時間短,35,諾和銳,商品名：諾和銳TM、Aspart通用名: 門冬胰島素由門冬氨酸替代人胰島素B28的脯氨酸而成,36,Pro,-Asp,諾和銳,37,人胰島素,六聚體,單體,38,諾和銳,40-50 min,80-120 min,

21、39,超短效胰島素與短效胰島素對比:,,,0 2 4 6 8 10小時,血漿胰島素濃度,40,諾和銳®30的組成,,,,,,,,,30,%,,,,,,,,30,%,,,NPH,預(yù)混人胰島素30/70,,,,30%,魚精蛋白結(jié)合的結(jié)晶門冬胰島素,可溶性門冬胰島素,預(yù)混混懸液:,,,,,,,,30%,可溶性人胰島素,,,諾和銳® 30,,,,,41,諾和銳®

22、;30藥代動力學(xué),Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403,快速達峰，快速回落，餐前即刻注射。,42,諾和銳®30藥代動力學(xué),McSorley PT et al. Clin Ther 2002;24(4):530–539,,血漿胰島素水平,120,80,60,40,20,0,100,全天時間,18:00,22:00,08:00,13:00,18:00,,,,,,,,

23、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

24、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,諾和銳 30,預(yù)混人胰島素30,,,,,*,*,43,超長效胰島素類似物,44,Long-acting Insulin Analogs,Insulin glargine（Lantus®）甘精胰島素（來得時）利用胰島素在等電點( isoelectric point ) 有結(jié)晶沉淀析出的特性，將正電荷加入胰島素制劑中使呈偏酸性( p

25、H4，注射部位較疼痛 )，皮下注射后會沉淀於皮下組織( pH7.4 )，約24小時緩慢而平穩(wěn)釋放。,45,,46,Long-acting Insulin Analogs,Insulin Detemir (Levemir®) 使胰島素與水溶性脂肪酸（Myristic acid）結(jié)合，皮下注射及被人體吸收后，在組織及血液中有98％與白蛋白albumin結(jié)合。在血中穩(wěn)定地釋放，而產(chǎn)生緩慢且延長的效果。沒有波峰且能維持24小

26、時，所以能提供血中穩(wěn)定而不波動的基礎(chǔ)胰島素濃度。 可溶于中性環(huán)境（不同于Insulin glargine），不會形成結(jié)晶，但仍不建議和其他insulin混合。pH 7.2~7.6，注射時無灼熱感。,47,,48,特殊情況下胰島素的應(yīng)用,腎功能不全時胰島素的應(yīng)用,胰島素的排泄,,Approximately 30~40% of the body's insulin is removed by the kidneys.,Insu

27、lin Metabolism in CKD,? Insulin has a MW of 6000 and is filtered at theglomerulus? Insulin is metabolized by proximal tubular cells into aminoacids? Less than 1% of filtered insulin appears in the urine?Contribution

28、of renal metabolism is augmented when exogenous insulin is administered,Mechanism of Insulin Resistance in CKD,Uremic toxins? Hyperparathyroidism? Anemia? Vitamin D defeciency? Inactivity,53,,Insulin requirements in

29、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 achi

30、eve glycemic control. In advanced renal 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

31、for insulin changes because the insulin sensitivity and liver metabolism improve,Risk of Hypoglycemia in CKD,Decreased clearance of insulin Impaired gluconeogenesis by the kidney Poor intake,不同胰島素在腎功能不全時的藥代動力學(xué)改變,The p

32、harmacokinetics of various insulin preparationshave not been well studied in patients with varyingdegrees of renal dysfunction, and there are no absolute guidelines defining appropriate dosing adjustment of insulin tha

33、t 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 r

34、isk of late hypoglycemic episodes. Long-acting analogues, such 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.S

35、ome suggest thatshould be avoided, while other support that such agents should be used.,RENAL FAILURE,With increasing doses, duration of action of regular insulin increases. This increases the risk for late-postprandial

36、 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 diabe

37、tes with various degrees of renal dysfunction.,62,,,胰島素劑量的調(diào)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,,,腎

38、功能不全者不同治療階段的血糖控制,CKD patient on peritoneal dialysisThe objective of is to maintain 'euglycemia' during the dwell time, to prevent postprandial or post-PD hyperglycemia, and to avoid delayed hypoglycemia. How

39、ever, 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:? Provides conti

40、nuous infusion? Eliminates need for injections? Physiologic Route: absorbed into portal vein decrease fluctuations of blood glucose decrease hyperinsulinemia decrease insulin antibodies Disadvantages:?

41、Source of bacterial contamination? increase in insulin requirement and Variable absorption? Fibroblastic proliferation and hepatic steatosis,腹膜透析液引起的假性高血糖,EXTRANEAL (icodextrin淀粉類多醣)，此藥物為長時間（8-16小時）的腹膜透析液，與4.25% dextro

42、se腹膜透析液比較，EXTRANEAL可以改善長時間的超過濾率和肌酐、尿素氮的廓清。 EXTRANEAL造成假性高血糖的原因  FDA2005年公告非腸道麥芽糖maltose（會代謝變成麥芽糖）、非腸道半乳糖、木醛糖 ，使用血糖儀（GDH- PQQ測定方法）無法辨別葡萄糖與麥芽糖的差異，因而產(chǎn)生假性高血糖。EXTRANEAL會釋放出麥芽糖（matose。假性高血糖可能過量使用胰島素導(dǎo)致低血糖，因此出現(xiàn)不可逆的腦部病變甚至死

43、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-dialys

44、is hypoglycemia manifests with non-specific symptoms 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 g

45、lucose to the dialysis fluid.,,,,,Post-transplant diabetes mellitus PTDM is a form of type 2 diabetes mellitus, develop from increased insulin resistance due to corticosteroid use, impaired insulin production because o

46、f 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 2. A

47、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, e

48、rythropoietin Pseudo-high A1c values Red cell turnover is low such as fe, B12 and folate deficiency，Uremia cause pseudo-elevation of HbA 1c are the presence of carbamylated hemoglobin and acidosis. Measurement of g

49、lycated albumin provides a better estimate of glycemic control in these patients.,EPO treatment---- Pseudo-low HbA 1c,類固醇性糖尿病或糖尿病使用皮質(zhì)激素,血糖變化特點1、典型的口服強的松導(dǎo)致的血糖變化：早餐后、中餐前后、晚餐前后高血糖，夜間逐漸下降，清晨空腹正常！2、地塞米松、氫化可的松、甲基強的松龍對血糖的影響持續(xù)