Type 1 diabetes: recent developments
http://www.100md.com
《英国医生杂志》
1 Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, 80262 CO, USA
Correspondence to: G S Eisenbarth George.Eisenbarth@UCHSC.edu
Introduction
This review is based on information obtained from a recent Medline search with type 1 diabetes, pathogenesis, prediction, prevention, and treatment as key words. We also consulted summaries of the literature on type 1 diabetes (available with teaching slides at www.barbaradaviscenter.org).
Epidemiology
Alleles or genetic variants associated with type 1 diabetes provide either susceptibility to or protection from the disease. An interplay between genetic susceptibility and environmental factors is thought to provide the fundamental element for disease and provides potential targets for both prediction and prevention of disease.6 The concordance for type 1 diabetes is approximately 50% for monozygotic twins, and the risk to a first degree relative is approximately 5%.7 The major genetic determinant of susceptibility to diabetes lies within the major histocompatibility complex (termed IDDM 1). More than 90% of patients who develop type 1 diabetes have either DR3, DQ2 or DR4, DQ8 haplotypes, whereas fewer than 40% of normal controls have these haplotypes.6 DR3-DR4 heterozygosity is highest in children who develop diabetes before age 5 (50%) and lowest in adults presenting with type 1 diabetes (20-30%), compared with a US population prevalence of 2.4%. Only one non-HLA gene has been identified with certainty—IDDM 2 on chromosome 11p5.5—and this contributes about 10% of the familial aggregation of type 1 diabetes.8 This locus is a polymorphic region that maps to a variable number of tandem nucleotide repeats (VNTR) 5' of the insulin gene. Studies in man indicate that different sizes of this VNTR 5' of the insulin gene are associated with risk for type 1 diabetes. The long form of the VNTR ( 100 repeats, class III) is associated with protection from diabetes.9 This influence of the insulin gene locus may relate to variation in expression of insulin within the thymus (greater thymic insulin message with protective VNTR). Table 1 shows a summary of the susceptibility loci for type 1 diabetes.
Table 1 Inherited susceptibility loci for type 1 diabetes with associated chromosome location and candidate genes or microsatellite markers
Environment
The hallmark of type 1 diabetes is the selective destruction of insulin-producing cells in the pancreas, or insulitis. Studies measuring the expression of diabetes related autoantibodies in young children from birth suggest that the appearance of these markers is a major risk for the future development of type 1 diabetes.18 However, the role of autoantibodies in the actual pathogenesis of type 1 diabetes has not been established in humans. In fact, a recent case report showed the development of type 1 diabetes in a patient with X linked agammaglobulinaemia, suggesting that autoantibodies are not needed for either the initiation or the progression of type 1 diabetes.19 In general, type 1 diabetes is considered primarily a T cell mediated disease, and extensive evidence exists in both man and mouse to support this. Examination of islet tissue obtained from pancreatic biopsy from patients with recent onset type 1 diabetes confirms insulitis, with the presence of an infiltrate composed of CD4 and CD8 T lymphocytes, B lymphocytes, and macrophages, suggesting that these cells have a role in destruction of the cells.20 Early studies in mice showed that anti-CD3 treatment prevented diabetes, and a trial using humanised anti-CD3 antibody in patients with new onset type 1 diabetes is under way.21 In figure 2 we describe a general model of cell destruction leading to type 1 diabetes. The initial interaction of genes and environmental factors seem to trigger an immune mediated response, with the appearance of autoantibodies as the first sign of cell destruction, followed eventually by the loss of the first phase insulin response. The progression to overt diabetes resulting in significant cell destruction is triggered by the development of a more aggressive T cell phenotype and a change in the Th1 to Th2 balance towards a more proinflammatory milieu. The expression of FasLigand on cytotoxic T cells also marks the progression to overt diabetes. Examination of islets during insulitis suggests that Fas mediated apoptosis occurs and therefore provides one possible mechanism of cell destruction.22
Fig 2 Model of pathogenesis and natural history of type 1 diabetes. Modified from Atkinson and Eisenbarth6 (Available in: Eisenbarth GS, ed. Type 1A diabetes: cellular, molecular and clinical immunology, teaching slides www.barbaradaviscenter.org)
Prediction
To date no treatment has been shown to prevent type 1 diabetes in humans. More than 100 different treatments prevent type 1 diabetes in the NOD mouse model, and this may indicate that disease prevention in this model is "too" easy.28 Two major trials have been conducted to try to prevent type 1 diabetes. In the United States, the diabetes prevention trial (DPT-1) was started in 1994 with the aim of determining whether antigen based treatment with insulin (oral and parenteral insulin treatment in relatives at high and moderate risk) would prevent or delay diabetes. These treatments did not overall slow the progression to diabetes. The European nicotinamide diabetes intervention trial (ENDIT) also found no difference in protection from diabetes when participants were assigned to either oral nicotinamide or placebo treatment (P Bingley, European Association of the Study of Diabetes, Budapest, September 2002). Many challenges remain in this field; in particular assays for pathogenic human T cells are not yet available. Such assays have the potential to provide surrogate markers to guide evaluation of immunotherapy; in the absence of such markers, the primary outcome of trials today is the preservation of insulin secretion (for example, measurement of C peptide secretion). TrialNet and the Immune Tolerance Network created by the US National Institutes of Health will be focusing not only on the prevention of diabetes but also on preventing further loss of islet cells in patients with new onset type 1 diabetes.
Insulin remains the main treatment in type 1 diabetes. The diabetes control and complications trial (DCCT) showed the importance of strict metabolic control in delaying and preventing complications.29 The risk of hypoglycaemia is still the major limiting factor in achieving euglycaemia with insulin treatment. The introduction of rapidly absorbed insulin analogues has reduced variability of insulin absorption and allows insulin administration in young children after meals.30 Another recent introduction to the insulin market has been insulin glargine, which functions as a very long acting insulin (peakless basal insulin).31 Combinations of engineered very long acting insulins and rapid acting insulins can provide control and convenience similar to that obtained with insulin pumps.
The use of metformin treatment alongside insulin has increased in patients with type 1 diabetes. Recent studies have suggested that metformin might benefit type 1 diabetes patients who are overweight, are receiving large doses of insulin, or have an HbA1c > 8%.32 The coexistence of insulin resistance in patients with type 1 diabetes is a new area of interest. Islet transplantation with modified immunosuppressive regimens can cure type 1 diabetes. Islet transplantation is a consideration for the limited but important subset of patients with recurrent severe hypoglycaemic episodes not responsive to medical management.33 Inability to control autoimmunity and alloimmunity and a lack of donor organs limit the application of islet transplantation.
Additional educational resources
Diabetes UK (www.diabetes.org.uk)—provides useful links for both patients and healthcare professionals in the United Kingdom
Barbara Davis Center for Childhood Diabetes (www.uchsc.edu/misc/diabetes/books.html)—provides an online teaching guide for healthcare professionals and guidance on type 1 diabetes for patients and their families
American Diabetes Association (www.diabetes.org)—provides useful links for both patients and healthcare professionals in the United States
Immunology of Diabetes Society (www.idsoc.org)—provides an update on current immune intervention trials, links to the Immune Tolerance Network, and current updates on autoantibody assay technology
See also p 741
Additional references, two figures, and a table are on bmj.com
Contributors: DD had the idea for the paper, did most of the background research, wrote the text and tables, and referenced the paper. EL helped to plan the content and wrote on the pathogenesis and T cell assays. GSE provided most of the information on new developments, created the figures, and edited the final paper. DD and GSE accept full responsibility for the content of the paper and controlled the decision to publish.
Funding: This work is supported by grants from the National Institute of Health (DK32082, AI39213, DK55969, DK62718, AI50864, AI95380, DK50970, AI46374), Diabetes Endocrine Research Center (P30 DK57516), Clinical Research Centers (MO1 RR00069, MO1 RR00051), American Diabetes Association, Juvenile Diabetes Foundation, and Children's Diabetes Foundation. DD is supported by an Eli Lilly fellowship award, and EL is supported by a NIH grant (DK 06405).
Competing interests: None declared.
References
Onkamo P, Vaananen S, Karvonen M, Tuomilehto J. Worldwide increase in incidence of type I diabetes—the analysis of the data on published incidence trends. Diabetologia 1999;42: 1395-403.
American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20: 1183-97.
Molbak AG, Christau B, Marner B, Borch-Johnsen K, Nerup J. Incidence of insulin-dependent diabetes mellitus in age groups over 30 years in Denmark. Diabet Med 1994;11: 650-5.
EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet 2000;355: 873-6.
Devendra D, Eisenbarth GS. Immunologic endocrine disorders. J Allergy Clin Immunol 2003;111: 624-36.
Atkinson MA, Eisenbarth GS. Type 1A diabetes: new perspectives on disease pathogenesis and treatment. Lancet 2001;358: 221-9.
Redondo MJ, Rewers M, Yu L, Garg S, Pilcher CC, Elliott RB, et al. Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1A diabetes: prospective twin study. BMJ 1999;318: 698-702.
Bennett ST, Todd JA. Human type 1A diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet 1996;30: 343-70.
Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 1997;15: 289-92.
Hyoty H, Taylor KW. The role of viruses in human diabetes. Diabetologia 2002;45: 1353-61.
Norris JM, Beaty B, Klingensmith G, Yu L, Hoffman M, Chase HP, et al. Lack of association between early exposure to cow's milk protein and -cell autoimmunity: diabetes autoimmunity study in the young (DAISY). JAMA 1996;276: 609-14.
Norris JM, Barriga K, Klingensmith G, Hoffman M, Eisenbarth GS, Erlich HA, et al. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA 2003;290: 1713-20.
Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E. Early infant feeding and risk of developing type 1A diabetes-associated autoantibodies. JAMA 2003;290: 1721-8.
Devendra D, Eisenbarth GS. Interferon alpha—a potential link in viral induced diabetes and autoimmunity. Clin Immunol 2004 (in press).
Moriyama H, Wen L, Abiru N, Liu E, Yu L, Miao D, et al. Induction and acceleration of insulitis/diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide. Proc Natl Acad Sci USA 2002;99: 5539-44.
Gale EA. A missing link in the hygiene hypothesis? Diabetologia 2002;45: 588-94.
Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347: 911-20.
Yu L, Robles DT, Abiru N, Kaur P, Rewers M, Kelemen K, et al. Early expression of anti-insulin autoantibodies of man and the NOD mouse: evidence for early determination of subsequent diabetes. Proc Natl Acad Sci USA 2000;97: 1701-6.
Martin S, Wolf-Eichbaum D, Duinkerken G, Scherbaum WA, Kolb H, Noordzij JG, et al. Development of type 1 diabetes despite severe hereditary B-lymphocyte deficiency. N Engl J Med 2001;345: 1036-40
Imagawa A, Hanafusa T, Itoh N, Waguri M, Yamamoto K, Miyagawa J, et al. Immunological abnormalities in islets at diagnosis paralleled further deterioration of glycaemic control in patients with recent-onset type I (insulin-dependent) diabetes mellitus. Diabetologia 1999;42: 574-8.
Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, et al. Anti-CD3 monoclonal antibody in new-onset type 1A diabetes mellitus. N Engl J Med 2002;346: 1692-8.
Foulis AK, Liddle CN, Farquharson MA, Richmond JA, Weir RS. The histopathology of the pancreas in type I diabetes (insulin dependent) mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia 1986;29: 267-74.
Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, et al. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 1996;45: 926-33.
LaGasse JM, Brantley MS, Leech NJ, Rowe RE, Monks S, Palmer JP, et al. Successful prospective prediction of type 1A diabetes in schoolchildren through multiple defined autoantibodies: an 8-year follow-up of the Washington State diabetes prediction study. Diabetes Care 2002;25: 505-11.
Johnson SB. Screening programs to identify children at risk for diabetes mellitus: psychological impact on children and parents. J Pediatr Endocrinol Metab 2001;14: 653-9.
Barker J, Klingensmith G, Barriga K, Rewers M. Clinical characteristics of type 1 diabetic children identified by a genetic screening and intensive follow-up program. Diabetes 2003;52(suppl 1): A188.
Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, et al. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet 1997;350: 1288-93.
Atkinson MA, Leiter EH. The NOD mouse model of type 1A diabetes: as good as it gets? Nat Med 1999;5: 601-4.
Diabetes Control and Complications Trial, Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1A diabetes four years after a trial of intensive therapy. N Engl J Med 2000;342: 381-9.
Vajo Z, Duckworth WC. Genetically engineered insulin analogs: diabetes in the new millennium. Pharmacol Rev 2000;52: 1-9.
Bolli GB, Owens DR. Insulin glargine. Lancet 2000;356: 443-5.
Meyer L, Guerci B. Metformin and insulin in type 1A diabetes: the first step. Diabetes Care 2003;26: 1655-6.
Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, et al. Islet transplantation in seven patients with type 1A diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343: 230-8.(Devasenan Devendra, post )
Correspondence to: G S Eisenbarth George.Eisenbarth@UCHSC.edu
Introduction
This review is based on information obtained from a recent Medline search with type 1 diabetes, pathogenesis, prediction, prevention, and treatment as key words. We also consulted summaries of the literature on type 1 diabetes (available with teaching slides at www.barbaradaviscenter.org).
Epidemiology
Alleles or genetic variants associated with type 1 diabetes provide either susceptibility to or protection from the disease. An interplay between genetic susceptibility and environmental factors is thought to provide the fundamental element for disease and provides potential targets for both prediction and prevention of disease.6 The concordance for type 1 diabetes is approximately 50% for monozygotic twins, and the risk to a first degree relative is approximately 5%.7 The major genetic determinant of susceptibility to diabetes lies within the major histocompatibility complex (termed IDDM 1). More than 90% of patients who develop type 1 diabetes have either DR3, DQ2 or DR4, DQ8 haplotypes, whereas fewer than 40% of normal controls have these haplotypes.6 DR3-DR4 heterozygosity is highest in children who develop diabetes before age 5 (50%) and lowest in adults presenting with type 1 diabetes (20-30%), compared with a US population prevalence of 2.4%. Only one non-HLA gene has been identified with certainty—IDDM 2 on chromosome 11p5.5—and this contributes about 10% of the familial aggregation of type 1 diabetes.8 This locus is a polymorphic region that maps to a variable number of tandem nucleotide repeats (VNTR) 5' of the insulin gene. Studies in man indicate that different sizes of this VNTR 5' of the insulin gene are associated with risk for type 1 diabetes. The long form of the VNTR ( 100 repeats, class III) is associated with protection from diabetes.9 This influence of the insulin gene locus may relate to variation in expression of insulin within the thymus (greater thymic insulin message with protective VNTR). Table 1 shows a summary of the susceptibility loci for type 1 diabetes.
Table 1 Inherited susceptibility loci for type 1 diabetes with associated chromosome location and candidate genes or microsatellite markers
Environment
The hallmark of type 1 diabetes is the selective destruction of insulin-producing cells in the pancreas, or insulitis. Studies measuring the expression of diabetes related autoantibodies in young children from birth suggest that the appearance of these markers is a major risk for the future development of type 1 diabetes.18 However, the role of autoantibodies in the actual pathogenesis of type 1 diabetes has not been established in humans. In fact, a recent case report showed the development of type 1 diabetes in a patient with X linked agammaglobulinaemia, suggesting that autoantibodies are not needed for either the initiation or the progression of type 1 diabetes.19 In general, type 1 diabetes is considered primarily a T cell mediated disease, and extensive evidence exists in both man and mouse to support this. Examination of islet tissue obtained from pancreatic biopsy from patients with recent onset type 1 diabetes confirms insulitis, with the presence of an infiltrate composed of CD4 and CD8 T lymphocytes, B lymphocytes, and macrophages, suggesting that these cells have a role in destruction of the cells.20 Early studies in mice showed that anti-CD3 treatment prevented diabetes, and a trial using humanised anti-CD3 antibody in patients with new onset type 1 diabetes is under way.21 In figure 2 we describe a general model of cell destruction leading to type 1 diabetes. The initial interaction of genes and environmental factors seem to trigger an immune mediated response, with the appearance of autoantibodies as the first sign of cell destruction, followed eventually by the loss of the first phase insulin response. The progression to overt diabetes resulting in significant cell destruction is triggered by the development of a more aggressive T cell phenotype and a change in the Th1 to Th2 balance towards a more proinflammatory milieu. The expression of FasLigand on cytotoxic T cells also marks the progression to overt diabetes. Examination of islets during insulitis suggests that Fas mediated apoptosis occurs and therefore provides one possible mechanism of cell destruction.22
Fig 2 Model of pathogenesis and natural history of type 1 diabetes. Modified from Atkinson and Eisenbarth6 (Available in: Eisenbarth GS, ed. Type 1A diabetes: cellular, molecular and clinical immunology, teaching slides www.barbaradaviscenter.org)
Prediction
To date no treatment has been shown to prevent type 1 diabetes in humans. More than 100 different treatments prevent type 1 diabetes in the NOD mouse model, and this may indicate that disease prevention in this model is "too" easy.28 Two major trials have been conducted to try to prevent type 1 diabetes. In the United States, the diabetes prevention trial (DPT-1) was started in 1994 with the aim of determining whether antigen based treatment with insulin (oral and parenteral insulin treatment in relatives at high and moderate risk) would prevent or delay diabetes. These treatments did not overall slow the progression to diabetes. The European nicotinamide diabetes intervention trial (ENDIT) also found no difference in protection from diabetes when participants were assigned to either oral nicotinamide or placebo treatment (P Bingley, European Association of the Study of Diabetes, Budapest, September 2002). Many challenges remain in this field; in particular assays for pathogenic human T cells are not yet available. Such assays have the potential to provide surrogate markers to guide evaluation of immunotherapy; in the absence of such markers, the primary outcome of trials today is the preservation of insulin secretion (for example, measurement of C peptide secretion). TrialNet and the Immune Tolerance Network created by the US National Institutes of Health will be focusing not only on the prevention of diabetes but also on preventing further loss of islet cells in patients with new onset type 1 diabetes.
Insulin remains the main treatment in type 1 diabetes. The diabetes control and complications trial (DCCT) showed the importance of strict metabolic control in delaying and preventing complications.29 The risk of hypoglycaemia is still the major limiting factor in achieving euglycaemia with insulin treatment. The introduction of rapidly absorbed insulin analogues has reduced variability of insulin absorption and allows insulin administration in young children after meals.30 Another recent introduction to the insulin market has been insulin glargine, which functions as a very long acting insulin (peakless basal insulin).31 Combinations of engineered very long acting insulins and rapid acting insulins can provide control and convenience similar to that obtained with insulin pumps.
The use of metformin treatment alongside insulin has increased in patients with type 1 diabetes. Recent studies have suggested that metformin might benefit type 1 diabetes patients who are overweight, are receiving large doses of insulin, or have an HbA1c > 8%.32 The coexistence of insulin resistance in patients with type 1 diabetes is a new area of interest. Islet transplantation with modified immunosuppressive regimens can cure type 1 diabetes. Islet transplantation is a consideration for the limited but important subset of patients with recurrent severe hypoglycaemic episodes not responsive to medical management.33 Inability to control autoimmunity and alloimmunity and a lack of donor organs limit the application of islet transplantation.
Additional educational resources
Diabetes UK (www.diabetes.org.uk)—provides useful links for both patients and healthcare professionals in the United Kingdom
Barbara Davis Center for Childhood Diabetes (www.uchsc.edu/misc/diabetes/books.html)—provides an online teaching guide for healthcare professionals and guidance on type 1 diabetes for patients and their families
American Diabetes Association (www.diabetes.org)—provides useful links for both patients and healthcare professionals in the United States
Immunology of Diabetes Society (www.idsoc.org)—provides an update on current immune intervention trials, links to the Immune Tolerance Network, and current updates on autoantibody assay technology
See also p 741
Additional references, two figures, and a table are on bmj.com
Contributors: DD had the idea for the paper, did most of the background research, wrote the text and tables, and referenced the paper. EL helped to plan the content and wrote on the pathogenesis and T cell assays. GSE provided most of the information on new developments, created the figures, and edited the final paper. DD and GSE accept full responsibility for the content of the paper and controlled the decision to publish.
Funding: This work is supported by grants from the National Institute of Health (DK32082, AI39213, DK55969, DK62718, AI50864, AI95380, DK50970, AI46374), Diabetes Endocrine Research Center (P30 DK57516), Clinical Research Centers (MO1 RR00069, MO1 RR00051), American Diabetes Association, Juvenile Diabetes Foundation, and Children's Diabetes Foundation. DD is supported by an Eli Lilly fellowship award, and EL is supported by a NIH grant (DK 06405).
Competing interests: None declared.
References
Onkamo P, Vaananen S, Karvonen M, Tuomilehto J. Worldwide increase in incidence of type I diabetes—the analysis of the data on published incidence trends. Diabetologia 1999;42: 1395-403.
American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20: 1183-97.
Molbak AG, Christau B, Marner B, Borch-Johnsen K, Nerup J. Incidence of insulin-dependent diabetes mellitus in age groups over 30 years in Denmark. Diabet Med 1994;11: 650-5.
EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet 2000;355: 873-6.
Devendra D, Eisenbarth GS. Immunologic endocrine disorders. J Allergy Clin Immunol 2003;111: 624-36.
Atkinson MA, Eisenbarth GS. Type 1A diabetes: new perspectives on disease pathogenesis and treatment. Lancet 2001;358: 221-9.
Redondo MJ, Rewers M, Yu L, Garg S, Pilcher CC, Elliott RB, et al. Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1A diabetes: prospective twin study. BMJ 1999;318: 698-702.
Bennett ST, Todd JA. Human type 1A diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet 1996;30: 343-70.
Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 1997;15: 289-92.
Hyoty H, Taylor KW. The role of viruses in human diabetes. Diabetologia 2002;45: 1353-61.
Norris JM, Beaty B, Klingensmith G, Yu L, Hoffman M, Chase HP, et al. Lack of association between early exposure to cow's milk protein and -cell autoimmunity: diabetes autoimmunity study in the young (DAISY). JAMA 1996;276: 609-14.
Norris JM, Barriga K, Klingensmith G, Hoffman M, Eisenbarth GS, Erlich HA, et al. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA 2003;290: 1713-20.
Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E. Early infant feeding and risk of developing type 1A diabetes-associated autoantibodies. JAMA 2003;290: 1721-8.
Devendra D, Eisenbarth GS. Interferon alpha—a potential link in viral induced diabetes and autoimmunity. Clin Immunol 2004 (in press).
Moriyama H, Wen L, Abiru N, Liu E, Yu L, Miao D, et al. Induction and acceleration of insulitis/diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide. Proc Natl Acad Sci USA 2002;99: 5539-44.
Gale EA. A missing link in the hygiene hypothesis? Diabetologia 2002;45: 588-94.
Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347: 911-20.
Yu L, Robles DT, Abiru N, Kaur P, Rewers M, Kelemen K, et al. Early expression of anti-insulin autoantibodies of man and the NOD mouse: evidence for early determination of subsequent diabetes. Proc Natl Acad Sci USA 2000;97: 1701-6.
Martin S, Wolf-Eichbaum D, Duinkerken G, Scherbaum WA, Kolb H, Noordzij JG, et al. Development of type 1 diabetes despite severe hereditary B-lymphocyte deficiency. N Engl J Med 2001;345: 1036-40
Imagawa A, Hanafusa T, Itoh N, Waguri M, Yamamoto K, Miyagawa J, et al. Immunological abnormalities in islets at diagnosis paralleled further deterioration of glycaemic control in patients with recent-onset type I (insulin-dependent) diabetes mellitus. Diabetologia 1999;42: 574-8.
Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, et al. Anti-CD3 monoclonal antibody in new-onset type 1A diabetes mellitus. N Engl J Med 2002;346: 1692-8.
Foulis AK, Liddle CN, Farquharson MA, Richmond JA, Weir RS. The histopathology of the pancreas in type I diabetes (insulin dependent) mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia 1986;29: 267-74.
Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, et al. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 1996;45: 926-33.
LaGasse JM, Brantley MS, Leech NJ, Rowe RE, Monks S, Palmer JP, et al. Successful prospective prediction of type 1A diabetes in schoolchildren through multiple defined autoantibodies: an 8-year follow-up of the Washington State diabetes prediction study. Diabetes Care 2002;25: 505-11.
Johnson SB. Screening programs to identify children at risk for diabetes mellitus: psychological impact on children and parents. J Pediatr Endocrinol Metab 2001;14: 653-9.
Barker J, Klingensmith G, Barriga K, Rewers M. Clinical characteristics of type 1 diabetic children identified by a genetic screening and intensive follow-up program. Diabetes 2003;52(suppl 1): A188.
Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, et al. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet 1997;350: 1288-93.
Atkinson MA, Leiter EH. The NOD mouse model of type 1A diabetes: as good as it gets? Nat Med 1999;5: 601-4.
Diabetes Control and Complications Trial, Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1A diabetes four years after a trial of intensive therapy. N Engl J Med 2000;342: 381-9.
Vajo Z, Duckworth WC. Genetically engineered insulin analogs: diabetes in the new millennium. Pharmacol Rev 2000;52: 1-9.
Bolli GB, Owens DR. Insulin glargine. Lancet 2000;356: 443-5.
Meyer L, Guerci B. Metformin and insulin in type 1A diabetes: the first step. Diabetes Care 2003;26: 1655-6.
Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, et al. Islet transplantation in seven patients with type 1A diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343: 230-8.(Devasenan Devendra, post )