糖尿病与基因课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2020/9/14,#,1,WHO,:,控制糖尿病,刻不容缓,糖尿病,(T2D,),是四大非传染病之一,是仅次于心脑血管疾病和癌症的第三位死亡原因,;,9,秒钟就有,1,人死于糖尿病,每年约死亡,400,失明约,1500;,使心脏病与脑卒中增加,34,倍,(US ,CDC 2007);,仅,2010,年全球为此支出,3,780,亿美元,占全球支出的,12%!,钱荣立 中国糖尿病杂志,2010;18:881882,2010,联合国糖尿病日,;,中国蓝光行动,1WHO:控制糖尿病,刻不容缓糖尿病(T2D)是四大非传染,2,糖尿病严重威胁人类健康,Source: WHO and IDF,流行性日益加剧,2000,2030,死亡,3+ million,截肢,1+ million,肾衰,500,000+,失明,300,000+,医疗开支,USD 156+,billion,糖尿病每年给全球带来的巨大损失,全球糖尿病患者（百万）,2糖尿病严重威胁人类健康Source: WHO and I,3,中国糖尿病患者居全球之首,“Prevalence of Diabetes among Men and Women in China”,中国成年人中糖尿病发病率为,9.7%(,远高于全球平均患病率,6.4%),现有患者,9,240,万例,约占全球糖尿病患者,1/3,居全球之首,第二位为印度,5080,万例,;,Wenying Yang etal. N Engl J Med 2010;362:1090-1101,CDS,与,IDF,联合调研结果指出,:,我国糖尿病治疗费用每年高达,1,734,亿元,(,约,250,亿美元,),是非糖尿病人的,34,倍,;,占全国医疗总支出的,13%!,2010,11,14,第,4,个联合国糖尿病日,IDF,主席,Mbanya,报告,3中国糖尿病患者居全球之首“Prevalence of Di,4,全球现有十一大类抗糖尿病药,1,胰岛素及其衍生物,;,2,磺脲类,;,3,双胍类,;,4,噻唑烷二酮类,;,5,-,糖苷酶抑制剂,;,6,格列奈类胰岛素促泌剂,(Meglitinides);,7,胰岛淀粉样肽,(Amylin analogues);,普兰林肽注射液,8,肠促胰岛素激素拟似药,(Incretin hormone mimetics);,艾塞那肽注射液,9,二肽基肽酶,抑制剂,(DPP4-I);,西他列汀,10,胰高血糖素样肽受体激动剂,(GLP-1);,利拉鲁肽,11,钠,-,葡萄糖共同转运体抑制剂,(Sodium-Glucose Co-Transport Inhibitors;,SGLTs-I,),。,注,:,黄色标记药物系目前认为与基因多态性密切相关者,4全球现有十一大类抗糖尿病药1,胰岛素及其衍生物;注:黄色标,5,当前,T2D,的控制率仅约,40%,而,T2D,却占全部糖尿病患者的,90%95%!,Presented by,Trudy N. Griffith BSc. Pharm (Hons),13 August 2010,5 当前T2D的控制率仅约40%,而T2D,6,服用降糖药的患者,40%,未能达标尤其是单一药物,!,过去的,10,年,约,40%T2D,患者的,糖化血红蛋白,(glycosylated hemoglobin ,HbA1c),未能达到, Val,突变病人的有效率降低,罗格列酮,PPAR,PPAR,Pro12Ala,突变者疗效更佳,易发生药源性水肿,瑞格列奈,OATP1B1,SLCO1B1 T521C,AUC,增高,CYP2C8,CYP2C8*3,AUC,和,Cmax,降低,40%,那格列奈,OATP1B1,SLCO1B1 T521C,Cmax,和,AUC,增高,CYP2C9,CYP2C9*3,血浆清除率下降,发生低血糖的机率增高,涉及降糖药的,PGx,19甲苯磺丁脲CYP2C9CYP2C9*3清除率降低SUR1,20,为什么有些人应用二甲双胍无效,?,FDA;1995,20为什么有些人应用二甲双胍无效?FDA;1995,21,二甲双胍是治疗,T2D,的一线药物,减少肝糖的输出,增加胰岛素敏感,降低,LDL,和,TG,降低,C,反应蛋白,减轻体重或保持,不引发低血糖风险,可引发恶心痉挛及腹泻,罕见乳酸中毒,禁忌证,:CHF,肾功不良,80,岁老人,!,21 二甲双胍是治疗T2D的一线药物减少肝,22,在服用二甲双胍的患者中,有,35-40%,禁食血糖水平未达标,!,Diabet. Care 1994, 17, 1100-1109,Diabet. Med. 1994, 11, 953-960,Metformin is not without adverse events such as diarrhea and nausea that occur in,about 30% of patients; or a more serious,but very rare side effect, lactic acidosis. Despite an exceptional efficacy and safety profile,several T2Ds (about 38%) still fail,to reach glycemic goals in metformin therapy,.,Pharmacogenomics and Personalized Medicine 2009:2 7991,22 在服用二甲双胍的患者中,有35-40%,23,临床证明单用二甲双胍易出现继,发性,失效,Secondary Failure of Metformin Monotherapy in Clinical Practice,作者报告,在,20042006,年间,用二甲双胍共治疗,T2D,患者,1,799,例,以,7%!,注,:,继发性失效定义,1,需加用或换用第二种降糖药,;,2,随后的,HbA1C7.5%,。,Diabetes Care 2010;33:501506,23临床证明单用二甲双胍易出现继发性失效Secondary,24,二甲双胍在体内的转运,二甲双胍为一亲水性有机阳离子,(pKa 12.4) ,是有机阳离子转运体,(organic cation transporters ;OCTs),包括,OCT1, OCT2,的底物, OCT1,主要在肝细胞表达, OCT2,则在肾细胞中表达,二者分別将二甲双胍转运至肝细胞内和肾脏上皮细胞内,.,Pharmaceuticals,2010;,3:,2610-2646,24二甲双胍在体内的转运二甲双胍为一亲水性有机阳离子(p,25,二甲双胍的摄取及其作用机制,LKB, alias of serine-threonine kinase 11 (STK11);,PGC-1, peroxisome proliferator activated receptor coactivator 1 ;,TORC2, target of rapamycin complex 2.,J. Clin. Invest 2007:17:1422-1431,25二甲双胍的摄取及其作用机制LKB, alias of s,26,涉及二甲双胍的,PGx,转运体,基因多态性,OCTs,:Organic cation transporter gene,(,有机阳离子,转运体基因,),OCT 1,:,由,SLC22A1,编码,承载肝摄取,;,OCT 2,:,由,SLC22A2,编码,承载肾排泄,;,MATE,:,Multidrug and toxin extrusion gene,(,多药与毒素外排基因,),MATE1,:,由,SLC47A1,编码,承载从肝细胞转运至胆汁,;,MATE2,:,由,SLC47A2,编码,承载肾排泄,.,Acta Pharm 60;387406,26涉及二甲双胍的PGx转运体基因多态性 OCTs :,27,OCTs,的表达及其基因多态性,OCT1,主要在肝细胞和肠上皮细胞表达,介导二甲双胍在这些细胞的摄取,;,OCT2,主要在远端肾小管细胞表达,介导、促进包括二甲双胍在内的许多生物异源性物质在尿中的排泄,OCT1,的变异已知有,12,个,:,S14F, R61C,F160L,S189L, G220V,P341L, R342H,G401S, V408M,420del,G465R, R488M,其中标记为,兰色者为功能降低的转运体,。,Pharmacogenomics and Personalized Medicine 2009:2 7991,27OCTs的表达及其基因多态性 OCT1 主要在肝细胞和,28,为什么二甲双胍必需个体化给药,?,应用最广泛,;,在美国处方量排名前,15,位,!,治疗指数窄,;,为多因素病,;,疗效差异大,;,有的有效,有的无效,有的甚至发生乳酸中毒,!,(MALA range from,three to nine cases per 100,000,patient-years) once it develops, it has been associated with a 50% to 75% mortality rate.,N Engl J Med. 1998; 338:265-6. Letter;,Diabetes Care. 1999; 22:925-7.,Ellenhorns medical toxicology:,1997;728-731,.,在肝脏起效,;,转运体或肝功能影响很大,主经肾排泄,;,转运体或肾功能影响很大,28为什么二甲双胍必需个体化给药?应用最广泛;在美国处方量,29,OCT1,等位基因对二甲双胍摄取的影响,*,P ,0.01,J. Clin. Invest 2007:17:1422-1431,29OCT1等位基因对二甲双胍摄取的影响*P 180 mg/dl),高达,34%,而罗格列酮为,15%;,二甲双胍为,21% ;,UKPDS,试验表明,每年约有,1%,服用磺脲类的患者发生严重低血糖,!,.,N. Engl. J. Med. 2006;355(23):24272443,36磺脲类的疗效差异很大据报告,每年有57%服用磺脲类的患,37,磺脲类降糖机制,Schematic Representation of the Pancreatic Beta Cell, Illustrating the Role of the,ATP-Sensitive Potassium(K,ATP,) Channel,in Insulin Secretion.,N Engl J Med 2004;350:1838-49.,37磺脲类降糖机制Schematic Repres,38,影响磺脲类作用的基因多态性,Acta Pharm. 60 (2010) 387406,transcription factor 1 (TCF1,transcription factor 2 (TCF2),38 影响磺脲类作用的基因多态性Acta Pharm.,39,涉及磺脲类的基因多态性,Kir6.2,pore,:,为,K,ATP,channels,的亚单位,由,KCNJ11,gene,编码,系,SU,的靶点,;,SUR1,subunits,:,为,K,ATP,channels,的亚单位由,ABCC8,gene,编码,系,SU,的靶点,;,Inactivating mutations cause the channel to be closed and thus the,-cells to over-secrete insulin, causing hyperinsulinaemic,hypoglycaemia.Activating mutations cause the,-cell to be unresponsive to glucose and therefore are a cause of neonatal,diabetes mellitus(NDM),TCF7L2,:,直接影响,SU,的疗效,;,CYP2C9,CYP2C19,:SU,的代谢,;,HNF1,&HNF1,:,直接影响,SU,的疗效,;,IRS1:,直接影响,SU,的疗效,;,NOS1AP,:,降低,SU,的疗效,.,Acta Pharm 2010;60:387406,39涉及磺脲类的基因多态性 Kir6.2 pore : 为,40,两种最重要的,CYP2C9,基因多态性,CYP2C9*2:,是单核苷酸中的外显子,3,位由,C T),其活性仅是正常功能者的,40%,左右,;,CYP2C9*3:,是单核苷酸中的外显子,7,位由,A C),其活性仅是正常功能者的,10%,左右,;,40两种最重要的CYP2C9基因多态性CYP2C9*2:,41,CYP2C9,基因多态性显著降低磺脲类的疗效,A recent population-based study of incident sulfonylurea users found that Type 2 diabetes patients with,CYP2C9,*,2,/*,2, *,2,/*,3,or *,3,/*,3,genotypes were 3.4-times,more likely to achieve a treatment HbA1c of less than 7% compared with,CYP2C9,wild-type,homozygotes . Furthermore, patients with at least one copy of the,CYP2C9,*,2,or *,3,allele were less likely to experience sulfonylurea monotherapy,treatment failure,Clin. Pharmacol. Ther. 2009;87(1):5256,41CYP2C9基因多态性显著降低磺脲类的疗效A rec,42,CYP2C9,基因多态性显著增加磺脲类的,ADR,CYP2C9 polymorphisms may also serve as useful predictors of adverse effects. For example, a different study showed that sulfonylurea-treated patients who possessed the,CYP2C9*3/*3 or *2/*3 genotype had 5.2-times the odds,of a,severe hypoglycemic,event than the other CYP2C9 genotype groups,.,Br. J. Clin. Pharmacol. 2005;60(1):103106.,42CYP2C9基因多态性显著增加磺脲类的ADRCYP2,43,CYP2C9,基因多态性影响磺脲类的疗效,携带杂合子,CYP2C9*1/*2,的患者可轻度减少格列本脲,的肾清除,较携带纯合子,CYP2C9*2/*2,者降低,10%;,携带杂合子,CYP2C9*1/*3,和,CYP2C9*2/*3,的患者可减少甲苯磺丁脲,肾清除率,50%;,携带纯合子,CYP2C9*3/*3,的患者可显著减少格列本脲,的肾清除。,Acta Pharm 2010;60:387406,43CYP2C9基因多态性影响磺脲类的疗效携带杂合子CY,44,携带杂合子,CYP2C9*1/*2,和 纯合子,CYP2C9*3/*3,的患者,与携带野生型,CYP2C9*1/*1,的患者相比,可分别减少,甲苯磺丁脲、格列本脲以及格列吡嗪,的肾清除率,16%,、,50%,和,20%,携带纯合子,CYP2C9*2/*2,的患者,与携带野生型,CYP2C9*1/*1,的患者相比,可分别减少,甲苯磺丁脲、格列本脲,的肾清除率,75%,和,90%,。,CYP2C9,基因多态性影响磺脲类的疗效,44携带杂合子CYP2C9*1/*2和 纯合子CYP2,45,为什么有些国人应用磺脲类易发生,ADR?,Br.J. Clin. Pharmacol.,2007,64, 67-74,.,因为亚洲人的,PM,占,10-25%,而白人仅有,2-6%,。如携带,CYP2C19,PM,的中国男性患者,服用格列齐特后的,AUC,与携带野生型,CYP2C9*1/*1,的患者相比增加,3.4-fold,95% CI 2.5, 4.7;,P,0.01,;,其半衰期也从,15.1h,延长至,44.5 h,(,P,0.01);,相似的差别,在多剂量研究时也同样存在,携带,CYP2C19,PM,的患者与携带野生型,CYP2C9*1/*1,的患者相比,AUCss, AUC0 and,C,max,分别增加,3.4,倍,(95% CI 2.9, 4.0),、,4.5,倍,(95% CI 3.8, 5.4),和,2.9,倍,(95% CI 2.4, 3.4) ,(,P,0.01) ,其,半衰期也从,13.5 h,延长至,24.6h (,P,1/2,依此给患者调整剂量极为重要。,Acta Pharm. 2010; 60 : 387406,近期,Zeller,等提岀将,格列苯脲,淘汰岀局,因显著增加,AMI,死亡率。是否与患者基因变异相关,?,JCEM 2010;95;49935002,46格列苯脲与CYP2C9基因多态性(glyburide,47,CYP2C9,基因多态性,与磺脲类等的清除率,47CYP2C9基因多态性与磺脲类等的清除率,48,相关生物标记物的基因多态性对磺脲类作用的重要影响,There are several other,KCNJ11,variants (which include F333I, F35V, R201H, R201C, Q52R, I296L, L164P, G53S,G53R) and,ABCC8,variants (which include I182V, H1023Y, I1424Y, F132L),Pharmacogenomics and Personalized Medicine 2009:2 7991,48 相关生物标记物的基因多态性对磺脲类作用的,49,CYP2C19,基因多态性,对格,列齐特,PK,的影响,(,单剂量,),Br.J. Clin. Pharmacol.2007, 64, 67-74,49CYP2C19基因多态性对格列齐特PK的影响(单剂量),50,CYP2C19,基因多态性对,格列齐特,PK,的影响,(,多剂量,),Br.J. Clin. Pharmacol.2007, 64, 67-74,50CYP2C19 基因多态性对格列齐特PK的影响(多剂量,51,磺脲类与,TCF7L2,变异,GoDARTS,(Genetics of Diabetes Audit and Research Tayside),study,方法,:1997 July 2006 ,901,例口服磺脲类,945,例口服二甲双胍,研究,转录因子,7-,相似物,2,(Transcription factor 7-like 2 ;,TCF7L2,),的等位基因,rs,12255372,和,rs7903146,是否影响两类药物的作用,;,无效指标是用药,312,个月后,HbA1C 7%,。,Diabetes 56:21782182, 2007,51 磺脲类与TCF7L2变异 GoDARTS,52,磺脲类与,TCF7L2,的变异,结果,:,携带,rs12255372 T/T,等位基因的患者与携带,rs12255372 G/G,的患者相比,无效率的,Odds ratio (OR),为,1.95 (95% CI 1.233.06;,P,0.005),如以基线,HbA1C,相比,则,OR,为,2.16 95% CI 1.213.86,P =,0.009);,携带,rs,7903146,等位基因的患者其结果相似,;,在二甲双胍组未见此相关性。,Diabetes 56:21782182, 2007,52磺脲类与TCF7L2的变异结果:,53,涉及,格列奈类,/,二甲双胍,/,噻唑烷二酮,的基因多态性,Acta Pharm. 60 (2010) 387406,53涉及格列奈类/二甲双胍/ 噻唑烷二酮的基因多态性Act,54,涉及格列奈类的基因多态性,CYP2C9,其基因变异有,CYP2C9*3,CYP2C8,其基因变异有,CYP2C8*3,SLCO1B1:,solute carrier organic anion transporter family,member 1B1),其基因变异有,521TT, 521TC,521CC,OATP:,其基因变异有,OATP,1B1,IGF2BP2(,insulin-like growth factor 2 mRNA binding protein 2,),Pharmaceuticals (Basel). 2010 August 1; 3(8): 26102646,Pharmacogenomics and Personalized Medicine 2009:2 7991,54涉及格列奈类的基因多态性CYP2C9其基因变异有CYP2,55,Pharmacogenomics and Personalized Medicine 2009:2 7991,转运体,/,药酶基因多态性影响格列奈类的疗效,55 Pharmacogenomics and Per,56,2C9,基因多态性影响格列奈类的清除,研究表明,CYP2C9*3,可减少格列奈类的清除,而,CYP2C8*3,则增加格列奈类的清除。,Mol Diagn Ther. 2007;11(5):291-302,562C9基因多态性影响格列奈类的清除研究表明 CYP2,57,2C9,基因多态性影响格列奈类的疗效,携带,CYP2C9*3,的患者,可显著降低那格列奈的清除率,;,而携带,CYP2C9*2,的患者,其药动学参数与携带野生型,CYP2C9*1,的患者却相似,;,携带,CYP2C9*3 /*3,的患者与携带野生型,CYP2C9*1/*1,的患者相比,可增加低血糖的风险,特别是那格列奈剂量超过,120 mg,时,!,Mol Diagn Ther. 2007;11(5):291-302,572C9基因多态性影响格列奈类的疗效携带CYP2C9,58,SLCO1B1,基因多态性对格列奈类的影响,SLCO1B1,有三个等位基因,:,521TT,521TC,521CC,;,携带杂合子,521TC,和纯合子,521CC,的患者与携带纯合子,521,TT,相比,可分别显著增加那格列奈的血浓度,83%,和,76%,;,半衰期延长,78%,(p = 0.036),;,提示,SLCO1B1,基因多态性可显著增加那格列奈血浓度,可能是减少了肝细胞的摄取所致。,58 SLCO1B1基因多态性对格列奈类的影响SLCO1B,59,涉及噻唑烷二酮类的基因多态性,PPAR- gene:,过氧化物体增殖激活受体,-,基因变异有,PPAR-,heterozygous,genotype (rs1801282; Pro12Ala),和,homozygous,genotype (Pro12Pro).,lipoprotein lipase gene:,其基因变异有,S447S,和,S447X,CYP2C8 gene:,其基因变异有,CYP2C8*1/*3,CYP2C8*3/*3,ACDC gene:,adipocyte C1q and collagen domain-containing (ACDC) gene,编码,adiponectin,其基因变异有,SNP45, SNP276,SNP11377,SLCO1B1 :,solute carrier organic anion transporter family,member 1B1),其基因变异有,521TT, 521TC,521CC,ADIPOQ,:,其基因变异有,rs1501288,和,rs2241766,PGC-1,(,PPAR-coactivator):,其基因变异有,Thr394,和,Gly482,Pharmaceuticals (Basel). 2010 August 1; 3(8): 26102646,Pharmacogenomics and Personalized Medicine 2009:2 7991,59涉及噻唑烷二酮类的基因多态性PPAR- gene:过氧,60,为什么有些患者,TZDs,无效,?,TZDs,未达标率,:,罗格列酮,(2mg/bid ;26week) 45.8%,罗格列酮,(4mg/bid ;26week) 36.1%,吡格列酮,(45 mg/d,;,26 weeks),25.0%,(,空腹血糖降低不超过,10%; 12%,患者,HbA1c,仅降低,0.5%1.0%),The Journal of Clinical Endocrinology & Metabolism 2001 86: 280-288,Diabetes Care 2003;26:825831,60为什么有些患者TZDs无效?TZDs未达标率:,61,ACDC/S447S,基因多态性对,TZDs,的影响,Pharmacogenomics and Personalized Medicine 2009:2 7991,61ACDC/S447S基因多态性对TZDs的影响Pharm,62,脂蛋白酯酶,(LDL),基因多态性对,TZDs,的影响,研究发现,中国,T2D,患者服用吡格列酮,如携带纯合子,S447S,其达标率较携带其他基因多态性者更高,反之如携带,S447X,则达标率较携带,S447S,患者降低,1/2,提示检测,LPL,基因多态性可预测吡格列酮的疗效。,62脂蛋白酯酶(LDL)基因多态性对TZDs的影响,63,脂联素,ADIPOQ,等位基因 对罗格列酮疗效的影响,Pharmaceuticals (Basel). 2010 Aug 1;3(8):2610-2646.,63 脂联素ADIPOQ等位基因,64,PGx,与噻唑烷二酮类的疗效,首先,过氧化物体增殖激活受体,-,(,PPAR-,),基因变异有,heterozygous,genotype (rs1801282; Pro12Ala),和,homozygous,genotype (Pro12Pro).,如携带,Pro/Ala,者,较携带,Pro/Pro,者显著降低罗格列酮的禁食血糖水平和,HbA1c,水平,;,如携带,Pro12Ala,则,PPAR-,增加,7.2,倍,Mol Diagn Ther. 2007;11(5):291-302,Pharmacogenomics 2007;8:917931,64PGx与噻唑烷二酮类的疗效首先,过氧化物体增殖激活受,65,CYP2C8/SLCO1B1,基因多态性 对罗格列酮疗效的影响,研究表明携带,CYP2C8,基因多态性者,可显著改变罗格列酮的,PK,并提高疗效,而,SLCO1B1,则否,;,Human,Genomics 2008;3:716,65 CYP2C8/SLCO1B1基因多态性,66,小结,:PGx,与口服抗高血糖药,British Journal of Diabetes & Vascular Disease 2011 11: 10,66小结:PGx与口服抗高血糖药British Journa,67,美国糖尿病协会,2010,年会重点研讨,PGx,与,T2D,的相关性,70th:PGx Abstracts from the American Diabetes Associations Annual Scientific Sessions,July 07, 2010,investigating SNPs showing variable patient responses to commonly prescribed medications; and analyzing genetic risk for conditions that can heighten peoples chances of developing diabetes.,67美国糖尿病协会2010年会重点研讨PGx与T2D的相关,68,PGx&,抗高血糖药,主要,关注三个基因多态性,1,针对药物,ADME,的,OCT1,和,2C9/8/19 3A4,;,2,针对药物受体的,KCNJ11;,3,针对疾病发展的,TCF7L2,68PGx&抗高血糖药主要关注三个基因多态性1,针对药物,经常,不断地学习,你就什么都知道。你知道得越多,你就越有,力量,Study Constantly, And You Will Know Everything. The More You Know, The More Powerful You Will,Be,写,在最后,经常不断地学习,你就什么都知道。你知道得越多,你就越有力量写,69,感谢聆听,不足之处请大家批评指导,Please Criticize And Guide The,Shortcomings,结束语,讲师,：,XXXXXX,XX,年,XX,月,XX,日,感谢聆听结束语讲师：XXXXXX,70,