青少年糖尿病分型 与 免疫遗传学

青少年糖尿病常见类型
青少年2型糖尿病增长趋势和危险因素
胰岛自身抗体测定与青少年糖尿病分型
HLAⅡ类基因多态性与青少年糖尿病分型
肥胖与青少年糖尿病南京军区总医院内分泌科王坚
 

Type 1A  DM
Type 1B  DM
Type 2  DM
MODY(maturity-onset diabetes of the young)1-5
继发性和内分泌性
少见的糖尿病综合证
Wolfram S
Prader-Willi S
Laurence-Moon-Biedle S
Leprechaunism S
Rabson-Mendenhall S

线粒体糖尿病(Mitochondrial diabetes)
A3243G mutation [Am J Hum Genet. 2003; 72:1005-1012 ]
T3271C transitional mutations[Pediatr Res. 2005; 58:258-262 ]
A1555G mutation[J Hum Genet. 2003;48:480-483 ]
Kearns Sayre syndrome (KSS) resulted from mtDNA deletions [Exp Clin Endocrinol Diabetes 2004; 112: 80-83 ]
 
线粒体糖尿病

mtDNA mutation
mtDNA deletion
糖尿病是许多线粒体病(呈现罕见综合证)的其中之一表现

青少年糖尿病分型困惑 ---Type 1b DM
 适合诊断Type 1b DM或能被归类于Type 1b DM 的病人在全球范围内持续性扩展
有必要对该组病人按照病因学进行重新分类使之成为临床上相关连的亚型
 
暴发性1型糖尿病(Fulminant type 1 DM,      a recently discovered subtype of type 1---- Type 1B? )

突然发作伴暴发性症状:显著高血糖,严重的DKA 昏迷正常或接近正常的 HbA1c
胰岛自身抗体阴性(ICA,  GADAb,  IA-2Ab/ICA512,  IAA)
Involvement of exocrine pancreas as well as pancreatic islets with elevated serum levels of pancreatic enzymes
Involvement of both genetic background-class II HLA genes-and viruses has been suggested.
暴发性1型糖尿病临床特征
高血糖症状平均4天
很高比例的前驱症状----感冒样和胃肠道症状
尽管严重高血糖和DKA,但接近正常的 HbA1c
有时与妊娠有关
胰酶水平增高
C-peptide水平缺乏
几乎不能检出胰岛ß-细胞自身抗体
The presence of the above characteristics strongly indicates the diagnosis of fulminant type 1 diabetes.
暴发性1型糖尿病基因组学
日本人经典的type 1 DM, DRB1*0405-DQB1*0401 和 DRB1*0901-DQB1*0303是主要的HLA-DR-DQ易感单倍型, DRB1*1502-DQB1*0601 和DRB1*1501-DQB1*0602是保护基因
日本人只有DRB1*0405-DQB1*0401纯合子可能与暴发性1型和经典的type 1DM 均有关
 a different contribution of class II HLA in the mechanisms of beta cell damage between fulminant and "classic" type 1 diabetes
酮症倾向性糖尿病(Ketosis-Prone Diabetes, KPD; type 1B ? )
KPD 是一种新命名的异质性综合证
目前分类type 1B 与病人长期预后无关
有的因为永久性的严重的ß-细胞功能衰竭,需要终身胰岛素治疗
others requiring only temporary insulin treatment due to partially preserved ß-cell function or reversible ß-cell defects
KPD
美国25?40% 新诊断少年儿童糖尿病存在DKA
但其中越来越多病人有肥胖及糖尿病家族史,而无自身免疫标记物
强化治疗可使ß-细胞功能恢复、胰岛素敏感性改善,以至血糖接近正常,可数月甚数年停用胰岛素
首先在非洲裔人群中发现,但其他人群均有报道
This variant of type 2 diabetes referrs to as idiopathic type 1 diabetes, atypical diabetes, Flatbush diabetes, diabetes type 1.5 ,and more recently as ketosis-prone type 2 diabetes
 
在西方大多数青少年糖尿病仍被诊断为1型DM, 仅少数患者被诊为2型DM
但是这种情况正在发生变化，在白人青少年中2型DM发病率增加迅猛
在亚洲人青少年DM中长期以来一直以2型为主

 
奥地利15岁以下儿童1999-2001资料
529 cases of DM <15 years were documented
of which 510 were T1DM resulting in an incidence rate of 12.4/100,000
8 cases were diagnosed as T2DM and two cases with an atypical form of T2DM
The age of onset of T2DM was 12?15 years and all patients were overweight.
The calculated incidence for T2DM <15 years in Austria was 0.25/100,000.

 
The prevalence of type 2 diabetes in children and youth is worldwide increasing
Recent reports indicate that type 2 diabetes accounts for 8% to 45% of all newly diagnosed diabetes among children and adolescents in the US
Before the 1990s, this percentage was still less than 4%
 
Clinically, children with non-insulin dependent over a one year period were considered T2DM
A total of 6922 German children were clinically classified as T1DM and 128 children as T2DM
36% children with T2DM had at least one beta-cell Ab, might be classified as "LADY" (latent autoimmune DM in youth)
 
北欧、西班牙、意大利等以高加索人种为主地区为Type1A DM高发区，平均发病率>15/10万人年
相对低发区，平均发病率<2/10万人年，主分布在中国、日本、韩国等蒙古人种东亚地区
 
在英国, MODY 大约占2型DM的 1%
However, a Caucasian child under age of 16 years may have a similar relative risk to develop MODY as type 2 diabetes with a crude minimum prevalence of 0.17/100 000
 
K(ATP)通道系磺脲类受体的一部分,负责介导beta细胞胰岛素释放
编码K(ATP)通道Kir6.2 亚单位的KCJN11 基因突变可介导
transient neonatal diabetes
permanent neonatal diabetes alone
a novel syndrome characterized by developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome.
 
编码加勒比海人Kir6.2 的E23K基因突变 与type 2 DM相关

nonobese diabetic (NOD) mouse
For the last 30 years, the classical model for type 1 diabetes research
numerous genes differentially regulated in the NOD mouse are more commonly associated with type 2 rather than type 1
include changes in gene expression related to insulin resistance, vascular pathology, altered cell-to-cell and cell-to-extracellular matrix interactions, and endoplasmic reticulum stress
抗胰岛自身抗体(Anti-islet autoantibodies)
Antibodies to Islet Autoantigens
glutamic acid decarboxylase-65(GAD65)
insulinoma-associated antigen-2(IA-2) / fragment 256?556:630?979 of tyrosine-phosphatase IA-2 molecule (ICA512)
Insulin(IAA)
Islet cell autoantibodies (ICA)
 
The fluid-phase filtration radioassay demonstrated high sensitivity and specificity for the detection of anti-dsDNA antibodies in SLE
The standard ELISA exhibiting lower specificity
 
Autoantibodies to ß cells and their antigens are detectable in the blood years before a person develops type 1 diabetes
Not everyone with detectable autoantibodies goes on to develop the disease
High levels of single autoantibodies and the presence of multiple autoantibodies are highly predictive of future disease
 
抗胰岛自身抗体可在type 1A diabetes发病前多年就存在 (Kukreja A, Maclaren NK. J Clin Endocrinol Metab 84:4371-4378, 1999)
且在type 1A diabetes发病后继续存在数年 (Decochez K, Tits J, Coolens JL,  et al. Diabetes Care 23:838-844, 2000)
其滴度逐渐下降,以至发病数年后 近一半病人最终转为阴性(Gianani R, Eisenbarth GS. Immunol Rev 204: 232-249, 2005 )
 
Insulin autoantibodies (IAA) are often the first autoantibodies to appear during the prediabetic phase (Kukreja, A. & Maclaren, N. K. 1999. J. Clin. Endocrinol. Metab. 84:4371-4378. )
IAA levels correlate inversely with age, the highest levels being seen in children who present with diabetes under the age of 5 years (Roberto Gianani , George S. Eisenbarth Immunological Reviews 204: 232  - April 2005 ) 
 
日本人1型DM发病初的抗体阳性率与白人相似

60-70% for GAD
45-50% for IAA
60-65% for IA-2
With combinatorial analysis, 90% of patients express at least one of these autoantibodies
 

With combinatorial analysis for antibodies, approximately 3.7-7.3% of Caucasian new onset type 1diabetes were found to be islet autoantibody negative
Expression of organ-specific autoAbs was very high in T1DM!
我们曾筛查814 例T1DM (病程 0.08?10.33年) 器官特异性自身抗体的阳性表达:
thyroid peroxidase antibody (TPOAb) and/or thyroglobulin antibody (TGAb)---29%
tissue transglutaminase antibody (TTGAb)---10.1%
21-hydroxylase antibody (21-OHAb)---1.6%

HLA DR/DQ were associated with the highest risk for expression of
21-OHAb (DRB1*0404-DQ8, DR3-DQ2)
TTGAb (DR3-DQ2- DR3-DQ2)

HLA typing
HLAⅡ类基因由DQ、DR、DP、TAP1和TAP2、LMP2和LMP7等30多个基因位点组成
DQ、DR、DP均为一条A链和一条B链组成的异二聚体分子，且A链基因和B链基因及其等位基因数目众多
1A型糖尿病的遗传易感性主要与DR、DQ基因及其单倍型相关联
HLA-DPB1基因是否具有独立危险性尚存争议
 
Rendondo对2817个高加索人 Anti-islet Abs 阳性的人群进行随访（最长8年），发现这些人群中若携带有DQ2和（或）DQ8，则表达的胰岛素自身抗体更多，发生T1DM的危险性更大，5年内有36％的人进展为T1DM
 
高加索人种中最易感的单倍型为DRB1*04-DQA1*0301-DQB1*0302（ DR4-DQ8）和DRB1*03-DQA1*0501-DQB1*02（DR3-DQ2）
尤其是DQ2/DQ8杂合子患病危险性最高
 
Heterozygous DR3-DQ2/ DR4-DQ8 is known to be the most susceptible gene for type 1 diabetes in Caucasians
Approximately 30-40% of patients carried heterozygous DR3/DR4 genotype
 
在亚洲其他T1DM的低发病率区域，DQ2和DQ8的报道并不多
日本Kanga 提出DQA1*0301-DQB1*0401（DQ4）和DQA1*0301-DQB1*0303（DQ9）为易感性最强的基因型
 
DQB1*0401、DQB1*03032编码第57位的天门冬氨酸， Jeesuk认为此为韩国TIDM儿童易感基因（OR值分别为3.07、2.89，P<0.05）
DQβ链上第57位天门冬氨酸与T1ADM的负相关在韩国人群中并不明显
Penny对广东籍T1ADM研究也指出，HLA-DQβ链第57位非天门冬氨酸与T1ADM的易感性无关
 
DQB1*0302是与所有人种T1ADM有关的基因
在波兰DQB1*0302的基因频率在T1ADM和正常人群中分别为27.8％和8.7％（P<10-5，OR值4.03）（ Izabela K, et al. Med Wieku Rozwoj ,2003,7: 157-64. ）
日本和台湾TIADM患者DQB1*0302的表达不高 ( Awata T,et al. Diabetologia,1992,35:419-424; Chen BH, et. Hum.Immunol,1999,60:1131-1137.)
在韩国DQB1*0302与保护性基因DRB1*0403、DRB1*0406连锁，使得DQB1*0302在T1DM中表达并不高(Yu J, Shin CH, Yang SW, Park MH, Eisenbarth GS. Clinical Immunology ,2004,113: 318-325.)
 
高加索人种中1A型糖尿病患者的DQB1*0401频率低于正常人，说明DQB1*0401是保护基因
而对韩国儿童的研究却发现，DQB1*0401为韩国TIDM患儿的易感基因（OR值为3.07）
对中国人分析也指出DQB1*0401（合并的OR值为2.00，P<0.05）是中国人的易感基因
 
DQB1*0602 has natural protection effect against type 1 diabetes
It can even prevent progression to overt diabetes in ICA positive relatives of type 1 diabetes
Protective effect associated with DQ6.2  is not absolute

 
亚洲地区与高加索人HLA异同主表现在：
DQ方面：亚洲人群中DQβ链上第57位天门冬氨酸与T1ADM的发病率并非有负相关
高加索人中易感性最强的基因型DQ2和DQ8与亚洲T1ADM人群的相关性并不强
DQB1*0302在欧美等高发区易感性较强，但在亚洲T1ADM中并未发现明显的易感性
在欧美高加索人种中作为保护基因的DQB1*0401，在亚洲人群中表现为易感基因
DQA1*0501在高加索人种中普遍认可为易感基因，但与中国人T1ADM的关系并不大
 
DR方面：DRB1*0401，*0402，*0407在韩国人群表达很低，此外亚洲人群发现DRB1*09可能与T1ADM相关，但其独立性尚存争议
从DR-DQ单倍型来讲，在高加索人种中，DRB1*0301和DRB1*0401常分别与DQ2和DQ8连锁在一起，构成T1ADM易感性最强的单倍型，但在亚洲人群中未发现此连锁现象与T1ADM的明显关联性
Obesity
 The incidence of obesity among children aged 6-16 years is now even greater than that among adults in the USA and Europe
Obesity in children has also led to a tremendous increase in the prevalence of impaired glucose tolerance (IGT), the percentages span from 25% in a multiethnic cohort in the USA, to 4% in Italian Caucasians.

 
肥胖不仅是青少年2型糖尿病的危险因素，也增加青少年1型糖尿病的发病率
Obesity shows strong correlations with the recent increased incidence of type 1 diabetes

 
Obesity Triples Among Kids with Type 1
The prevalence of being overweight at the onset of type 1 diabetes had tripled from the 1980s to the 1990s, following a parallel rise in obesity among the general population
 
A diagnosis of type 2 diabetes was self-reported in 11.4% of 587 obese children in the USA
16.7% of the non-Hispanic black children
9.5% of the non-Hispanic white children,
19% of the Hispanic children
 
All children aged 4 to 19 years in the community  in northern Manitoba, Canada were invited to participate, with a response rate of 82% (n = 719)
 5.1% have T2 DM or IGT
新发青少年糖尿病胰岛自身抗体谱
胰岛自身抗体mIAA、 GAD65、ICA512 以RIA测定
ICA512 (fragment 256-556/ 630-979 of tyrosine- phosphatase IA2 molecule) 阴性者加测抗IA-2细胞内全部区域605?979片断的抗体ICA512 ic (fragment 605-979)
上述抗体均阴性加测抗胰岛细胞抗体ICA

Percentage of HLA in Ab+/- patients

Summary
现行的青少年糖尿病分型有缺陷,要更改,对Type 1b DM有必要按照病因学进行重新分类
抗胰岛自身抗体仍是青少年糖尿病分型的重要依据,但抗体谱改变与病程和发病年龄关系密切
随着年龄的增加Type 1A DM 所有Ab- 的比例显著高于5岁以下者
 
HLA基因型测定对Ab-青少年糖尿病诊断分型有重要意义
具有保护作用的HLA等位基因 DQB1*0602 在Ab+青少年明显减少
青少年中2型糖尿病比例还会继续上升,肥胖与Ab- 青少年DM相关

 
A subset of autoantibody negative patients are likely to have type 1A diabetes (e.g. DR3/4-DQ8)

Among Ab- patients > age10, there is likely to be type 2 diabetes patients (64% BMI>30 all Ab negative).
Particularly among Ab- patients with younger age there are likely to be subset with neither type 1A nor type 2 diabetes.