糖尿病治疗三重奏到八重奏ppt课件

从三重奏到恶兆八重奏:新的2型糖尿病治疗模式*三重奏胰岛素分泌受损高血糖葡萄糖摄取减少肝糖生成增加*2型糖尿病自然病程肥胖-糖尿病低INSDeFronzo&FelberDiabetes37:667-687,1988Metabolism39:1068-75,1990NGT:正常糖耐量IGT:糖耐量异常INS：胰岛素**2型糖尿病β细胞功能衰竭的自然病程β-细胞衰竭在2型糖尿病自然病程中发生得更早，且比以前所意识到的更严重*圣安东尼奥代谢研究和退伍军人遗传流行病学研究受试者 例数 NGT 318 IGT 259 T2DM201 受试者分为:非肥胖 ifBMI<30kg/m2肥胖 ifBMI>30kg/m2Gastaldelli,Ferrannini,Abdul-Ghani,DeFronzo,Diabetologia47:31-39,2004;JCEM90:493-500,2005,Diabetes55:1430-35,2006研究方法:OGTT和胰岛素钳夹VAGESstudy:VeteransAdministrationGeneticEpidemiologyStudy**血浆葡萄糖和胰岛素曲线下面积（AUC）葡萄糖AUC(mmol/L120min)胰岛素AUC(pmol/L120min)**OGTT期间胰岛素分泌/胰岛素抵抗指数(DISPOSITIONIndex处置指数)∆INS/∆GLU÷IR非肥胖2-小时血糖(mg/dl)**2-小时血浆葡萄糖和胰岛素分泌/胰岛素抵抗指数之间对数正态的相关性Ln∆I/∆G÷IR(ml/min•kgFFM)Ln2h-血浆葡萄糖(mg/dl)r=0.91p<0.00001T2DMIGTNGT**IGT(HBA1c=5.9%)IGT…………7.9%糖尿病周围神经病变(%):在IGT人群发病率…………5-10%DPPGroup,DiabMed24:137-144,2007DiabetesCare24:1148-53,2001;31:464-469,2008IGT人群微血管并发症发病率糖尿病视网膜病变(%):**小结 具有最大/几乎最大程度的胰岛素抵抗 β细胞功能丢失~80% 糖尿病视网膜病变发病率~10%IGT个体:**2型糖尿病β细胞衰竭的预防 必须早期干预(IGT/IFG) 应该针对已知的促进β细胞衰竭的病理机制进行干预**2型糖尿病的发病机制高血糖葡萄糖摄取减少肝糖生成增加*胰岛素抵抗空腹状态胰岛素刺激状态*2型糖尿病基础肝糖生成(HGP):与空腹血浆葡萄糖(FPG)的关系DeFronzoetal,Metabolism38:387-395,1989对照*胰岛素抵抗空腹状态胰岛素刺激状态*2型糖尿病胰岛素介导的葡萄糖摄取减少DeFronzoetal,JCI63:939-46,1979;JCI76:149-55,1985*Movetheptomiddle?高血糖协调的四重奏葡萄糖摄取减少胰岛素分泌减少肝糖生成增加*不协调的四重奏胰岛素分泌减少脂解作用增强肝糖生成增加葡萄糖摄取减少高血糖*Hyperglycemia2型糖尿病的治疗:基于病理生理机制的有效治疗 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 胰岛素分泌受损高血糖噻唑酮类GLP-1类似物脂解作用增强肝糖生成增加葡萄糖摄取减少*平均HBA1c(%)时间(年数)格列苯脲9876003691215UKPDS352:837-853and853-865,1998UKPDS:磺脲类&二甲双胍治疗对HBA1c的影响*MedianHBA1c(%)Time(years)格列苯脲9876003691215UKPDS:磺脲类&二甲双胍治疗对HBA1c的影响UKPDS352:837-853and853-865,1998*UKPDS:HbA1C降低1%时糖尿病相关并发症危险的降低情况Stratten,BMJ321:405,2000微血管并发症心梗中风-37%**-14%*-12%*-40-30-20-100危险降低(%)**UKPDS:二甲双胍对糖尿病并发症的影响危险降低(%)微血管并发症心梗中风死亡29%39%41%42%**心血管危险因素心血管危险因素 二甲双胍 高血糖 高甘油三酯血症 高胆固醇血症 肥胖 高胰岛素血症 胰岛素抵抗 1型纤溶酶原激活物抑制物（PAI-1） 内皮功能异常 **二甲双胍的作用机制:临床观察15010050040200*p<0.01*p<0.01二甲双胍对葡萄糖代谢和胰岛素分泌的影响葡萄糖代谢(mg/m2permin)血浆胰岛素(I)浓度(mU/ml)M/I比率之前之后之前之后之前之后7.55.02.50*肝脏葡萄糖输出(HGP)二甲双胍治疗前二甲双胍治疗后2型糖尿病正常对照HGP(mmol/kgmin)糖原分解糖原合成151050P<0.01*二甲双胍腺苷酸活化蛋白激酶(AMPK)磷酸化&激活血浆葡萄糖&甘油三脂乙酰辅酶A羧化酶(ACC)活性类固醇调控单元结合蛋白-1(SREBP-1)表达肝脏基因表达葡萄糖转运*Kahnetal,NEJM355:2427-43,2006ADOPT:HBA1c随治疗时间的变化HBA1c(%)年数6.46.87.27.68.0p<0.001*-2-101HbA1c的改变(%)时间(年数)012345610Hanefeld(n=250)Charbonnel(n=313)Chicago(n=230)ADOPT(n=1,441)UKPDS(n=1,573)格列齐特PERISCOPE(n=181)磺脲类格列美脲格列苯脲格列苯脲格列苯脲格列苯脲磺脲类磺脲类Alvarsson(n=39)Alvarsson(n=48)RECORD(n=272)Tan(n=297)格列齐特磺脲类控制血糖的持续性**-2-101HbA1c的改变(%)时间(年数)0123456PIOPIO吡格列酮Rosiglitazone罗格列酮噻唑酮类控制血糖的持续性Hanefeld(n=250)Charbonnel(n=317)Chicago(n=232)ADOPT(n=1,456)PIOPERISCOPE(n=178)PIORECORD(n=301)ROSENSTOCK(n=115)ROSITan(n=249)PIO**PROACTIVE研究在高危的2型糖尿病人群: 观察吡格列酮治疗是否减少总体死亡率和大血管事件发生率19欧洲国家5238例2型糖尿病**PROACTIVE:构成主要复合终点的主要事件发生次数任何终点 514 572死亡 110 122非致死性心梗(除外无症状性) 85 95无症状性心梗 20 23中风 76 96截肢 9 15急性冠脉综合征 42 63冠脉旁路移植/经皮冠脉介入治疗 101 101下肢血运重建 71 57吡格列酮n=2605安慰剂n=2633**PlcPIO35830114.4%12.3%危险比P值安慰剂vs比格列酮0.840.027安慰剂吡格列酮PROACTIVE(n=5238)死亡,心梗,或中风的时间变化LANCET366:1279-89,2005Kaplan-Meier事件率0.150.100.0500122436时间(月)#事件数3年估计值*吡格列酮临床试验荟萃分析的心血管结局(除外PROactive研究)Kaplan-Meier死亡,心梗,中风事件估计率00.020.040.064080120160Comp 5203 2978 1297 488 34 Pio 5949 2859 1247 459 40 对照药物吡格列酮0事件概率时间(周)FDA和药物评价和与研究中心;July30,2007CI=0.55-1.02危险比=0.75吡格列酮(治疗1.5年)抑制2型糖尿病颈动脉内膜中层厚度(IMT)和冠状动脉粥样硬化进展Nissenetal,JAMA299:1567-73,2008Mazzoneetal,JAMA,296:2572-81,2006*TRIPOD(52%)ACTNOW(81%)DREAM(62%)TZDs预防IGT进展为2型糖尿病PIPOD(62%)*筛查人群总数(n=1850)安慰剂(n=299)IGT*(n=602)吡格列酮(n=302)*采用单次OGTT(2-小时血糖=140-199mg/dl)进行诊断*累积危险比#atrisk安慰剂 299 吡格列酮 303时间:月HR=0.19(95%,CI)=0.09,0.39p<0.00001进展为糖尿病的时间10204050安慰剂吡格列酮0.50.40.30.20.10215220306.8%每年1.5%每年0**需要治疗的例数预防1例IGT个体进展为2型糖尿病,需要治疗23例IGT个体1年*艾塞那肽(BYETTA)*艾塞那肽对HbA1c的疗效时程时间按(周数)DHbA1c(%)020406080156-2.0-1.000.5安慰剂-对照试验Dataonfile,AmylinPharmDeFronzoetal,DiabetesCare28:1092-1100,2005*RequiredDISCUSSIONPOINTS:--87%ofthesubjectswhocompletedthe30-weekplacebo-controlled,double-blind,Phase3studieschosetocontinueinopen-labelextension(OLE)studies.--Allsubjectsweregiven5mcgBYETTAforthefirst4weeksoftheOLE(overall,Weeks30to34),afterwhichtheyreceived10mcgBYETTAfortheremainderoftheirparticipationintheOLE.--Shownis82-weekdata(30weeksfromplacebo-controlled,double-blindstudyand52weeksfromOLE)for393patients.--Ofthe1446subjectsrandomizedtothethree30week,blinded,placebo-controlledtrials,1125completedandwereeligibleforenrollmentintotheopenlabelextensionstudies(OLE).--Ofthe1125subjects,977(87%)enrolledintotheOLEs.Atthetimeofthisdataanalysis,795hadcompletedtreatmentthrough52weeksand393hadcompletedtreatmentthrough82weeks.--Usingtheintent-to-treat(ITT)andLastObservationCarriedForward(LOCF)analysismethod,the977ITTpopulationhadA1Candweightreductionsat82weeksconsistentwiththe82-weekcompleterpopulationshownhere.--PlacebocohortuponreceivingBYETTAshowedanimmediatedecreaseofA1CsimilartothatobservedwithBYETTAtreatmentinthefirst30weeks.--MeanA1Creductionsfrombaselinewereverysimilarat82weeks(atleast-1.1%)forallthreeoriginalstudytreatmentgroups.--Forpatientsreceiving10mcgBYETTAfor82weeks,51%achievedanA1Cof7%at82weeks.SLIDEBACKGROUND:--TheslightupwardtrendseenforboththeplaceboandBYETTAtreatmentgroupsfromWeeks18to30likelyrepresentsaninitialstudyeffectthatdisappearsovertime,andissimilarinmagnitudetothedecreaseinA1Cduringthe4-weekplacebolead-inperiod.艾塞那肽治疗对餐后血糖和胰岛素水平的影响可评价的餐耐量队列*基线体重220lbs215lbs220lbs0102030405060708090-12-10-8-6-4-202安慰剂BID(N=128)艾塞那肽5mcgBID(N=128)艾塞那肽10mcgBID(N=137)开放标签延长期安慰剂-对照试验时间(周)D体重(lbs)艾塞那肽对体重的影响**RequiredDISCUSSIONPOINTS:--87%ofthesubjectswhocompletedthe30-weekplacebo-controlled,double-blind,Phase3studieschosetocontinueinopen-labelextension(OLE)studies.--Allsubjectsweregiven5mcgBYETTAforthefirst4weeksoftheOLE(overall,Weeks30to34),afterwhichtheyreceived10mcgBYETTAfortheremainderoftheirparticipationintheOLE.--Shownis82-weekdata(30weeksfromplacebo-controlled,double-blindstudyand52weeksfromOLE)for393patients.--Ofthe1446subjectsrandomizedtothethree30-week,blinded,placebo-controlledtrials,1125completedandwereeligibleforenrollmentintotheOLE.--Ofthe1125subjects,977(87%)enrolledintotheOLEs.Atthetimeofthisdataanalysis,795hadcompletedtreatmentthrough52weeksand393hadcompletedtreatmentthrough82weeks.--Usingtheintent-to-treat(ITT)andLastObservationCarriedForward(LOCF)analysismethod,the977ITTpopulationhadA1Candweightreductionsat82weeksconsistentwiththe82-weekcompleterpopulationshownhere.--PlacebocohortuponreceivingBYETTAshowedanimmediatedecreaseofweightsimilartothatobservedwithBYETTAtreatmentinthefirst30weeks.--MeanbodyweightreductionsmediatedbyBYETTAduringthefirst30weeksweresustainedandappearedtobeprogressivethrough82weeks.SLIDEBACKGROUND:--Dietandexercisecounselingwerenotprovidedduringthestudy.D甘油三酯(mg/dL)DHDL-C(mg/dL)治疗82周后四等分下降体重对应的甘油三酯和HDL-C的变化下降体重四等分级IIIIIIIV-120-80-400-92-58-5-3048+7.4+4.1+3.5+3.0下降体重四等分级IIIIIIIV**加用西他列汀西他列汀对HbA1c的影响：与基线相比的变化(HbA1c~8.0%)DiabetesCare29:2638,2006;ClinTher28:1556,2006;Diabetolgia49:2564,2006-1.0-0.50无药物治疗二甲双胍吡格列酮DHbA1c(%)-0.60-0.67-0.85**高血糖精萃的五重奏肠促胰岛素作用减弱胰岛素分泌减少肝糖生成增加脂解作用增强葡萄糖摄取减少*IGT和T2DM患者餐后GLP-1水平降低Toft-NielsenMetal,JCEM86:3717-23,200120151050时间(分钟)GLP-1(pmol/l)********正常糖耐量T2DMIGT进餐P<0.012型糖尿病的GLP-1和GIP反应*高血糖尖锐参差的六重奏葡萄糖摄取减少脂解作用增强肠促胰岛素作用减弱胰岛素分泌减少胰岛–a细胞胰高血糖素分泌增加肝糖生成增加*2型糖尿病基础胰高血糖素水平对维持基础肝糖生成的作用Baronetal,Diabetes36:274-283,1987血浆胰高血糖素(pg/ml)基础HGP(mg/m2•min)04080120160基础基础*Elevatedratesofbasalhepaticglucoseoutput(bHGO)aresignificantlycorrelatedwiththefastingserumglucose(FSG)levelinsubjectswithnon-insulin-dependentdiabetesmellitus(NIDDM).ThisobservationsuggeststhatbHGOisamajordeterminantoftheseverityofthediabeticstateinthesesubjects.Inaddition,basalglucagonlevels(bGL)arehigherinthesediabeticsthanincontrolsubjects,despitetheconcurrentbasalhyperglycemiaandhyperinsulinemia,twofactorsknowntosuppressglucagonsecretion.AlthoughbGLisresponsibleforsustainingtwo-thirdsofbHGOinnormalhumans,itsroleinsustainingelevatedratesofbHGOinNIDDMhasnotbeenpreviouslydefined.Tothisend,wehavestudied13normaland10NIDDMsubjects;meanFSGlevelswere90+/-2and262+/-21mg/dl,respectively(Plessthan.001).Themeanfastingseruminsulinandglucagonlevelswerehigherinthediabeticsthaninthecontrols:17+/-2vs.9+/-1microU/ml(Plessthan.01)and208+/-37vs.104+/-15pg/ml(Plessthan.01),respectively.Onseparatedays,HGOwasassessedisotopically(with3-[3H]glucose)inthebasalstateandduringinfusionofsomatostatin(SRIF)(600micrograms/h)aloneandinconjunctionwithreplacementinfusionsofglucoseandinsulin.TheresultsdemonstratethatbHGOishigherindiabeticsthanincontrols(145+/-12vs.89+/-3mgXm-2Xmin-1,Plessthan.01);duringinfusionofSRIFalone,HGOwassuppressedby25%(Plessthan.05)and34%(Plessthan.05)ofthebasalvalueincontrolsanddiabetics,respectively;whenthestudieswererepeatedwithglucoselevelsheldconstantatorneartheFSGlevelbytheglucose-clamptechnique,thepatternanddegreeofHGOsuppressionwassimilartothatobtainedbyinfusionofSRIFalone;duringisolatedglucagondeficiency(SRIF+insulin,5mUXm-2min-1,withserumglucosemaintainedatbasallevel),HGOwassuppressedby71+/-8%ofthebasalvalueincontrols(Plessthan.001)andby58+/-7%indiabetics(Plessthan.001);andwhenisolatedglucagondeficiencywithsimilarhyperglycemiawascreatedincontrolsubjects,HGOwassuppressedby87%ofthebasalvalue.(ABSTRACTTRUNCATEDAT250WORDS)肝糖生成增加葡萄糖摄取减少脂解作用增强肠促胰岛素作用减弱胰岛素分泌减少胰岛–a细胞胰高血糖素分泌增加隔裂的七重奏葡萄糖重吸收增加*SGLT1SGLT2(钠葡萄糖共转运蛋白-2)肾脏对葡萄糖的处理(180L/天)(900mg/L)=162g/天10%90%葡萄糖无葡萄糖S1S3**人体肾脏近端肾小管细胞的钠葡萄糖共转运蛋白-(2SGLT2)mRNA和蛋白水平增加Rahmouneetal,Diabetes54:3427-34,2005AMG=甲基--D-[U14C]-吡喃葡萄糖苷；CPM=countsperminute(每分钟計數)*129957-12/04根皮苷对空腹和进食后血浆葡萄糖的影响空腹葡萄糖(mg/dl)进食后葡萄糖(mg/dl)******129957-12/04糖尿病大鼠根皮苷治疗后胰岛素介导的葡萄糖摄取Rd(mg/kg•min)Rd(mg/kg•min)第1阶段第2阶段******达格列净(DAPAGLIFLOZIN)增加尿糖排泄降低HbA1c:一项剂量范围试验受试者 389例未接受过药物治疗的2型糖尿病患者 HbA1c>7.0%研究设计12周双盲安慰剂对照观察指标 (i) 达格列净:2.5,5,10,and50mg/day(ii) 二甲双胍XR:1500mg/day(iii) 安慰剂空腹血糖FPG,餐后血糖PPG,HbA1cListJetal,ADA,SanFranciscoJune2008*达格列净对HbA1c的影响HbA1c的下降幅度(%)*达格列净:尿糖和代谢影响尿糖=52-85g/天降低空腹血糖=16-30mg/dl降低餐后血糖=23-29mg/dl降低体重=2.2-3.2kg(2.5%-3.4%)增加尿量=107-470ml/天**恶兆的八重奏*2型糖尿病的治疗(1) 将需要联合使用多种药物，以纠正多重病理生理缺陷(2) 应该基于已知的病因性异常，而不是简单的基于降低HBA1c(3) 如果要预防进展性的β细胞衰竭，必须在2型糖尿病自然病程的早期开始治疗*ADA治疗模式生活方式干预+二甲双胍*ADA治疗模式生活方式干预+二甲双胍等级1等级2*基于病理生理机制的(DEFRONZO)治疗模式生活方式干预+三联药物治疗:二甲双胍+噻唑酮+艾塞那肽*两种治疗模式的比较 ADA基于病理生理机制疗效持续性 No Yesβ细胞保护 No Yes低血糖 Yes No体重增加 Yes No**起始治疗方案应该有使HbA1c到6.0%目标的可能起始HbA1c6.0%(IGT)7.0%(T2DM)≥7.5%治疗方案吡格列酮二甲双胍+吡格列酮二甲双胍+吡格列酮+艾塞那肽*********Movetheptomiddle?*********RequiredDISCUSSIONPOINTS:--87%ofthesubjectswhocompletedthe30-weekplacebo-controlled,double-blind,Phase3studieschosetocontinueinopen-labelextension(OLE)studies.--Allsubjectsweregiven5mcgBYETTAforthefirst4weeksoftheOLE(overall,Weeks30to34),afterwhichtheyreceived10mcgBYETTAfortheremainderoftheirparticipationintheOLE.--Shownis82-weekdata(30weeksfromplacebo-controlled,double-blindstudyand52weeksfromOLE)for393patients.--Ofthe1446subjectsrandomizedtothethree30week,blinded,placebo-controlledtrials,1125completedandwereeligibleforenrollmentintotheopenlabelextensionstudies(OLE).--Ofthe1125subjects,977(87%)enrolledintotheOLEs.Atthetimeofthisdataanalysis,795hadcompletedtreatmentthrough52weeksand393hadcompletedtreatmentthrough82weeks.--Usingtheintent-to-treat(ITT)andLastObservationCarriedForward(LOCF)analysismethod,the977ITTpopulationhadA1Candweightreductionsat82weeksconsistentwiththe82-weekcompleterpopulationshownhere.--PlacebocohortuponreceivingBYETTAshowedanimmediatedecreaseofA1CsimilartothatobservedwithBYETTAtreatmentinthefirst30weeks.--MeanA1Creductionsfrombaselinewereverysimilarat82weeks(atleast-1.1%)forallthreeoriginalstudytreatmentgroups.--Forpatientsreceiving10mcgBYETTAfor82weeks,51%achievedanA1Cof7%at82weeks.SLIDEBACKGROUND:--TheslightupwardtrendseenforboththeplaceboandBYETTAtreatmentgroupsfromWeeks18to30likelyrepresentsaninitialstudyeffectthatdisappearsovertime,andissimilarinmagnitudetothedecreaseinA1Cduringthe4-weekplacebolead-inperiod.*RequiredDISCUSSIONPOINTS:--87%ofthesubjectswhocompletedthe30-weekplacebo-controlled,double-blind,Phase3studieschosetocontinueinopen-labelextension(OLE)studies.--Allsubjectsweregiven5mcgBYETTAforthefirst4weeksoftheOLE(overall,Weeks30to34),afterwhichtheyreceived10mcgBYETTAfortheremainderoftheirparticipationintheOLE.--Shownis82-weekdata(30weeksfromplacebo-controlled,double-blindstudyand52weeksfromOLE)for393patients.--Ofthe1446subjectsrandomizedtothethree30-week,blinded,placebo-controlledtrials,1125completedandwereeligibleforenrollmentintotheOLE.--Ofthe1125subjects,977(87%)enrolledintotheOLEs.Atthetimeofthisdataanalysis,795hadcompletedtreatmentthrough52weeksand393hadcompletedtreatmentthrough82weeks.--Usingtheintent-to-treat(ITT)andLastObservationCarriedForward(LOCF)analysismethod,the977ITTpopulationhadA1Candweightreductionsat82weeksconsistentwiththe82-weekcompleterpopulationshownhere.--PlacebocohortuponreceivingBYETTAshowedanimmediatedecreaseofweightsimilartothatobservedwithBYETTAtreatmentinthefirst30weeks.--MeanbodyweightreductionsmediatedbyBYETTAduringthefirst30weeksweresustainedandappearedtobeprogressivethrough82weeks.SLIDEBACKGROUND:--Dietandexercisecounselingwerenotprovidedduringthestudy.**Elevatedratesofbasalhepaticglucoseoutput(bHGO)aresignificantlycorrelatedwiththefastingserumglucose(FSG)levelinsubjectswithnon-insulin-dependentdiabetesmellitus(NIDDM).ThisobservationsuggeststhatbHGOisamajordeterminantoftheseverityofthediabeticstateinthesesubjects.Inaddition,basalglucagonlevels(bGL)arehigherinthesediabeticsthanincontrolsubjects,despitetheconcurrentbasalhyperglycemiaandhyperinsulinemia,twofactorsknowntosuppressglucagonsecretion.AlthoughbGLisresponsibleforsustainingtwo-thirdsofbHGOinnormalhumans,itsroleinsustainingelevatedratesofbHGOinNIDDMhasnotbeenpreviouslydefined.Tothisend,wehavestudied13normaland10NIDDMsubjects;meanFSGlevelswere90+/-2and262+/-21mg/dl,respectively(Plessthan.001).Themeanfastingseruminsulinandglucagonlevelswerehigherinthediabeticsthaninthecontrols:17+/-2vs.9+/-1microU/ml(Plessthan.01)and208+/-37vs.104+/-15pg/ml(Plessthan.01),respectively.Onseparatedays,HGOwasassessedisotopically(with3-[3H]glucose)inthebasalstateandduringinfusionofsomatostatin(SRIF)(600micrograms/h)aloneandinconjunctionwithreplacementinfusionsofglucoseandinsulin.TheresultsdemonstratethatbHGOishigherindiabeticsthanincontrols(145+/-12vs.89+/-3mgXm-2Xmin-1,Plessthan.01);duringinfusionofSRIFalone,HGOwassuppressedby25%(Plessthan.05)and34%(Plessthan.05)ofthebasalvalueincontrolsanddiabetics,respectively;whenthestudieswererepeatedwithglucoselevelsheldconstantatorneartheFSGlevelbytheglucose-clamptechnique,thepatternanddegreeofHGOsuppressionwassimilartothatobtainedbyinfusionofSRIFalone;duringisolatedglucagondeficiency(SRIF+insulin,5mUXm-2min-1,withserumglucosemaintainedatbasallevel),HGOwassuppressedby71+/-8%ofthebasalvalueincontrols(Plessthan.001)andby58+/-7%indiabetics(Plessthan.001);andwhenisolatedglucagondeficiencywithsimilarhyperglycemiawascreatedincontrolsubjects,HGOwassuppressedby87%ofthebasalvalue.(ABSTRACTTRUNCATEDAT250WORDS)*****