罕见病例在认识糖尿病中的重要作用-英文版课件

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

2、 disease 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 MODYOnset

3、age less than 25 yearsBMI 24kg/m2No insulin was required for at least 2 years after diagnosisThree or more than three generations of family history of diabetesAutosomal dominant inheritanceComparison of clinical characteristics between MODY and T2DMClinical CharacteristicsMODYT2DMAge of onsetChildre

4、n, adolescenceor youngpeople (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 MOD

5、YMODY1：HNF4 MODY2：Glucokinase（GCK）MODY3：HNF1 MODY4：IPF1MODY5：HNF1MODY6：NeuroD/Beta 2MODY7：KLF11MODY8：CELMODY9：PAX4MODY10：INSMODY11：BLKMODY12：ABCC8MODY13：KCNJ11The action mode of MODY proteins in the beta cellPAX4KLF11KCNJ11ABCC8CELBLKT1D was diagnosed 1 month after birth, without ketosisInsulin ther

6、apy (CSII)Hypoglycemic coma twiceGenetic 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 2006Whether sulfonylurea drugs can be used to treat KCNJ11 mutation?Mec

7、hanisms of KCNJ11 mutations lead to diabetesSulfonylurea therapy instead of insulinWell-controlled blood glucose, without hypoglycemic comaThe Lilly Jaffe StorySulfonylureas are targeted drugs for KCNJ11SulfonylureasClose KATP channelMembrane DepolarizatioCa2+influxInsulin secretionFor KCNJ11 mutati

8、on carriers, sulfonylureas are superior to insulin in blood glucose controlPearson et al NEJM, 2006InsulinSulfonylureasN=38KCNJ11 and early-onset “T2DM” in Chinese pedigrees96 early-onset T2D probands and their family membersAutosomal dominant inheritance (At least 3 generations of family history of

9、 diabetes)At least one member of onset before the age of 40Exclusion of mitochondrial mutations diabetesSequencing of KCNJ11 coding and flanking regionLiu L et al. Diabetologia, 2013, 56: 26093 novel mutations in KCNJ113 novel mutations in KCNJ11： R27H, R192H,S116F117delMutations may affect potassiu

10、m channels function and result in insulin secretion defectsLiu L et al. Diabetologia, 2013, 56: 2609Functional studies of KCNJ11 mutationR192HR27HWTR192H and R27H mutation decrease KATP channel activity significantlyAfter sulfonylurea treatment, no significant differences in KATP channel activity be

11、tween 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 Chinese?Sulfonylureas?Neonatal Diabetes Mellitus (NDM)Association of KCNJ11 E23K

12、and 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 ShanghaiT2D (case=1,849) vs. NGT (control=1,785

13、） KCNJ11 rs5219 variant is the susceptible gene in Chinese, which can increase the T2D risk of 13.8%Pharmacogenomic research of KCNJ11 E23K in ChineseNewly diagnosed T2D patients, Gliclazide monotherapy and follow-up 16w (N=108)The cumulative rate of fasting blood glucose in KK carriers was signific

14、antly better than that of other genotypesKCNJ11 E23K can affect gliclazide efficacyPlog-rank= 0.028Li Q et al. CEPP, 2014, 41: 748754EEEKKKweekPAR164WThai MODY pedigreeKnown MODY gene mutations were not foundPAX4 gene screeningTwo novel mutationsmissensemutation: R164W Splice mutation: IVS71GAThe mu

15、tations were not 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 i

16、n silico replication 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 ct

17、rsJapanese4465 cases vs. 3023 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 ctrsGWA

18、S of T2DM in ChineseMa R Jia W. Diabetologia, 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 replicat

19、ions19767171451.14 (1.09 - 1.19)5.810-9Replication 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 populati

20、onLarge-scale GWAS for T2D (90,000 samples)Chinese East Asians South Asians and EuropeansPAX4 rs10229583 is a novel susceptible variant of T2DM in ChineseThe effect of PAX4 on T2DM has significant ethnic heterogeneitySingapore replicationOR (95% CI)Hong Kong GWAS 1Hong Kong replication 1Shanghai rep

21、lication 1Hong Kong replication 2Shanghai replication 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

22、 AsiansWeak effects in EuropeansOR = 1.14 (1.09, 1.19), 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 functionPAX4 may cause T2DM mainly through cell functionMa R

23、 Jia W. Diabetologia, 2013, 56(6):1291-305. PAX4Pancreatic development cell proliferationMutationVariantMODY9T2DClinical treatment？Study design of pharmacogenomics48 weekN=910.5mg tid2mg tid1mg tid2 week 0.5mg tidRepaglinideN=104Well-controlled GlucoseBad-controlled Glucose48 weekN=934mg qd8 week 4m

24、g qdRosiglitazoneN=104Well-controlled GlucoseBad-controlled Glucose8mg qdStudy Samples:Newly diagnosed type 2 diabetic patientsno history of prior antidiabetic medicationsBMI 18.5 kg/m2HbA1c 6.5%Clinical informationAnthropometric parameters: Height, Weight, BMIBiochemical testing：OGTT, Arginine stim

25、ulation test, et al.PAX4 rs6467136 and rosiglitazone efficacy2hPG (mmol/l)P = 0.0063n=64n=28Plog-rank=0.0093RosiglitazoneGA+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

26、J, 2014,14: 488492Defective b-cell function subgroupPlog-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 PPARPAX4 rs6467136 GA+AA carriers improve glycemic control after rosiglitazone treatmentTZD drug ca