治療糖尿病--現(xiàn)狀及未來(lái)

1、T2DMT2DM1900190020002000發(fā)現(xiàn)胰島素發(fā)現(xiàn)胰島素基因重組人胰島素基因重組人胰島素b b- -細(xì)胞治療細(xì)胞治療 / /控制控制 b b- -細(xì)胞再生和自身免疫細(xì)胞再生和自身免疫拯救拯救1 1型糖尿病型糖尿病患者生命的治療患者生命的治療無(wú)限制供應(yīng)無(wú)限制供應(yīng)消除糖尿病晚期消除糖尿病晚期并發(fā)癥并發(fā)癥? ?改善血糖改善血糖控制控制類(lèi)似物類(lèi)似物糖尿病治療的重點(diǎn)糖尿病治療的重點(diǎn)之前之前之后之后BantingBanting & & BestBest192219224:004:0025255050757516:0016:0020:00 20:00 24:0024:004:00

2、4:00早餐早餐中餐中餐晚餐晚餐血漿胰島素（血漿胰島素（ U/ml) U/ml) 理想的基礎(chǔ)餐前強(qiáng)化胰島素治理想的基礎(chǔ)餐前強(qiáng)化胰島素治療的模式療的模式8:008:0012:0012:008:008:00時(shí)間時(shí)間Insulin Insulin DetemirDetemir Lys(B29)-N- Lys(B29)-N- -Tetradecanoyl,Des(B30)-Insulin-Tetradecanoyl,Des(B30)-InsulinSchmitz Ole M.D. 丹麥Aarhus大學(xué)糖尿病患者對(duì)包括嚴(yán)重低血糖在內(nèi)糖尿病患者對(duì)包括嚴(yán)重低血糖在內(nèi)等問(wèn)題的態(tài)度等問(wèn)題的態(tài)度 Pramming

3、 et al, Diabetic Medicine 1991;8:217-22DCCT (Type 1)視網(wǎng)膜病變視網(wǎng)膜病變161284056789101112A1C (%)發(fā)生率發(fā)生率/100人年人年UKPDS (Type 2)A1C (%)Incidence/100Patient Years86420567891011微血管病變微血管病變Data from DCCT Research Group. Diabetes 1996; 45:1289-1298Data from Stratton IM, et al. BMJ 2000; 321:405-412Data from DCCT/EDIC

4、 Research Group. New Engl J Med 2000; 342:381-389Data from Steffes M, et al. Diabetes 2001; 50(suppl 2):A63Data from UKPDS Group (UKPDS 33). Lancet 1998; 352:837-853DCCT EDIC(Type 1)UKPDS (Type 2)胰島素組DCCTEDIC468109.08.17.37.906.5+4+6A1C (%)時(shí)間（年）時(shí)間（年）A1C (%)Normal基線(xiàn)基線(xiàn)0246810時(shí)間（年）時(shí)間（年）0678嚴(yán)重低血糖DCCT (T

5、ype 1)UKPDS (Type 2)病人比例病人比例(%)A1C (%)1008060402005791113發(fā)生率發(fā)生率/100人年人年54321003691215時(shí)間（年）時(shí)間（年）Major EpisodesData from DCCT Research Group. Diabetes 1997; 46:271-286Data from UKPDS Group (UKPDS 33). Lancet 1998; 352:837-853 15強(qiáng)化組強(qiáng)化組常規(guī)組常規(guī)組強(qiáng)化組強(qiáng)化組常規(guī)組常規(guī)組6(年份年份)806040200024681012血漿游離胰島素血漿游離胰島素 (U/ml)進(jìn)餐或注

6、射胰島素后的時(shí)間進(jìn)餐或注射胰島素后的時(shí)間 (小時(shí)小時(shí))正常餐后水平(Mean SD, n=23)糖尿病患者注射胰島素后in diabetic subjects(Mean SEM, n=20)Bolli G.B., N.Engl.J.Med. 310:1706, 1984皮下組織Mol/l擴(kuò)散毛細(xì)血管膜10-310-410-510-8Adapted from Brange et al. 1990時(shí)間點(diǎn)血漿葡萄糖 (mmol/l) 晚餐NPH早餐中餐Insulin aspartSoluble human insulinAdapted from Home et al. 199808101214161

7、806001200180024000600血清胰島素時(shí)間點(diǎn)晚餐NPH早餐t午餐Adapted from Home et al. 1998胰島素aspart可溶性人胰島素(mU/l) (pmol/l) 600300010020040050002040608010006001200180024000600Plank J et al. Arch Intern Med 2005;165:1337-44理想的基礎(chǔ)胰島素理想的基礎(chǔ)胰島素胰島素濃度胰島素濃度餐前餐前大劑量大劑量下午下午餐前餐前大劑量大劑量晚間晚間基礎(chǔ)輸注基礎(chǔ)輸注夜間夜間餐前餐前大劑量大劑量上午上午持續(xù)皮下胰島素輸注持續(xù)皮下胰島素輸注 胰島素

8、 Glargine:21A-Gly-30Ba-L-Arg-30Bb-L-Arg-insulin代謝產(chǎn)物:M1-21A-Gly-insulinM2-21A-Gly-des-30B-Thr-insulinGlyAsnACHAINB-CHAIN15152025151015203010ArgArgSUBS ITUTIONEXTENSION0102030405060708090100024681012141618202224放射活性放射活性 (%)胰島素 glargine (0.3 IU/kg)胰島素NPH (0.3 IU/kg)注射后時(shí)間注射后時(shí)間 (小時(shí)小時(shí))Luzio et al. Diabete

9、s 1999;48(suppl 1):A111. Abstract 480.GlargineNPHUltralenteCSIIn=20 T1DMMean SEM皮下注射胰島素4.03.02.01.002420161284004812162024Time (hours)mg/Kg/minmol/Kg/minThrGluLysValPheAsnGluLeuGlnTyrLeuSerCysIleSerCysCysGlnGluValIleGlyTyrCysAsnLysProThrTyrPhePheArgGlyGluGlyCysValLeuTyrLeuAlaValLeuHisSerGlyCysAsnGln

10、LeuHisB1A21A1B29C14 脂肪酸鏈脂肪酸鏈(肉豆蔻酸肉豆蔻酸)Thr胰島素detemir 0.1 U/kg胰島素 detemir 0.2 U/kg胰島素 detemir 0.4 U/kgNPH 胰島素0.3 IU/kg2.01.51.00.5004816202412注射胰島素后時(shí)間 (hours)GIR (mg/kg/min)Study reported as:J Plank et al. Diabetes Care 2005;28(5):1107-12胰島素劑量 (IU/kg - U/kg)0.302468GIRmax (mg/kg/min)0.20.40.81.6NPH胰島素

11、 detemir0.1Study reported as:J Plank et al. Diabetes Care 2005;28(5):1107-12NPH0.10.20.40.81.60.3Insulin detemir胰島素劑量 (IU/kg - U/kg)10152025作用時(shí)間 (h)05Study reported as:J Plank et al. Diabetes Care 2005;28(5):1107-12 p 0.006p 0.001024681012胰島素 detemir 早餐+晚餐胰島素detemir 早餐+睡前NPH 早餐+睡前空腹血漿葡萄糖 (mmol/l)基線(xiàn)基

12、線(xiàn)基線(xiàn)16 周16 周16 周16周時(shí)與NPH比較的p值Study reported as:T. Pieber et al. Diabetic Medicine 2005:22(7):850-7. 1086420123456調(diào)藥階段 治療月數(shù)p 0.05每人每月事件數(shù) Study reported as:P. Vague et al. Diabetes Care 2003;26(3):5906.胰島素 detemir (HbA1c 7.60)NPH I (HbA1c 7.64) Time (hours)胰島素 detemirNPH 321不同個(gè)體的平均 平均血糖波動(dòng) (mmol/l)01261

13、418226210日間夜間Study reported as:D. Russell-Jones et al. Clin Ther 2004;26:724-736 胰島素detemirNPH 6.577.588.599.510-201224WeeksHbA1cStudy reported as:K. Hermansen et al. Diabetologia 2004;47(Suppl. 1):A273胰島素detemir (n = 230)NPH (n = 232)Mean (SE)6.58(0.064)6.46(0.063)0400800120016002000胰島素detemir (n =

14、 237)NPH (n = 238)所有嚴(yán)重低血糖事件經(jīng)證實(shí)的輕度低血糖事件有低血糖癥狀但未經(jīng)證實(shí)908168818387755519923* p 0.001低血糖 (事件數(shù))Study reported as:K. Hermansen et al. Diabetologia 2004;47(Suppl. 1):A2730100200300400胰島素 detemir (n = 237)NPH (n = 238)所有低血糖數(shù)嚴(yán)重低血糖事件經(jīng)證實(shí)的輕度低血糖事件有低血糖癥狀但未經(jīng)證實(shí)夜間低血糖 (事件數(shù))160349017418785161* p 0.001 * p 0.01*Study rep

15、orted as:K. Hermansen et al. Diabetologia 2004;47(Suppl. 1):A27377.588.599.510基線(xiàn)26 周HbA1c (%)胰島素 detemir + IAsp胰島素 glargine + IAsp8.768.708.128.11Study reported as:T. Pieber EASD 2005 Oral Presentation*0.00.51.01.52.02.53.03.5 早餐前-午餐前 晚餐前SD (mmol/L)09182736455463SD (mg/dL)7.777.01#7.247.567.66 7.64*

16、p0.05 #p0.0012.442.242.412.522.622.89Study reported as:T. Pieber EASD 2005 Oral Presentation胰島素 detemir + IAsp胰島素 glargine + IAsp嚴(yán)重低血糖事件00.10.20.30.4每人年事件數(shù)0102030每人年事件數(shù)0.10.333.233.1所有事件 嚴(yán)重低血糖事件胰島素 detemir: 2人4次胰島素 glargine: 12人15次 *p0.05Study reported as:T. Pieber EASD 2005 Oral Presentation胰島素dete

17、mir + IAsp胰島素glargine + IAsp2x 平均血糖平均血糖0.5x 平均血糖95%的個(gè)體相對(duì)均值的藥代動(dòng)力學(xué)反應(yīng)范圍relative to the mean GIR AUC 24 hours (mg/kg/min)NPH 胰島素glargine胰島素detemir43210Study reported as:T. Heise et al. Diabetes 2004; 53:1614-1620 假設(shè)某人平均的代謝作用是 1mg/kg/min.那么代謝作用低于 0.5 mg/kg/min 的機(jī)率:0.5% 如使用胰島素如使用胰島素detemir7.5% 如使用胰島素如使用胰島

18、素 glargine15.5% 如使用如使用 NPH 胰島素胰島素個(gè)體內(nèi)變異低提示低血糖風(fēng)險(xiǎn)小個(gè)體內(nèi)變異低提示低血糖風(fēng)險(xiǎn)小Study reported as:T. Heise et al. Diabetes 2004; 53:1614-1620胰島素類(lèi)似物與受體結(jié)合及代謝和促有絲分裂效應(yīng)的相關(guān)性Kurtzhals et al Diabetes 2000 Advertisement0120240360480600720840960 1080 1200 1320 1440Time (min)3456Plasma glucose (mmol/L)DetemirGlargineNPH在健康人0.4 U

19、nit/kg 皮下注射胰島素進(jìn)行的正糖鉗夾試驗(yàn)的24小時(shí)血糖水平0120240360480600720840960 1080 1200 1320 1440Time (min)01234Glucose infusion (mgmin-1kg-1)DetemirGlargineNPH健康人皮下注射0.4 U/kg 胰島素后的葡萄糖輸注率個(gè)體的葡萄糖輸注率個(gè)體的葡萄糖輸注率0123456Subject 10123456Subject 20123456Subject 30240480720960 1200 1440Time (min)0123456Subject 60240480720960 1200

20、 1440Time (min)0123456Subject 7Glucose infusion rate (mgmin-1kg-1)DetemirGlargineNPH0123456Subject 80123456Subject 90123456Subject 10024048072096012001440Time (min)0123456Subject 11024048072096012001440Time (min)0123456Subject 12Glucose infusion rate (mgmin-1kg-1)DetemirGlargineNPHPrimary Endpoints0

21、50010001500200025003000AUCGIR, 0-1440 min (mgkg-1 )DetemirGlargine NPH024048072096012001440TRmax, GIR (min)DetemirGlargineNPH012345Rmax, GIR (mgmin-1 kg -1 )Detemir GlargineNPHSupplementary Analyses of GIR0-12 h12-24 h0500100015002000AUCGIR, 12 h intervals (mgkg-1 )DetemirGlargineNPH0-8 h8-16 h16-24

22、 h0500100015002000AUCGIR, 8 h intervals (mgkg-1 )DetemirGlargineNPH0-6 h6-12 h 12-18 h18-24 h020040060080010001200AUCGIR, 6 h intervals (mgkg-1 )DetemirGlargineNPH(P = 0.024)0-4 h 4-8 h8-12 h 12-16 h16-20 h20-24 h020040060080010001200AUCGIR, 4 h intervals (mgkg-1 )DetemirGlargineNPH(P = 0.0045)0 120

23、240360480600720840960 1080 1200 1320 1440Time (min)020406080100Insulin (pmol/L)DetemirGlargine NPH0 120240360480600720840960 1080 1200 1320 1440Time (min)0100200300400500600C-peptide (pmol/L)DetemirGlargine NPH吸入胰島素原理：肺組織有100 m2 的吸收面積結(jié)合胰島素結(jié)合位點(diǎn)1刺激TM區(qū)域的b亞單位2刺激胰島素受體的酪氨酸激酶3抑制IRTK, i.e. PT激酶4使用使用方便方便給藥給藥

24、劑量可精確到劑量可精確到1 1個(gè)單位個(gè)單位劑量劑量精確給藥精確給藥避免針頭注射避免針頭注射持續(xù)皮下胰島素輸注系統(tǒng)持續(xù)皮下胰島素輸注系統(tǒng)( (CSII)CSII)“My pump has helped me a lot. Part of playing better has been feeling better.”Scott Verplank, PGA Winner1414年后我又獲得了冠軍！年后我又獲得了冠軍！ 餐后血糖空腹血糖胰島素抵抗胰島素分泌血漿血漿葡萄糖葡萄糖水平水平相對(duì)的相對(duì)的b 細(xì)胞細(xì)胞功能功能126 mg/dL患糖尿病的年數(shù)患糖尿病的年數(shù)Adapted from Interna

25、tional Diabetes Center (IDC), Minneapolis, Minnesota.9876正常范圍ADA控制目標(biāo)ADA 建議行動(dòng)目標(biāo)00369隨機(jī)化后的年限1218常規(guī)治療強(qiáng)化治療強(qiáng)化治療7.4%6.6%8.4%7.5%8.7%8.1%Median HbA1c (%)A. 空腹血糖 B. HbA1c C. 體重 D. 胰島素 傳統(tǒng)療法(n=676) 胰島素(n=689) 磺酰脲(n=922)Diabetes 1995, 44: 1249ABCD0 1 2 3 4 5 6 年0 1 2 3 4 5 6 年0 1 2 3 4 5 6 年0 1 2 3 4 5 6 年 Pos

26、t meal glucoseObese subjects Fasting glucoseDyslipidemia FPG - Post meal glucose2 2型糖尿病中進(jìn)行型糖尿病中進(jìn)行 胰島素治療的障礙胰島素治療的障礙578053874067020406080100GarveyAndrewsScarlett基線(xiàn)數(shù)值胰島素治療后葡葡 萄萄 糖糖 處處 置置 率率% of Matched Control Values所有研究對(duì)象所有研究對(duì)象(N = 620)風(fēng)險(xiǎn)降低風(fēng)險(xiǎn)降低 (28%) P = .011傳統(tǒng)治療傳統(tǒng)治療0.3.2.4.7.1.5.601隨訪(fǎng)年限隨訪(fǎng)年限2345低心血管風(fēng)險(xiǎn)

27、研究對(duì)象低心血管風(fēng)險(xiǎn)研究對(duì)象(N = 272)風(fēng)險(xiǎn)降低風(fēng)險(xiǎn)降低 (51%) P = .0004靜脈滴注胰島素靜脈滴注胰島素2天，此后每天天，此后每天4次皮下注射胰島素次皮下注射胰島素0.3.2.4.7.1.5.601隨訪(fǎng)年限隨訪(fǎng)年限2345注注: 這些都是示意圖這些都是示意圖.胰島素吸收與效果胰島素吸收與效果: MDI 與與 CSIIUltralente和和NPH 胰島素的吸收最多有胰島素的吸收最多有52%的的變化變化, 而而 Lantus每天注射時(shí)最多有每天注射時(shí)最多有32%的變的變化化, 這就為多達(dá)這就為多達(dá)80 % 的日常血糖變異率提供了的日常血糖變異率提供了解釋解釋. 2, 31. L

28、auritzen T, Pramming S, Deckert T, Binder C. Pharmacokinetics of Continuous Subcutaneous Insulin Infusion. Diabetologia 1983; 24: 326-9.2. Scholtz HE, et al. An assessment of the variability in the pharmacodynamics (glucose lowering effect) of HOE901 (glargine-Lantus) compared to NPH and ultralente

29、human insulins using the euglycaemic clamp technique. Abstract 0882. Poster Event D: 1999, Brussels, Belgium.Note: Schematic representation only.泵比注射可以提供更好的控制泵比注射可以提供更好的控制, 原因在于原因在于: 速效胰島素輸注的吸收變化小于速效胰島素輸注的吸收變化小于3 %. 1 可程控能力允許特別確定輸注可程控能力允許特別確定輸注, 滿(mǎn)足各基礎(chǔ)胰滿(mǎn)足各基礎(chǔ)胰 島素的要求及可變大劑量的需要島素的要求及可變大劑量的需要. 1. Lauritze

30、n T, Pramming S, Deckert T, Binder C. Pharmacokinetics of Continuous Subcutaneous Insulin Infustion. Diabetologia 1983; 24: 326-9. 01.02.03.04.05.06.012am4am8am12pm4pm8pm12am大劑量胰島素輸注大劑量胰島素輸注基礎(chǔ)胰島素輸注基礎(chǔ)胰島素輸注對(duì)基礎(chǔ)率進(jìn)行程控,幫助防止延遲現(xiàn)象雙波大劑量峰運(yùn)動(dòng)過(guò)程中的臨時(shí)基礎(chǔ)率,幫助防止低血糖t進(jìn)餐大劑量基礎(chǔ)率降低,幫助防止低血糖胰島素單位數(shù)胰島素單位數(shù)第第1天天: 預(yù)期峰值預(yù)期峰值1第第2天天:

31、未成熟峰舉例未成熟峰舉例 20胰島素作用胰島素作用 (峰值峰值)作用的小時(shí)數(shù)作用的小時(shí)數(shù)6121824第第3天天: 延遲峰舉例延遲峰舉例,胰島素累積的結(jié)果胰島素累積的結(jié)果 2已被證實(shí)胰島素泵治療的優(yōu)勢(shì)已被證實(shí)胰島素泵治療的優(yōu)勢(shì) （四）（四）已被證實(shí)胰島素泵治療的優(yōu)勢(shì)已被證實(shí)胰島素泵治療的優(yōu)勢(shì) （五）（五）年齡（歲）44.010.0病程（年）0.160.07體重指數(shù)25.32.76腰圍（厘米）88.09.32治療前空腹血糖mmol/L15.03.9治療前餐后2小時(shí)血糖mmol/L21.75.3治療后空腹血糖mmol/L6.61.0治療后餐后2小時(shí)血糖（早）mmol/L8.72.5治療后餐后2小時(shí)

32、血糖（午）mmol/L9.52.2治療后餐后2小時(shí)血糖（晚）mmol/L9.42.7治療后0Am血糖mmol/L6.31.4治療后3Am血糖mmol/L6.11.3血糖達(dá)滿(mǎn)意的天數(shù)(day)5.52.3基礎(chǔ)量(u/day)13.84.1每公斤體重的基礎(chǔ)量(u/kg,day)0.200.06早餐前大劑量(u)7.72.5每公斤體重的早餐前大劑量(u/kg)0.110.03午餐前大劑量(u)9.03.4每公斤體重的午餐前大劑量(u/kg)0.130.05晚餐前大劑量(u)8.83.8每公斤體重的晚餐前大劑量(u/kg)0.130.06 CSII在在2型糖尿病治療中的應(yīng)用型糖尿病治療中的應(yīng)用-北大人

33、民醫(yī)院經(jīng)驗(yàn)北大人民醫(yī)院經(jīng)驗(yàn)胰島素泵在胰島素泵在2 2型糖尿病中應(yīng)用指征型糖尿病中應(yīng)用指征病例選擇病例選擇一天胰島素總量一天胰島素總量0 05 510101515202025256AM6AM9AM9AM11AM11AM1PM1PM4PM4PM7PM7PM9PM9PM用泵前用泵后CSII-PATIENTCSII-PATIENT使用第六天05101520256AM6AM9AM9AM11AM11AM1PM1PM4PM4PM7PM7PMBASIC 24.9 BULOS 9-8-8使用前使用前使用后使用后3 3A M - 6A M 1. 2u/ h A M - 6A M 1. 2u/ h 9A M - 9

34、P M 0. 9u/ h 9PM - 3A M 9A M - 9P M 0. 9u/ h 9PM - 3A M0. 7u/ h B O LU S ; 5u- 4u- 4u.0. 7u/ h B O LU S ; 5u- 4u- 4u.3A M - 6A M 1. 4u/ h 6A M - 3P M 1. 5u/ h 3P M - 9P M3A M - 6A M 1. 4u/ h 6A M - 3P M 1. 5u/ h 3P M - 9P M1. 3u/ h 9P M -3A M 0. 7u/ h1. 3u/ h 9P M -3A M 0. 7u/ hB O LU S ; 6u- 5u- 5u

35、.B O LU S ; 6u- 5u- 5u.0 05 510101515202025256AM6AM9AM9AM11AM11AM2PM2PM5PM5PM9PM9PMB.GB.GPUMP BGPUMP BG0 00-20-2A M 0. 7u/h 2AM -3AM 1. 1u/ h 3A M -4A M 1.3u/hA M 0. 7u/h 2AM -3AM 1. 1u/ h 3A M -4A M 1.3u/h4A M -6A M 1. 8u/ h 6AM -12N0.2u/h 12N-3PM 0.4u/ h4A M -6A M 1. 8u/ h 6AM -12N0.2u/h 12N-3PM 0

36、.4u/ h3PM -4PM 0.6u/h3PM -4PM 0.6u/h4PM -6PM 0.7u/h 6PM -7PM 0.5u/h 7PM -8PM O . 4u/ h4PM -6PM 0.7u/h 6PM -7PM 0.5u/h 7PM -8PM O . 4u/ h8PM -10PM 0. 6u/h 10PM -24PM O .7u/h8PM -10PM 0. 6u/h 10PM -24PM O .7u/hTO TA L;15.2u/ 24hTO TA L;15.2u/ 24h B O LU S;2u-2u-2u B O LU S;2u-2u-2u0 05 510101515202025

37、256AM6AM9AM9AM11AM11AM2PM2PM5PM5PM8PM8PM10PM10PMB GB GPUMP BGPUMP BG折線(xiàn)圖 3折線(xiàn)圖 3哪些哪些2 2型糖尿病患者可以采用型糖尿病患者可以采用CSIICSIIp=0.026p=0.040n=11HbA1c (%)Davidson et al., Diabetologia 1999, 42(suppl 1):A212. J.Weinstein u.a.: 36th EASD Kongress 2001, Glasgow Abstract 94, Diabetologia (2001) 44 Suppl.1, A26J.Weinstein u.a.: 36th EASD Kongress 2001, Glasgow Abstract 94, Diabetologia (2001) 44 Suppl.1, A26Glucose (mg/dl)300100MDI We