Prediction of type 1 diabetes mellitus
- Massimo Pietropaolo, MD
Massimo Pietropaolo, MD
- McNair Type 1 Diabetes Scholar
- Professor of Medicine, Pathology and Immunology
- Baylor College of Medicine
- Section Editors
- Irl B Hirsch, MD
Irl B Hirsch, MD
- Section Editor — Diabetes Mellitus
- Professor of Medicine
- University of Washington School of Medicine
- Joseph I Wolfsdorf, MB, BCh
Joseph I Wolfsdorf, MB, BCh
- Section Editor — Pediatric Endocrinology
- Professor of Pediatrics
- Harvard Medical School
Type 1 diabetes mellitus is an autoimmune disease arising through a complex interaction of both genetic and immunologic factors . The increase in understanding of the pathogenesis of type 1 diabetes mellitus has made it possible to consider intervention to delay the autoimmune disease process in an attempt to delay or even prevent the onset of hyperglycemia (figure 1). Although no successful strategy for the prevention of type 1 diabetes has yet been identified, subjects who are at high risk for type 1 diabetes can be identified using a combination of immune, genetic, and metabolic markers.
This topic will review the use of genetic, immunologic, and metabolic markers to predict type 1 diabetes. The definition, epidemiology, pathogenesis, and prevention of type 1 diabetes are discussed in detail elsewhere. (See "Classification of diabetes mellitus and genetic diabetic syndromes" and "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents" and "Pathogenesis of type 1 diabetes mellitus" and "Prevention of type 1 diabetes mellitus".)
OVERVIEW OF TYPE 1 DIABETES
Type 1 diabetes mellitus is an autoimmune disease arising through a complex interaction of both genetic and immunologic factors . It is usually caused by an immune-mediated destruction of the insulin-producing beta cells in the islets of Langerhans . Immune-mediated type 1 diabetes is called type 1A to distinguish it from some rarer cases in which an autoimmune etiology cannot be determined (type 1B); the latter are said to be idiopathic . The term type 1 diabetes used here refers to type 1A, or autoimmune diabetes. (See "Classification of diabetes mellitus and genetic diabetic syndromes".)
●Genetic – Type 1 diabetes occurs in genetically susceptible subjects. It is a polygenic disease with a small number of genes having large effects, (ie, human leukocyte antigen [HLA]) and a large number of genes having small effects. Risk of type 1 diabetes progression is conferred by specific HLA DR/DQ alleles (eg, DRB1*03-DQB1*0201 [DR3] or DRB1*04-DQB1*0302 [DR4]). In addition, HLA alleles such as DQB1*0602 are associated with dominant protection from disease in multiple populations . (See 'Genetic markers' below.)
●Immunologic – Similar to the majority of autoimmune diseases, type 1 diabetes usually has a relapsing remitting disease course with autoantibody and T cellular responses to islet autoantigens that precede the clinical onset of the disease process. The immunological diagnosis of autoimmune diseases relies primarily on the detection of autoantibodies directed to islet autoantigens in the serum of type 1 diabetic patients. Although their pathogenic significance remains uncertain, they have the practical advantage of serving as surrogate biomarkers for predicting the clinical onset of type 1 diabetes. (See 'Immunologic markers' below.)
- Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 2010; 464:1293.
- Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med 1994; 331:1428.
- Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20:1183.
- Morran MP, Vonberg A, Khadra A, Pietropaolo M. Immunogenetics of type 1 diabetes mellitus. Mol Aspects Med 2015; 42:42.
- McCulloch DK, Klaff LJ, Kahn SE, et al. Nonprogression of subclinical beta-cell dysfunction among first-degree relatives of IDDM patients. 5-yr follow-up of the Seattle Family Study. Diabetes 1990; 39:549.
- Bärmeier H, McCulloch DK, Neifing JL, et al. Risk for developing type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies. Diabetologia 1991; 34:727.
- Tarn AC, Thomas JM, Dean BM, et al. Predicting insulin-dependent diabetes. Lancet 1988; 1:845.
- Greenbaum CJ, Sears KL, Kahn SE, Palmer JP. Relationship of beta-cell function and autoantibodies to progression and nonprogression of subclinical type 1 diabetes: follow-up of the Seattle Family Study. Diabetes 1999; 48:170.
- Peakman M, Leslie RD, Alviggi L, et al. Persistent activation of CD8+ T-cells characterizes prediabetic twins. Diabetes Care 1996; 19:1177.
- Sempé P, Richard MF, Bach JF, Boitard C. Evidence of CD4+ regulatory T cells in the non-obese diabetic male mouse. Diabetologia 1994; 37:337.
- Zekzer D, Wong FS, Wen L, et al. Inhibition of diabetes by an insulin-reactive CD4 T-cell clone in the nonobese diabetic mouse. Diabetes 1997; 46:1124.
- Mordes JP, Desemone J, Rossini AA. The BB rat. Diabetes Metab Rev 1987; 3:725.
- Kolb H. Mouse models of insulin dependent diabetes: low-dose streptozocin-induced diabetes and nonobese diabetic (NOD) mice. Diabetes Metab Rev 1987; 3:751.
- Elias D, Cohen IR. Peptide therapy for diabetes in NOD mice. Lancet 1994; 343:704.
- Shehadeh N, Calcinaro F, Bradley BJ, et al. Effect of adjuvant therapy on development of diabetes in mouse and man. Lancet 1994; 343:706.
- Thomson G, Robinson WP, Kuhner MK, et al. Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. Am J Hum Genet 1988; 43:799.
- 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.
- Undlien DE, Friede T, Rammensee HG, et al. HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection. Diabetes 1997; 46:143.
- Bingley PJ, Bonifacio E, Gale EA. Can we really predict IDDM? Diabetes 1993; 42:213.
- Aly TA, Ide A, Jahromi MM, et al. Extreme genetic risk for type 1A diabetes. Proc Natl Acad Sci U S A 2006; 103:14074.
- Rewers M, Bugawan TL, Norris JM, et al. Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY). Diabetologia 1996; 39:807.
- 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. The Childhood Diabetes in Finland (DiMe) Study Group. Diabetes Care 1996; 19:795.
- Pietropaolo M, Becker DJ, LaPorte RE, et al. Progression to insulin-requiring diabetes in seronegative prediabetic subjects: the role of two HLA-DQ high-risk haplotypes. Diabetologia 2002; 45:66.
- Pietropaolo M, Eisenbarth GS. Autoantibodies in human diabetes. Curr Dir Autoimmun 2001; 4:252.
- Wenzlau JM, Juhl K, Yu L, et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 2007; 104:17040.
- Mahon JL, Sosenko JM, Rafkin-Mervis L, et al. The TrialNet Natural History Study of the Development of Type 1 Diabetes: objectives, design, and initial results. Pediatr Diabetes 2009; 10:97.
- Verge CF, Gianani R, Kawasaki E, 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.
- 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.
- Achenbach P, Warncke K, Reiter J, et al. Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics. Diabetes 2004; 53:384.
- Morran MP, Casu A, Arena VC, et al. Humoral autoimmunity against the extracellular domain of the neuroendocrine autoantigen IA-2 heightens the risk of type 1 diabetes. Endocrinology 2010; 151:2528.
- Kaufman DL, Clare-Salzler M, Tian J, et al. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 1993; 366:69.
- Tisch R, Yang XD, Singer SM, et al. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 1993; 366:72.
- Neifing JL, Greenbaum CJ, Kahn SE, et al. Prospective evaluation of beta-cell function in insulin autoantibody-positive relatives of insulin-dependent diabetic patients. Metabolism 1993; 42:482.
- Dean BM, Becker F, McNally JM, et al. Insulin autoantibodies in the pre-diabetic period: correlation with islet cell antibodies and development of diabetes. Diabetologia 1986; 29:339.
- Srikanta S, Ricker AT, McCulloch DK, et al. Autoimmunity to insulin, beta cell dysfunction, and development of insulin-dependent diabetes mellitus. Diabetes 1986; 35:139.
- 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.
- Ziegler AG, Hummel M, Schenker M, Bonifacio E. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes 1999; 48:460.
- Hummel M, Bonifacio E, Schmid S, et al. Brief communication: early appearance of islet autoantibodies predicts childhood type 1 diabetes in offspring of diabetic parents. Ann Intern Med 2004; 140:882.
- Lindberg B, Ivarsson SA, Landin-Olsson M, et al. Islet autoantibodies in cord blood from children who developed type I (insulin-dependent) diabetes mellitus before 15 years of age. Diabetologia 1999; 42:181.
- Sosenko JM, Skyler JS, Palmer JP, et al. The prediction of type 1 diabetes by multiple autoantibody levels and their incorporation into an autoantibody risk score in relatives of type 1 diabetic patients. Diabetes Care 2013; 36:2615.
- Littorin B, Sundkvist G, Hagopian W, et al. Islet cell and glutamic acid decarboxylase antibodies present at diagnosis of diabetes predict the need for insulin treatment. A cohort study in young adults whose disease was initially labeled as type 2 or unclassifiable diabetes. Diabetes Care 1999; 22:409.
- Davidson HW, Wenzlau JM, O'Brien RM. Zinc transporter 8 (ZnT8) and β cell function. Trends Endocrinol Metab 2014; 25:415.
- LaGasse JM, Brantley MS, Leech NJ, et al. Successful prospective prediction of type 1 diabetes in schoolchildren through multiple defined autoantibodies: an 8-year follow-up of the Washington State Diabetes Prediction Study. Diabetes Care 2002; 25:505.
- Dorman JS, McCarthy BJ, O'Leary LA, Koehler AN. Risk factors for insulin-dependent diabetes. In: Diabetes in America, 2nd, Aubert R (Ed), Diane Pub Co., 1995. p.165.
- Pietropaolo M, Becker DJ. Type 1 diabetes intervention trials. Pediatr Diabetes 2001; 2:2.
- Ongagna JC, Levy-Marchal C. Sensitivity at diagnosis of combined beta-cell autoantibodies in insulin-dependent diabetic children. French Registry of IDDM in Children Study Group. Diabetes Metab 1997; 23:155.
- Atkinson MA, Maclaren NK, Scharp DW, et al. 64,000 Mr autoantibodies as predictors of insulin-dependent diabetes. Lancet 1990; 335:1357.
- Aanstoot HJ, Sigurdsson E, Jaffe M, et al. Value of antibodies to GAD65 combined with islet cell cytoplasmic antibodies for predicting IDDM in a childhood population. Diabetologia 1994; 37:917.
- Bingley PJ, Colman P, Eisenbarth GS, et al. Standardization of IVGTT to predict IDDM. Diabetes Care 1992; 15:1313.
- McCulloch DK, Bingley PJ, Colman PG, et al. Comparison of bolus and infusion protocols for determining acute insulin response to intravenous glucose in normal humans. The ICARUS Group. Islet Cell Antibody Register User's Study. Diabetes Care 1993; 16:911.
- Barker JM, McFann K, Harrison LC, et al. Pre-type 1 diabetes dysmetabolism: maximal sensitivity achieved with both oral and intravenous glucose tolerance testing. J Pediatr 2007; 150:31.
- Ward WK, LaCava EC, Paquette TL, et al. Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia 1987; 30:698.
- Spinas GA, Snorgaard O, Hartling SG, et al. Elevated proinsulin levels related to islet cell antibodies in first-degree relatives of IDDM patients. Diabetes Care 1992; 15:632.
- Sosenko JM, Skyler JS, Mahon J, et al. Use of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for improving the accuracy of the risk classification of type 1 diabetes. Diabetes Care 2014; 37:979.
- OVERVIEW OF TYPE 1 DIABETES
- ANIMAL MODELS OF TYPE 1 DIABETES
- USE OF MARKERS TO PREDICT TYPE 1 DIABETES
- Genetic markers
- Immunologic markers
- - Islet autoantibodies
- - Zinc transporter antibodies
- - Screening low risk populations
- Metabolic markers
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS