Abstract
The clinical manifestation of type 1 diabetes mellitus is preceded by an asymptomatic prodromal period called prediabetes or preclinical diabetes. It may last from a few months to several years, during which the autoimmune destruction of the insulin-producing β-cells in the pancreas progresses. The genes on the human leukocyte antigen (HLA) and insulin gene region are major genetic determinants for genetic disease susceptibility, while dietary compounds and viral infections are the most likely environmental factors contributing to the etiopathogenesis. T cells are thought to be the effector cells for the β-cell destruction, and glutamic acid decarboxylase, insulinoma-associated protein 2 and insulin represent the three major autoantigens. Autoantibodies are early detectable markers of an ongoing disease process and are used to diagnose prediabetes. Among first-degree relatives of patients with type 1 diabetes, the risk for clinical disease can be graded from <5% in those with one or no antibodies to >90% in individuals who carry the HLA-DQB1*02/0302 risk genotype and are positive for multiple autoantibodies. β-Cell function may also be tested in autoantibody-positive individuals and low first-phase insulin response is highly predictive for rapid progression to the clinical disease. However, dynamic course and individual variation of the disease process complicates the disease prediction, and it is not known whether all individuals with signs of prediabetes will inevitably progress to clinical type 1 diabetes.
Until clinically applicable prevention for the condition exists, the screening for the risk markers of type 1 diabetes should actively be undertaken only in the context of research projects. Several major national and international multicenter studies are ongoing to test the potential of various agents (e.g. insulin and nicotinamide) or early elimination of dietary compounds (e.g. cow’s milk proteins) to delay or prevent the onset of clinical type 1 diabetes.
Similar content being viewed by others
References
White N. Diabetes mellitus in children. In: Rudolph AM, Hoffman JIE, Rudolph CD, editors. Rudolph’s pediatrics. 20th ed. Stamford (CT): Appleton & Lange, 1996: 1803–27
Onkamo P, Väänänen S, Karvonen M, et al. Worldwide increase in incidence of type I diabetes: the analysis of the data on published incidence trends. Diabetologia 1999; 42: 1395–403
Eisenbarth GS. Type I diabetes mellitus: a chronic autoimmune disease. N Engl J Med 1986; 314: 1360–8
Greenbaum CJ, Sears KL, Kahn SE, et al. Relationship of β-cell function and autoantibodies to progression and nonprogression of subclinical type 1 diabetes: follow-up of the Seattle Family Study. Diabetes 1999; 48: 170–5
Gardner SG, Gale EAM, Williams AJK, et al. Progression to diabetes in relatives with islet autoantibodies: is it inevitable. Diabetes Care 1999; 22: 2049–54
Tuomilehto J, Karvonen M, Pitkäniemi J, et al. Record-high incidence of Type I (insulin-dependent) diabetes mellitus in Finnish children. Diabetologia 1999; 42: 655–60
Schatz DA, Bingley PJ. Update on major trials for the prevention of type 1 diabetes mellitus: the American Diabetes Prevention Trial (DPT-1) and the European Nicotinamide Diabetes Intervention Trial (ENDIT). J Pediatr Endocrinol Metab 2001; 14Suppl. 1: 619–22
Gepts W. Pathological anatomy of human pancreas in juvenile diabetes mellitus. Diabetes 1965; 14: 619–33
Singal DP, Blajchman MA. Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes 1973; 22: 429–32
Barbosa J, Chern MM, Reinsmoen N, et al. HLA-Dw antigens in unrelated juvenile, insulin-dependent diabetics. Tissue Antigens 1979; 14: 426–36
Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 1974; II: 1279–82
Baekkeskov S, Nielsen JH, Marner B, et al. Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature 1982; 298: 167–9
Naquet P, Ellis J, Tibensky D, et al. T cell autoreactivity to insulin in diabetic and related non-diabetic individuals. J Immunol 1988; 140: 2569–78
Betterle C, Presotto F, Pedini B, et al. Islet cell and insulin autoantibodies in organ-specific autoimmune patients: their behaviour and predictive value for the development of type 1 (insulin-dependent) diabetes mellitus: a 10-year follow-up study. Diabetologia 1987; 30: 292–7
Henquin JC, Carton F, Ongemba LN, et al. Improvement of mild hypoinsulinaemic diabetes in the rat by low non-toxic doses of vanadate. J Endocrinol 1994; 142: 555–61
Ugazio G, Bosia S, Burdino E, et al. Amelioration of diabetes and cataract by Na3V04 plus U-83836E in streptozotocin treated rats. Res Commun Mol Pathol Pharmacol 1994; 85: 313–28
Bosi E, Bottazzo GF, Secchi A, et al. Islet cell autoimmunity in type I diabetic patients after HLA-mismatched pancreas transplantation. Diabetes 1989; 38Suppl. 1: 82–4
Brooks-Worrell BM, Peterson KP, Peterson CM, et al. Reactivation of type 1 diabetes in patients receiving human fetal pancreatic tissue transplants without immunosuppression. Transplantation 2000; 69: 166–72
Owerbach D, Gabbay KH. The search for IDDM susceptibility genes: the next generation. Diabetes 1996; 45: 544–51
Wassmuth R, Lernmark Å. The genetics of susceptibility to diabetes. Clin Immunol Immunopathol 1989; 53: 358–99
Deschamps I, Khalil I. The role of DQ alpha-beta heterodimers in genetic susceptibility to insulin-dependent diabetes. Diabetes Metab Rev 1993; 9: 71–92
Lernmark Å. Molecular biology of IDDM. Diabetologia 1994; 37Suppl. 2: S73–81
Ilonen J, Reijonen H, Herva E, et al. Rapid HLA-DQB1 genotyping for four alleles in the assessment of risk for IDDM in the Finnish population. Diabetes Care 1996; 19: 795–800
Veijola R, Reijonen H, Vähäsalo P, et al. HLA-DQB 1 defined genetic susceptibility, beta-cell autoimmunity and metabolic characteristics in familial and non-familial insulin-dependent diabetes mellitus. J Clin Invest 1996; 98: 2489–95
Baisch JM, Weeks T, Giles R, et al. Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus. N Engl J Med 1990; 322: 1836–41
Kulmala P, Savola K, Reijonen H, et al. Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in siblings of affected children. Diabetes 2000; 49: 48–58
Sheehy MJ, Scharf SJ, Rowe JR, et al. A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles. J Clin Invest 1989; 83: 830–5
Nepom GT, Kwok WW. Molecular basis for HLA-DQ associations with IDDM. Diabetes 1998; 47: 1177–84
Owerbach D, Gabbay KH. Localization of a type-I diabetes susceptibility locus to the variable tandem repeat region flanking the insulin gene. Diabetes 1993; 42: 1708–14
Bennett ST, Lucassen AM, Gough SCL, et al. Susceptibility to human type 1 diabetes and IDDM2 is determined by tandem repeat variation at the insulin gene mini satellite locus. Nat Genet 1995; 9: 284–92
Vafiadis P, Bennett ST, Todd JA, et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 1997; 15: 289–92
Petersen JS, Kyvik KO, Bingley PJ, et al. Population based study of prevalence of islet cell autoantibodies in monozygotic and dizygotic Danish twin pairs with insulin-dependent diabetes mellitus. BMJ 1997; 314: 1575–9
Redondo MJ, Yu L, Hawa M, et al. Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia 2001; 44: 354–62
Åkerblom HK, Vaarala O, Hyöty H, et al. Environmental factors in the etiology of type 1 diabetes. Am J Med Genet 2002; 115: 18–29
Yoon J-W, Austin M, Onodera T, et al. Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med 1979; 300: 1173–9
Clements GB, Galbraith DN, Taylor KW. Coxsackie B virus infection and onset of childhood diabetes. Lancet 1995; 346: 221–3
King ML, Shaikh A, Bidwell D, et al. Coxsackie-B viras-specific IgM responses in children with insulin-dependent (juvenile-onset type I) diabetes mellitus. Lancet 1983; I: 1397–9
Varela-Calvino R, Ellis R, Sgarbi G, et al. Characterization of the T-cell response to coxsackievirus B4: evidence that effector memory cells predominate in patients with type 1 diabetes. Diabetes 2002; 51: 1745–53
Lönnrot M, Korpela K, Knip M, et al. Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study. Diabetes 2000; 49: 1314–8
Borch-Johnsen K, Mandrup-Poulsen T, Zachau-Christiansen B, et al. Relation between breast-feeding and incidence rates of insulin-dependent diabetes mellitus. Lancet 1984; II: 1083–6
Elliot RB, Martin JM. Dietary protein: a trigger of insulin-dependent diabetes in the BB rat. Diabetologia 1984; 26: 297–9
Scott FW, Norris JM, Kolb H. Milk and type 1 diabetes: examining the evidence and broadening the focus. Diabetes Care 1996; 19: 379–83
Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med 1994; 331: 1428–36
Gray DWR. Type 1 diabetes: the facts fit a deficient inhibitory signal given by MHC class II. Diabetes Metab Res Rev 1999; 15: 29–41
Itoh N, Hanafusa T, Miyazaki A, et al. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest 1993; 92: 2313–22
Solimena M. Vesicular autoantigens of type 1 diabetes. Diabetes Metab Rev 1998; 14: 227–40
Erlander MG, Tobin AJ. The structural and functional heterogeneity of glutamic acid decarboxylase: a review. Neurochem Res 1991; 16: 215–26
Erdö SL, Wolff JR. γ-Aminobutyric acid outside the mammalian brain. J Neurochem 1990; 54: 363–72
Fischer EH, Charbonneau H, Tonks NK. Protein tyrosine phosphatases: a diverse family of intracellular and transmembrane enzymes. Science 1991; 253: 401–6
Lan MS, Wasserfall CW, Maclaren NK, et al. IA-2, a transmembrane protein of the protein tyrosine phosphatase family, is a major autoantigen in insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A 1996; 93: 6367–70
Solimena M, Dirkx RJ, Hermel JM, et al. ICA 512, an autoantigen of type 1 diabetes, is an intrinsic membrane protein of neurosecretory granules. EMBO J 1996; 15: 2102–14
Notkins AL, Lan MS, Leslie RDG. IA-2 and IA-2b: the immune response in IDDM. Diabetes Metab Rev 1998; 14: 85–93
Srikanta S, Ganda OP, Gleason RE, et al. Pre-type I diabetes: linear loss of beta cell response to intravenous glucose. Diabetes 1984; 33: 717–20
Vardi P, Ziegler AG, Mathews JH, et al. Concentration of insulin autoantibodies at onset of type 1 diabetes: inverse log-linear correlation with age. Diabetes Care 1988; 11: 736–9
Ziegler AG, Ziegler R, Vardi P, et al. Life-table analysis of progression to diabetes of anti-insulin autoantibody positive relatives of individuals with type I diabetes. Diabetes 1989; 38: 1320–5
Eisenbarth GS, Gianani R, Yu L, et al. Dual-parameter model for prediction of type I diabetes mellitus. Proc Assoc Am Physicians 1998; 110: 126–35
McCulloch DK, Klaff LJ, Kahn SE, et al. Nonprogression of subclinical β-cell dysfunction among first-degree relatives of IDDM patients: 5-yr follow-up of the Seattle family study. Diabetes 1990; 39: 549–56
Knip M, Vähäsalo P, Karjalainen J, et al. Natural history of preclinical IDDM in high risk siblings. Diabetologia 1994; 37: 388–93
Roll U, Christie MR, Füchtenbusch M, et al. Perinatal autoimmunity in offspring of diabetic parents. The German multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood. Diabetes 1996; 45: 967–73
Yu L, Rewers M, Gianani R, et al. Antiislet autoantibodies usually develop sequentially rather than simultaneously. J Clin Endocrinol Metab 1996; 81: 4264–7
Kimpimäki T, Kupila A, Hämäläinen A-M, et al. The first signs of beta-cell autoimmunity appear in infancy in genetically susceptible children from the general population: the Finnish Type 1 Diabetes Prediction and Prevention Study. J Clin Endocrinol Metab 2001; 86: 4782–8
Savola K, Läärä E, Vähäsalo P, et al. Dynamie pattern of disease-associated autoantibodies in siblings of children with type 1 diabetes: a population-based study. Diabetes 2001; 50: 2625–32
Ziegler A-G, Hummel M, Schenker M, et al. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes. Diabetes 1999; 48: 460–8
Spencer KM, Tarn A, Dean BM, et al. Fluctuating islet cell autoimmunity in unaffected relatives of patients with insulin dependent diabetes. Lancet 1984; I: 746–66
Bonifacio E, Scirpoli M, Kredel K, et al. Early autoantibody responses in prediabetes are IgGl dominated and suggest antigen-specific regulation. J Immunol 1999; 163: 525–32
Gorsuch AN, Spencer KM, Lister J, et al. Evidence for a long prediabetic period in type 1 (insulin-dependent) diabetes mellitus. Lancet 1981; II: 1363–5
Sabbah E, Savola K, Kulmala P, et al. Disease-associated autoantibodies and HLA-DQB1 genotypes in children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). Clin Exp Immunol 1999; 116: 78–83
Myers MA, Rabin DU, Rowley MJ. Pancreatic islet cell cytoplasmic antibody in diabetes is represented by antibodies to islet cell antigen 512 and glutamic acid decarboxylase. Diabetes 1995; 44: 1290–5
Pugliese A, Gianani R, Moromisato R, et al. HLA-DQB1*0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM. Diabetes 1995; 44: 608–13
Bingley PJ, Williams AJK, Gale EAM. Optimized autoantibody-based risk assessment in family members: implications for future intervention trials. Diabetes Care 1999; 22: 1796–801
Pastore MR, Bazzigaluppi E, Bonfanti R, et al. Two-step islet autoantibody screening for risk assessment of type 1 diabetes in relatives. Diabetes Care 1998; 21: 1445–50
Jaeger C, Hatziagelaki E, Stroedter A, et al. The Giessen-Bad Oyenhausen family study: improved prediction of type I diabetes in a low incidence population of relatives using combinations of islet autoantibodies in a dual step model. Exp Clin Endocrinol Diabetes 1999; 107: 496–505
Krischer JP, Cuthbertson DD, Yu L, et al. Screening strategies for the identification of multiple antibody-positive relatives of individuals with type 1 diabetes. J Clin Endocrinol Metab 2003; 88: 103–8
Bingley PJ, Bonifacio E, Ziegler A-G, et al. Proposed guidelines on screening for risk of type 1 diabetes. Diabetes Care 2001; 24: 398
Kulmala P, Savola K, Petersen JS, et al. Prediction of insulin-dependent diabetes mellitus in siblings of children with diabetes: a population based study. J Clin Invest 1998; 101: 327–36
Vardi P, Crisa L, Jackson RA. Predictive value of intravenous glucose tolerance test insulin secretion less than or greater than the first percentile in islet cell antibody positive relatives of type 1 (insulin-dependent) diabetic patients. Diabetologia 1991; 34: 93–102
Bingley PJ. Interactions of age, islet cell antibodies, insulin autoantibodies, and first-phase insulin response in predicting risk of progression to IDDM in ICA+relatives: the ICARUS data set. Islet Cell Antibody Register Users Study. Diabetes 1996; 45: 1720–8
Kimpimäki T, Knip M. Disease associated autoantibodies as predictive markers of type 1 diabetes mellitus in siblings of affected children. J Pediatr Endocrinol Metab 2001; 14: 575–87
Greenbaum CJ, Cuthbertson D, Krischer JP, et al. Type I diabetes manifested solely by 2-h oral glucose tolerance test criteria. Diabetes 2001; 50: 470–6
Kulmala P, Rahko J, Savola K, et al. Beta-cell autoimmunity, genetic susceptibility, and progression to type 1 diabetes in unaffected schoolchildren. Diabetes Care 2001; 24: 171–3
LaGasse JM, Brantley MS, Leech NJ, et al. Successful prospective prediction of type 1 diabetes in schoolchildren through multiple defined autoantibodies. Diabetes Care 2002; 25: 505–11
Bingley PJ, Bonifacio E, Williams AJK, et al. Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. Diabetes 1997; 46: 1701–10
Kupila A, Muona P, Simell T, et al. Feasibility of genetic and immunological prediction of type I diabetes in a population-based birth cohort. Diabetologia 2001; 44: 290–7
Robles DT, Eisenbarth GS, Wang T, et al. Millennium award recipient contribution: Identification of children with early onset and high incidence of anti-islet autoantibodies. Clin Immunol 2002; 102: 217–24
Hahl J, Simell T, Ilonen J, et al. Costs of predicting IDDM. Diabetologia 1998; 41: 79–85
Johnson SB. Screening programs to identify children at risk for diabetes mellitus: psychological impact on children and parents. J Pediatr Endocrinol Metab 2001; 14Suppl. 1: 653–9
Roth R. Psychological and ethical aspects of prevention trials. J Pediatr Endocrinol Metab 2001; 14Suppl. 1: 669–74
Galatzer A, Green E, Ofan R, et al. Psychological impact of islet cell antibody screening. J Pediatr Endocrinol Metab 2001; 14Suppl. 1: 675–9
Yu MS, Norris JM, Mitchell CM, et al. Impact on maternal parenting stress of receipt of genetic information regarding risk of diabetes in newborn infants. Am J Med Genet 1999; 86: 219–26
Ludvigsson J, Gustafsson-Stolt U, Liss PE, et al. Mothers of children in ABIS, a population-based screening for prediabetes, experience few ethical conflicts and have a positive attitude. Ann N Y Acad Sci 2002; 958: 376–81
Reddy S, Stefanovic N, Karanam M. Prevention of autoimmune diabetes by oral administration of syngeneic pancreatic extract to young NOD mice. Pancreas 2000; 20: 55–60
Åkerblom HK, Savilahti E, Saukkonen T, et al. The case for elimination of cow’s milk in early infancy in the prevention of type 1 diabetes: the Finnish experience. Diabetes Metab Rev 1993; 9: 269–78
Pozzilli P. Prevention of insulin-dependent diabetes mellitus 1998. Diabetes Metab Rev 1998; 14: 69–84
Kolb H. Immune intervention in type 1 diabetes mellitus: current clinical and experimental approaches. Exp Clin Endocrinol 1994; 102: 269–72
Gale EAM. Theory and practice of nicotinamine trials in pre-type 1 diabetes. J Pediatr Endocrinol Metab 1996; 9: 375–9
Gale E. Prevention of type 1 diabetes: results of the ENDIT trial [oral presentation]. 38th European Association for the Study of Diabetes Meeting; 2002 Sep 1–5; Budapest
DPT-1 Study Group. The Diabetes Prevention Trial-Type 1 Diabetes (DPT-1): implementation of screening and staging of relatives. Transplant Proc 1995; 27: 3377
Diabetes Prevention Trial-Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002; 346: 1685–91
Honeyman M, Wasserfall C, Nerup J, et al. Prediction and prevention of IDDM. Diabetologia 1997; 40: B58–61
Raz I, Elias D, Avron A, et al. Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. Lancet 2001; 358: 1749–53
Elias D, Cohen IR. Peptide therapy for diabetes in NOD mice. Lancet 1994; 343: 704–6
Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002; 346: 1740–2
Roep BO, Atkinson MA, van Endert PM, et al. Autoreactive T cell responses in insulin-dependent (type 1) diabetes mellitus. J Autoimmun 1999; 13: 267–82
Acknowledgements
No sources of funding were used to assist in the preparation of this manuscript. The author has no conflicts of interest that are directly relevant to the content of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kulmala, P. Prediabetes in Children. Pediatr-Drugs 5, 211–221 (2003). https://doi.org/10.2165/00128072-200305040-00001
Published:
Issue Date:
DOI: https://doi.org/10.2165/00128072-200305040-00001