罕见病例在认识糖尿病中的重要作用-英文版课件.pptx

1、Monogenic diabetes and polygenic diabetesClassification of diabetes mellitusType 2 diabetes(8590%)Type 1 diabetesSpecial types of diabetes(3%)Gestational diabetes mellitus(GDM)Hereditary syndrome with diabetes Genetic defects in beta cells Genetic defects in insulin action T2DM T1DM GDM Endocrine di

2、sease Exocrine pancreas disease Drugs InfectionClassification and pathogenesis of diabetes mellitusGenetic factorsEnvironmental factorsIII-8III-1III-2IIIIII-7IVIII-4III-3III-5III-6Insulin secretion and/or action defectsMODYMaturity-Onset Diabetes of the YoungClinical characteristics of MODY Onset ag

3、e less than 25 years BMI 24kg/m2 No insulin was required for at least 2 years after diagnosis Three or more than three generations of family history of diabetes Autosomal dominant inheritanceComparison of clinical characteristics between MODY and T2DMClinical CharacteristicsMODYT2DMAge of onsetChild

4、ren,adolescenceor young people(usually 25 y）Adult(usually 40-60 y)ObesityWithout obesityUsually with obesityMetabolic SyndromeWithout MSUsually with MSPathophysiological characteristicsInsulin secretion defectsInsulin secretion/action defectsN Engl J Med 2001,345:971-980Molecular subtyping of MODY M

5、ODY1：HNF4 MODY2：Glucokinase（GCK）MODY3：HNF1 MODY4：IPF1 MODY5：HNF1 MODY6：NeuroD/Beta 2 MODY7：KLF11 MODY8：CEL MODY9：PAX4 MODY10：INS MODY11：BLK MODY12：ABCC8 MODY13：KCNJ11The action mode of MODY proteins in the beta cellPAX4KLF11KCNJ11ABCC8CELBLK T1D was diagnosed 1 month after birth,without ketosis Insu

6、lin therapy(CSII)Hypoglycemic coma twice Genetic testing at 6.5 years old De novo mutation-KCNJ11 R201CThe Lilly Jaffe StoryMechanisms of KCNJ11 mutations lead to diabetesPearson ER et al.N Engl J Med 2006Pearson ER et al.N Engl J Med 2006 Whether sulfonylurea drugs can be used to treat KCNJ11 mutat

7、ion?Mechanisms of KCNJ11 mutations lead to diabetes Sulfonylurea therapy instead of insulin Well-controlled blood glucose,without hypoglycemic comaThe Lilly Jaffe StorySulfonylureas are targeted drugs for KCNJ11SulfonylureasClose KATP channelMembrane DepolarizatioCa2+influxInsulin secretion For KCNJ

8、11 mutation carriers,sulfonylureas are superior to insulin in blood glucose controlPearson et al NEJM,2006InsulinSulfonylureasN=38KCNJ11 and early-onset“T2DM”in Chinese pedigrees 96 early-onset T2D probands and their family members1)Autosomal dominant inheritance(At least 3 generations of family his

9、tory of diabetes)2)At least one member of onset before the age of 403)Exclusion of mitochondrial mutations diabetes Sequencing of KCNJ11 coding and flanking regionLiu L et al.Diabetologia,2013,56:26093 novel mutations in KCNJ11 3 novel mutations in KCNJ11：R27H,R192H,S116F117del Mutations may affect

10、potassium channels function and result in insulin secretion defectsLiu L et al.Diabetologia,2013,56:2609Functional studies of KCNJ11 mutationR192HR27HWT R192H and R27H mutation decrease KATP channel activity significantly After sulfonylurea treatment,no significant differences in KATP channel activi

11、ty between WT and Mut Sulfonylurea can close KATP channel effectively and stimulate insulin secretionsulfonylurea treatmentLiu L et al.Diabetologia,2013,56:2609KCNJ11KATP channelRare mutationsMODY13Common variantsT2D in ChineseSulfonylureasNeonatal Diabetes Mellitus(NDM)Association of KCNJ11 E23K an

12、d T2D in ChineseMajor/Minor alleleRisk alleleRisk allele frequencyOR(95%CI)PallelePgenotypeCases:T2D(n=1849)Controls:NGT(n=1785)C:TT0.4250.3941.138(1.034-1.251)0.00790.0031KCNJ11 E23K(rs5219)Hu C et al.PLoS ONE,2009,4(10):e7643.Residents in Shanghai T2D(case=1,849)vs.NGT(control=1,785）KCNJ11 rs5219

13、variant is the susceptible gene in Chinese,which can increase the T2D risk of 13.8%Pharmacogenomic research of KCNJ11 E23K in Chinese Newly diagnosed T2D patients,Gliclazide monotherapy and follow-up 16w(N=108)The cumulative rate of fasting blood glucose in KK carriers was significantly better than

14、that of other genotypes KCNJ11 E23K can affect gliclazide efficacyPlog-rank=0.028Li Q et al.CEPP,2014,41:748754EEEKKKweekPAR164W Thai MODY pedigree Known MODY gene mutations were not found PAX4 gene screening Two novel mutations missense mutation:R164W Splice mutation:IVS71GA The mutations were not

15、found in normal controlsJ Clin Endocrinol Metab,2007,92(7):2821-6.Stage 1 Meta-analysis of GWAS in Chinese populationHong Kong GWAS199 cases vs.99 ctrsHong Kong GWAS2388 cases vs.659 ctrsShanghai GWAS197 cases vs.197 ctrsStage 2 de novo replication in Chinese populationStage 3 in silico replication

16、in EA populations Stage 4 in silico replication in non-EA populations Replicate in case-ctr Hong Kong 1 5366 cases vs.2474 ctrsShanghai 1 4035 cases vs.3964 ctrsReplicate in families Hong Kong 2(178 families)325 cases vs.368 ctrsShanghai 2(248 families)657 cases vs.168 ctrsJapanese4465 cases vs.3023

17、 ctrsSingapore Chinese2010 cases vs.1945 ctrsKorean 11042 cases vs.2943 ctrsKorean 21183 cases vs.1305 ctrsSingapore Malaysian794 cases vs.1204 ctrsSingapore Indian977 cases vs.1169 ctrsCaucasians(DIAGRAM+)8130 cases vs.38987 ctrsShanghai1873 cases vs.1839 ctrsGWAS of T2DM in ChineseMa R Jia W.Diabe

18、tologia,2013,56(6):1291-305.Global meta-analysis in stage 1+2+3+4CohortNOR(95%CI)P valueT2DControlAll discovery GWAS6849551.66(1.33-2.07)7.710-6All discovery GWAS+all Chinese replications1106779291.18(1.11-1.25)2.610-8All discovery GWAS+all EA replications19767171451.14(1.09-1.19)5.810-9Replication

19、in non-East Asian9901413601.03(0.99-1.08)0.1156All discovery GWAS+all global replications29668585051.08(1.05-1.12)1.810-7PAX4 and T2DMMa R Jia W.Diabetologia,2013,56(6):1291-305.PAX4 is a novel susceptible gene for T2DM in Chinese population Large-scale GWAS for T2D(90,000 samples)Chinese East Asian

20、s South Asians and Europeans PAX4 rs10229583 is a novel susceptible variant of T2DM in Chinese The effect of PAX4 on T2DM has significant ethnic heterogeneitySingapore replication0.01.02.03.04.0OR(95%CI)Hong Kong GWAS 1Hong Kong replication 1Shanghai replication 1Hong Kong replication 2Shanghai repl

21、ication 2Meta-of ChineseJapanese replicationKorean replication 1Korean replication 2Meta-of East Asian Malay replicationIndian replicationDIAGRAM+Hong Kong GWAS 2Shanghai GWASMeta-of GWASSIN replicationSimilar effects in East AsiansNo effects in South AsiansWeak effects in EuropeansOR =1.14(1.09,1.1

22、9),p=2.3 10-10Consistent effects in ChineseMa R Jia W.Diabetologia,2013,56(6):1291-305.Association of PAX4 rs10229583 variant and clinical phenotypesHOMA-FPGStumvoll index of-cell function PAX4 may cause T2DM mainly through cell functionMa R Jia W.Diabetologia,2013,56(6):1291-305.PAX4Pancreatic deve

23、lopment cell proliferationMutationVariantMODY9T2DClinical treatmentStudy design of pharmacogenomics48 weekN=910.5mg tid2mg tid1mg tid2 week 0.5mg tidRepaglinideN=104Well-controlled GlucoseBad-controlled Glucose48 weekN=934mg qd8 week 4mg qdRosiglitazoneN=104Well-controlled GlucoseBad-controlled Gluc

24、ose8mg qdStudy Samples:Newly diagnosed type 2 diabetic patients no history of prior antidiabetic medications BMI 18.5 kg/m2 HbA1c 6.5%Clinical information Anthropometric parameters:Height,Weight,BMI Biochemical testing：OGTT,Arginine stimulation test,et al.PAX4 rs6467136 and rosiglitazone efficacy-7-

25、6-5-4-3-2-10GGGA+AA2hPG(mmol/l)P=0.0063n=64n=28Plog-rank=0.0093Rosiglitazone GA+AA carriers showed greater decrease in 2-h glucose levels and higher cumulative attainment rates of target 2-h glucose levels than GG homozygotesChen M et al.Pharmacogenomics J,2014,14:488492Defective b-cell function sub

26、groupPlog-rank=0.0091Plog-rank=0.0070GAtAA carriers were more likely to attain the target fasting and 2-h glucose levelChen M et al.Pharmacogenomics J,2014,14:488492PAX4 rs6467136 and rosiglitazone efficacyTZD can regulate PAX4 through acting PPAR PAX4 rs6467136 GA+AA carriers improve glycemic contr

27、ol after rosiglitazone treatment TZD drug can regulate PAX4 through acting PPAR and thus promote cell proliferationProliferationPAX4ApoptosisPPARPDX-1,NKX6.1,BETA2/NeuroDTZDCausal genes/variantsFunctional studiesElucidate the mechanismProbands and family membersClinical InformationMutation screening

28、Molecular typingDiagnosisTreatmentMonogenic diabetesPolygeneticT2DMSusceptible genes/variantsPersonalized therapySummary Special pedigreesAcknowledgementFunding:NSFCNational 973 ProgrameNIDDKEFSDAcademician Kunsan Xiang Cheng Hu,Yuqian Bao,Congrong Wang,Chen Wang,Limei Liu,Rong Zhang,Xiaojing Ma,Hui

29、juan Lu,Feng Jiang,Jing Xu,Xiaosi LiThank you!Epidemiological status of diabetes in China2.59.73.215.502468101214161819942008DiabetesPre-diabetesPrevalence(%)3.29.011.518.120.424.5051015202530DiabetesPre-diabetes20-3940-5960Nationwide epidemiological survey of T2D in 2010 High prevalence Diabetes:9.7%Pre-diabetes:15.5%Early-onset Diabetes before the age 40:6%Yang W.N Engl J Med 2010;362:1090-101.1999 WHO criteriaPrevalence(%)