成人隐匿性自身免疫糖尿病（LADA）的临床特征和MICA微卫星等位基因A5.1与中国人LADA相关联的研究
|
摘要
目的：了解T2DM患者中GADA的阳性率和ICA的阳性率。GADA阳性患者、ICA阳性患者、GADA和ICA均阳性患者之间临床特征有无差别。方法：住院和门诊T2DM患者482例。符合下列条件：发病年龄＞30岁，发病6个月内无酮症的T2DM，起病时不需要胰岛素治疗。所有患者ELISA测定血清GADA。对其中的253例患者(包括全部GAD阳性患者71例和随机选取部分GAD阴性患者182例)ELISA测定血清ICA。结果：GADA在2型糖尿病患者的阳性率是14.73％。ICA阳性率18.97％。GADA和ICA均阳性2.70％。GADA+组、ICA+组和GADAICA+组三组间年龄、性别、BMI和病程无显著差异，三组间OGTT试验0’，30’，60’，120’，180’各点的血糖和胰岛素(INS)水平都无显著性差异(均P＞0.05)。三组间TC、TG、HDL-C、LDL-C均无显著性差异(P＞0.05)，甲状腺抗体TRAb、TSI、TGAb、TMAb阳性率也无差异(x~2=1.80，1.58，0.29，0.07，P＞0.05)。抗体阳性患者中发现其他自身免疫性疾病4例。结论：在2型糖尿病患者中有较大比例的患者是LADA。GAD和ICA的ELISA测定对LADA的鉴别非常重要。抗体阳性T2DM患者应高度警惕其他自身免疫疾病的存在。
Objective: To investigate the frequency of GADA and ICA in patients initially diagnosed as type 2 DM. The clinical characteristic in patients with GADA(+),ICA(+),GADAICA(+). Methods: 482 inpatients and outpatients initially classified as type 2 DM who met all of the following criteria at diagnosis were recruited: age>30years,no history of ketonuria or ketoacidosis for >6 months after diagnosis, and not requiring insulin treatment at onset of disease. Serum antibodies to glutamic acid decarboxylase were determined by ELISA in all the patients. Serum antibodies to islet cell cytoplasmic antigens were determined by ELISA in part of the patients (including all the patients with GADA(+) and part of the patients with GADA(-)). Results: The overall prevalence of GADA was 14.73%,and ICA was 18.97%.2.70%were positive for 2 antibodies. There were no significant difference among the GADA+ group, ICA+group and GADAICA+group in age, sex, BMI and duration. There were no significant difference among the three groups in the
levels of blood glucose and serum insulin of the OGTT0',30', 60',120', 180'.There were no significant difference among the three groups in the levels of plasma TC,TG,HDL-C,LDL-C and the prevalence of the 4 thyroid antibodidies (x2=1.80, 1.58, 0.29, 0.07, P>0.05) .Four cases of other autoimmune diseases were found in the patients with islet autoantibodies positive.Conclusion:In patients initially diagnosed as type 2 DM may in many
cases suffer from LADA. Testing by GADA and ICA ELISA may be important in identifying LADA. Screening for other autoimmune diseases should be performed in all the type 2 DM patients with islet autoantibodies positive.
Objective: To investigate the frequency of GADA and ICA in patients initially diagnosed as type 2 DM. The clinical characteristic in patients with GADA(+),ICA(+),GADAICA(+). Methods: 482 inpatients and outpatients initially classified as type 2 DM who met all of the following criteria at diagnosis were recruited: age>30years,no history of ketonuria or ketoacidosis for >6 months after diagnosis, and not requiring insulin treatment at onset of disease. Serum antibodies to glutamic acid decarboxylase were determined by ELISA in all the patients. Serum antibodies to islet cell cytoplasmic antigens were determined by ELISA in part of the patients (including all the patients with GADA(+) and part of the patients with GADA(-)). Results: The overall prevalence of GADA was 14.73%,and ICA was 18.97%.2.70%were positive for 2 antibodies. There were no significant difference among the GADA+ group, ICA+group and GADAICA+group in age, sex, BMI and duration. There were no significant difference among the three groups in the
levels of blood glucose and serum insulin of the OGTT0',30', 60',120', 180'.There were no significant difference among the three groups in the levels of plasma TC,TG,HDL-C,LDL-C and the prevalence of the 4 thyroid antibodidies (x2=1.80, 1.58, 0.29, 0.07, P>0.05) .Four cases of other autoimmune diseases were found in the patients with islet autoantibodies positive.Conclusion:In patients initially diagnosed as type 2 DM may in many
cases suffer from LADA. Testing by GADA and ICA ELISA may be important in identifying LADA. Screening for other autoimmune diseases should be performed in all the type 2 DM patients with islet autoantibodies positive.
引文
1. Alberti KG,Zimmet PZ.1998.Definition,diagnosis and classification of diabetes mellitus and its complications.Part 1 :diagnosis and classification of diabetes mellitus:provisional report of a WHO consultation.Diabet Med 15:539-553.
2. Tuomi T,Groop L C,Zimmet P Z,et al. 1993.Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin dependent onset of disease.Diabetes.,42:359-362.
3. Zimmet PZ,Tuomi T,Mackay IR, etal.1994.Latent autoimmune diabetes mellitus in adults(LADA),the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency.Diabet Med 11:299-303.
4. Irvine WJ,Sawers JS,Feek CM,etal. 1979.The value of islet cell antibodies in predicting secondary failure of oral hypoglycaemic agent therapy in diabetes mellitus.J Clin Lab Immunol.2:23-26.
5. Irvine WJ,Gray RS,Mccallum CJ,etal.Clinical and pathogenic significance of pancreatic-islet-cell antibodies in diabetics treated with oral hypoglycemic agents.Lancet 1:1025-1027,1977.
6. Groop LC,Bottazzo GF,Doniach D. 1986.Islet cell antibodies identify latent type 1 diabetes in patients aged 35-75 years at diagnosis.Diabetes 35:237-241.
7. Rowley MJ,Mackay IR,Chen QY,etal.1992.Antibodies to glutamic acid decarboxylase discriminate major types of diabetes mellitus.Diabetes 41:548-561.
8. Landin-Olsson M.Latent autoimmune diabetes in adults.2002, Ann N Y Acad Sci.2002,958:112-116.
9. Tuomi T,Carlsson A,Li H,etal.Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies.Diabetes 1999,48:150-157.
10. Zimmet PZ.The pathogenesis and prevention of diabetes in adults: genes, autoimmunity, and demography. Diabetes Care18: 1050-1064,1994.
11. Turner R, Stratton I, Horton V, etal. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet. 1997 Nov 1 ;350(9087): 1288-93.
12. Torn C, Landin-Olsson M, Ostman J, etal.2000.Glutamic acid decarboxylase autoantibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1
diabetes on clinical grounds.Diabetes Metab Res Rev. 16:442-447.
13. Lohmann T, Kellner K, Verlohren HJ, etal. Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults(LADA).Diabetologia 2001,44:1005-1010.
14. Pietropaolo M, Barinas-Mitchell E, Pietropaolo SL. etal. Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. Diabetes 2000. 49:32-38.
15. Falorni A, Calcinaro F. Autoantibody profile and epitope mapping in latent autoimmune diabetes in adults. 2002, Ann N Y Acad Sci. 2002,958:99-106.
16. Bosi E,Garancini MP,Poggiali F, etal. Low prevalence of islet autoimmunity in adult diabetes and low predictive value of islet autoantibodies in the general adult population of northern Italy.Diabetologia 1999. 42:840-844.
17. Horton V, Stratton I, Bottazzo GF, etal. Genetic heterogeneity of autoimmune diabetes:age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes(UKPDS 43). Diabetologia, 1999.42:608-616.
18. Hosszǘfalusi N,Vatay A,Rajczy K,et al. Similar Genetic Features and Different Islet Cell Autoantibody Pattern of Latent Autoimmune Diabetes in Adults (LADA) Compared With Adult-Onset Type 1 Diabetes With Rapid Progression.Diabetes Care 2003,26(2):452-457.
19. Sanjeevi C.B, Gambelunghe G, Falorni A, et al. Genetics of latent autoimmune diabetes in adults. Ann.N.Y.Acad.Sci. 2002, 958:107-111.
20. Gambelunghe G, Ghaderi M, Tortoioli C, etal. Two distinct MICA gene markers discriminate major autoimmune diabetes types. J Clin Endocrinol metab 2001, 86(8): 3754-3760.
21. Shtauvere-Brameus A, Ghaderi M, Rumba I, et al. Microsatellite allele 5 of MHC class 1 chain-related gene A increases the risk for insulin-dependent diabetes mellitus in Latvians.Ann.N.Y.Acad.Sci.2002,958:349-352.
22. Berzina L, Shtauvere-Brameus A, Rumba I, et al. Microsatellite allele A5.1 of MHC class 1 chain-related gene A is associated with latent autoimmune diabetes in adults in Latvia.Ann.N.Y.Acad.Sci.2002,958:353-356.
23. Vatay A, Rajczy K,Pozsonyi E, etal.2002 Differences in the genetic background of latent autoimmune diabetes in aldults (LADA) and type 1 diabetes mellitus.Immunology Letters 84 (2) :109-115.
24. Cosentino A, Gambelunghe G, Tortoioli C,etal. CTLA-4 gene polymorphism contributes to the genetic risk for latent autoimmune diabetes in adults.Ann N Y Acad Sci. 2002 Apr;958:337-40.
25．成人自身免疫迟发性1型糖尿病与青少年发病的2型糖尿病．廖二元主编．内分泌学．1496-1501．
26. Harrison LC, Honeyman MC.Cow' milk and type 1 diabetes.The real debate is about mucosal immune function.Diabetes 1999,48:1501 - 1507.
27. Akerblom HK,Knip M.Putative environmental factors in Type 1 diabetes.Diabetes/Metabolism Reviews 1998,14:31-67.
28. Cavallo MG,Fava D,Monetini L,etal.Cell mediated immune response to β -casein in recent onset insulin dependent diabetes:Implication for disease pathogenesis.Lancet 1996,348:926-928.
29. L.Monetini,M.G.Cavallo,S.Manfrini,et al.Antibodies to bovine beta-casein in diabetes and other autoimmune diseases.Horm Metab Res 2002,34:455-459
30. Isomaa B,Almgren P,Henricsson M,etal.Chronic complications in patients with slowly progressing autoimmune type 1 diabetes(LADA)o Diabetes Care22:1347-1353,1999.
31. Kobayashi T. Subtype of insulin-dependent diabetes mellitus (IDDM)in Japan: slowly progressive IDDM-the clinical characteristics and pathogenesis of the syndrome. Diabetes Res Clin Prac 24:S96-S99,1994.
32. Kobayashi T,Tamemoto K,Nakanishi K,etal.Immunogenetic and clinical characterization of slowly progressive IDDM.Diabetes Care 16:780-788,1993。
33．吴艺捷，赵立，胡远峰等．成人迟发自身免疫性糖尿病与1、T2DM临床表现的比较。中国糖尿病杂志．2000．10(4)：212．
34．王维平，张洪德，胡远峰等．谷氨酸脱羧酶抗体和胰岛细胞抗体联合检测对T1DM早期诊断的意义．中华内分泌代谢杂志．1999，15(5)：267-270．
35．宫芸，蒋绿芝，李郑芳等．联合三种抗体检测诊断成人隐匿性自身免疫性糖尿病的意义．中华内分泌代谢杂志．2002，18(1)：50-51．
36. ZG Zhou, LL Ouyang,J Peng,etal.Diagnostic role of antibodies to glutamic acid decarboxylase in latent autoimmune diabetes mellitus in adults.Chinese Medical Journal 1999,112(6):554-557.
37．王娈，于宏伟，闫胜利等．细胞毒性T淋巴细胞相关抗原4基因多态性与中国汉族人T1DM、自身免疫性甲状腺病的相关性研究．中华内分泌代谢杂志．2001，17(4)：228-231．
2. Tuomi T,Groop L C,Zimmet P Z,et al. 1993.Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin dependent onset of disease.Diabetes.,42:359-362.
3. Zimmet PZ,Tuomi T,Mackay IR, etal.1994.Latent autoimmune diabetes mellitus in adults(LADA),the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency.Diabet Med 11:299-303.
4. Irvine WJ,Sawers JS,Feek CM,etal. 1979.The value of islet cell antibodies in predicting secondary failure of oral hypoglycaemic agent therapy in diabetes mellitus.J Clin Lab Immunol.2:23-26.
5. Irvine WJ,Gray RS,Mccallum CJ,etal.Clinical and pathogenic significance of pancreatic-islet-cell antibodies in diabetics treated with oral hypoglycemic agents.Lancet 1:1025-1027,1977.
6. Groop LC,Bottazzo GF,Doniach D. 1986.Islet cell antibodies identify latent type 1 diabetes in patients aged 35-75 years at diagnosis.Diabetes 35:237-241.
7. Rowley MJ,Mackay IR,Chen QY,etal.1992.Antibodies to glutamic acid decarboxylase discriminate major types of diabetes mellitus.Diabetes 41:548-561.
8. Landin-Olsson M.Latent autoimmune diabetes in adults.2002, Ann N Y Acad Sci.2002,958:112-116.
9. Tuomi T,Carlsson A,Li H,etal.Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies.Diabetes 1999,48:150-157.
10. Zimmet PZ.The pathogenesis and prevention of diabetes in adults: genes, autoimmunity, and demography. Diabetes Care18: 1050-1064,1994.
11. Turner R, Stratton I, Horton V, etal. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet. 1997 Nov 1 ;350(9087): 1288-93.
12. Torn C, Landin-Olsson M, Ostman J, etal.2000.Glutamic acid decarboxylase autoantibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1
diabetes on clinical grounds.Diabetes Metab Res Rev. 16:442-447.
13. Lohmann T, Kellner K, Verlohren HJ, etal. Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults(LADA).Diabetologia 2001,44:1005-1010.
14. Pietropaolo M, Barinas-Mitchell E, Pietropaolo SL. etal. Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. Diabetes 2000. 49:32-38.
15. Falorni A, Calcinaro F. Autoantibody profile and epitope mapping in latent autoimmune diabetes in adults. 2002, Ann N Y Acad Sci. 2002,958:99-106.
16. Bosi E,Garancini MP,Poggiali F, etal. Low prevalence of islet autoimmunity in adult diabetes and low predictive value of islet autoantibodies in the general adult population of northern Italy.Diabetologia 1999. 42:840-844.
17. Horton V, Stratton I, Bottazzo GF, etal. Genetic heterogeneity of autoimmune diabetes:age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes(UKPDS 43). Diabetologia, 1999.42:608-616.
18. Hosszǘfalusi N,Vatay A,Rajczy K,et al. Similar Genetic Features and Different Islet Cell Autoantibody Pattern of Latent Autoimmune Diabetes in Adults (LADA) Compared With Adult-Onset Type 1 Diabetes With Rapid Progression.Diabetes Care 2003,26(2):452-457.
19. Sanjeevi C.B, Gambelunghe G, Falorni A, et al. Genetics of latent autoimmune diabetes in adults. Ann.N.Y.Acad.Sci. 2002, 958:107-111.
20. Gambelunghe G, Ghaderi M, Tortoioli C, etal. Two distinct MICA gene markers discriminate major autoimmune diabetes types. J Clin Endocrinol metab 2001, 86(8): 3754-3760.
21. Shtauvere-Brameus A, Ghaderi M, Rumba I, et al. Microsatellite allele 5 of MHC class 1 chain-related gene A increases the risk for insulin-dependent diabetes mellitus in Latvians.Ann.N.Y.Acad.Sci.2002,958:349-352.
22. Berzina L, Shtauvere-Brameus A, Rumba I, et al. Microsatellite allele A5.1 of MHC class 1 chain-related gene A is associated with latent autoimmune diabetes in adults in Latvia.Ann.N.Y.Acad.Sci.2002,958:353-356.
23. Vatay A, Rajczy K,Pozsonyi E, etal.2002 Differences in the genetic background of latent autoimmune diabetes in aldults (LADA) and type 1 diabetes mellitus.Immunology Letters 84 (2) :109-115.
24. Cosentino A, Gambelunghe G, Tortoioli C,etal. CTLA-4 gene polymorphism contributes to the genetic risk for latent autoimmune diabetes in adults.Ann N Y Acad Sci. 2002 Apr;958:337-40.
25．成人自身免疫迟发性1型糖尿病与青少年发病的2型糖尿病．廖二元主编．内分泌学．1496-1501．
26. Harrison LC, Honeyman MC.Cow' milk and type 1 diabetes.The real debate is about mucosal immune function.Diabetes 1999,48:1501 - 1507.
27. Akerblom HK,Knip M.Putative environmental factors in Type 1 diabetes.Diabetes/Metabolism Reviews 1998,14:31-67.
28. Cavallo MG,Fava D,Monetini L,etal.Cell mediated immune response to β -casein in recent onset insulin dependent diabetes:Implication for disease pathogenesis.Lancet 1996,348:926-928.
29. L.Monetini,M.G.Cavallo,S.Manfrini,et al.Antibodies to bovine beta-casein in diabetes and other autoimmune diseases.Horm Metab Res 2002,34:455-459
30. Isomaa B,Almgren P,Henricsson M,etal.Chronic complications in patients with slowly progressing autoimmune type 1 diabetes(LADA)o Diabetes Care22:1347-1353,1999.
31. Kobayashi T. Subtype of insulin-dependent diabetes mellitus (IDDM)in Japan: slowly progressive IDDM-the clinical characteristics and pathogenesis of the syndrome. Diabetes Res Clin Prac 24:S96-S99,1994.
32. Kobayashi T,Tamemoto K,Nakanishi K,etal.Immunogenetic and clinical characterization of slowly progressive IDDM.Diabetes Care 16:780-788,1993。
33．吴艺捷，赵立，胡远峰等．成人迟发自身免疫性糖尿病与1、T2DM临床表现的比较。中国糖尿病杂志．2000．10(4)：212．
34．王维平，张洪德，胡远峰等．谷氨酸脱羧酶抗体和胰岛细胞抗体联合检测对T1DM早期诊断的意义．中华内分泌代谢杂志．1999，15(5)：267-270．
35．宫芸，蒋绿芝，李郑芳等．联合三种抗体检测诊断成人隐匿性自身免疫性糖尿病的意义．中华内分泌代谢杂志．2002，18(1)：50-51．
36. ZG Zhou, LL Ouyang,J Peng,etal.Diagnostic role of antibodies to glutamic acid decarboxylase in latent autoimmune diabetes mellitus in adults.Chinese Medical Journal 1999,112(6):554-557.
37．王娈，于宏伟，闫胜利等．细胞毒性T淋巴细胞相关抗原4基因多态性与中国汉族人T1DM、自身免疫性甲状腺病的相关性研究．中华内分泌代谢杂志．2001，17(4)：228-231．