Understanding Pre-Type 1 Diabetes: The Key to Prevention

Laura M Jacobsen, Michael J Haller, Desmond A Schatz, Laura M Jacobsen, Michael J Haller, Desmond A Schatz

Abstract

While the incidence of type 1 diabetes continues to rise by 3% each year, the ability to prevent this disease remains elusive. Hybrid closed loop devices, artificial pancreas systems, and continuous glucose monitoring technology have helped to ease the daily burden for many people living with type 1 diabetes. However, the artificial pancreas is not a cure; more research is needed to achieve our ultimate goal of preventing type 1 diabetes. The preceding decades have generated a wealth of information regarding the natural history of pre-type 1 diabetes. Islet autoimmunity in the form of multiple autoantibodies is known to be highly predictive of progression to disease. Staging systems have been devised to better characterize pre-type 1, direct mechanistic understanding of disease, and guide the design of prevention studies. However, there are no evidence-based recommendations for practitioners caring for autoantibody patients other than to encourage enrollment in research studies. Close monitoring of high-risk patients in natural history studies markedly reduces diabetic ketoacidosis rates at diagnosis and research participation is critical to finding a means of preventing type 1 diabetes. The discovery of an effective preventative strategy for type 1 diabetes will justify universal risk screening for all children.

Keywords: autoimmune diseases; mechanisms; prevention; staging; type 1 diabetes.

Figures

Figure 1
Figure 1
Development of diabetes in children stratified for islet autoantibody outcome. The numbers at risk represent the children receiving follow-up at age 0, 5, 10, 15, and 20 years. Reproduced with permission from Ziegler et al. (21).
Figure 2
Figure 2
Early stages of type 1 diabetes. Reproduced with permission from Insel et al. (23).

References

    1. International Diabetes Federation. Diabetes Atlas. 5th ed Brussels: IDF; (2011).
    1. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; (2017).
    1. Thomas NJ, Jones SE, Weedon MN, Shields BM, Oram RA, Hattersley AT. Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank. Lancet Diabetes Endocrinol (2017) 6(2):122–9.10.1016/S2213-8587(17)30362-5
    1. The Diabetes Control and Complications Trial Research Group. Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med (1993) 329:977–86.10.1056/NEJM199309303291401
    1. Miller KM, Foster NC, Beck RW, Bergenstal RM, DuBose SN, DiMeglio LA, et al. Current state of type 1 diabetes treatment in the U.S.: updated data from the T1D exchange clinic registry. Diabetes Care (2015) 38(6):971–8.10.2337/dc15-0078
    1. Elding Larsson H, Vehik K, Bell R, Dabelea D, Dolan L, Pihoker C, et al. Reduced prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in young children participating in longitudinal follow-up. Diabetes Care (2011) 34(11):2347–52.10.2337/dc11-1026
    1. Lundgren M, Sahlin Å, Svensson C, Carlsson A, Cedervall E, Jönsson B, et al. Reduced morbidity at diagnosis and improved glycemic control in children previously enrolled in DiPiS follow-up. Pediatr Diabetes (2014) 15(7):494–501.10.1111/pedi.12151
    1. Hekkala AM, Ilonen J, Toppari J, Knip M, Veijola R. Ketoacidosis at diagnosis of type 1 diabetes: effect of prospective studies with newborn genetic screening and follow up of risk children. Pediatr Diabetes (2018)19(2):314–9.10.1111/pedi.12541
    1. Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Chapter 1: epidemiology of type 1 diabetes. Endocrinol Metab Clin North Am (2010) 39(3):481–97.10.1016/j.ecl.2010.05.011
    1. Wenzlau JM, Hutton JC. Novel diabetes autoantibodies and prediction of type 1 diabetes. Curr Diab Rep (2013) 13(5):608–15.10.1007/s11892-013-0405-9
    1. Decochez K, Keymeulen B, Somers G, Dorchy H, De Leeuw IH, Mathieu C, et al. Use of an Islet cell antibody assay to identify type 1 diabetic patients with rapid decrease in C-peptide levels after clinical onset. Diabetes Care (2000) 23:1072–8.10.2337/diacare.23.8.1072
    1. Miao D, Steck AK, Zhang L, Guyer KM, Jiang L, Armstrong T, et al. Electrochemiluminescence assays for insulin and glutamic acid decarboxylase autoantibodies improve prediction of type 1 diabetes risk. Diabetes Technol Ther (2015) 17(2):119–27.10.1089/dia.2014.0186
    1. Achenbach P, Bonifacio E, Koczwara K, Ziegler AG. Natural history of type 1 diabetes. Diabetes (2005) 54(Suppl 2):S25–31.10.2337/diabetes.54.suppl_2.S25
    1. Nokoff N, Rewers M. Pathogenesis of type 1 diabetes: lessons from natural history studies of high-risk individuals. Ann N Y Acad Sci (2013) 1281:1–15.10.1111/nyas.12021
    1. Krischer JP, Lynch KF, Schatz DA, Ilonen J, Lernmark Å, Hagopian WA, et al. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia (2015) 58(5):980–7.10.1007/s00125-015-3514-y
    1. Koczwara K, Bonifacio E, Ziegler AG. Transmission of maternal islet antibodies and risk of autoimmune diabetes in offspring of mothers with type 1 diabetes. Diabetes (2004) 53:1–4.10.2337/diabetes.53.1.1
    1. TEDDY Study Group. The environmental determinants of diabetes in the young (TEDDY) study: study design. Pediatr Diabetes (2007) 8(5):286–98.10.1111/j.1399-5448.2007.00269.x
    1. Krischer JP, Liu X, Lernmark Å, Hagopian WA, Rewers MJ, She JX, et al. The influence of type 1 diabetes genetic susceptibility regions, age, sex, and family history to the progression from multiple autoantibodies to type 1 diabetes: a TEDDY study report. Diabetes (2017) 66(12):3122–9.10.2337/db17-0261
    1. Steck AK, Vehik K, Bonifacio E, Lernmark Å, Ziegler AG, Hagopian WA, et al. Predictors of progression from the appearance of islet autoantibodies to early childhood diabetes: the environmental determinants of diabetes in the young (TEDDY). Diabetes Care (2015) 38:808–13.10.2337/dc14-2426
    1. Krischer JP, Lynch KF, Lernmark Å, Hagopian WA, Rewers MJ, She JX, et al. Genetic and environmental interactions modify the risk of diabetes-related autoimmunity by 6 years of age: the TEDDY study. Diabetes Care (2017) 40:1194–202.10.2337/dc17-0238
    1. Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA (2013) 309(23):2473–9.10.1001/jama.2013.6285
    1. American Diabetes Association. 2. Classification and diagnosis of diabetes. Diabetes Care (2017) 40(Suppl 1):S11–24.10.2337/dc17-S005
    1. Insel RA, Dunne JL, Atkinson MA, Chiang JL, Dabelea D, Gottlieb PA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the endocrine society, and the American Diabetes Association. Diabetes Care (2015) 38(10):1964–74.10.2337/dc15-1419
    1. Usher-Smith JA, Thompson M, Ercole A, Walter FM. Variation between countries in the frequency of diabetic ketoacidosis at first presentation of type 1 diabetes in children: a systematic review. Diabetologia (2012) 55:2878–94.10.1007/s00125-012-2690-2
    1. Duca LM, Wang B, Rewers M, Rewers A. Diabetic ketoacidosis at diagnosis of type 1 diabetes predicts poor long-term glycemic control. Diabetes Care (2017) 40(9):1249–55.10.2337/dc17-0558
    1. Shalitin S, Fisher S, Yackbovitch-Gavan M, de Vries L, Lazar L, Lebenthal Y, et al. Ketoacidosis at onset of type 1 diabetes is a predictor of long-term glycemic control. Pediatr Diabetes (2017) 19(2):320–8.10.1111/pedi.12546
    1. Sosenko JM, Skyler JS, DiMeglio LA, Beam CA, Krischer JP, Greenbaum CJ, et al. A new approach for diagnosing type 1 diabetes in autoantibody-positive individuals based on prediction and natural history. Diabetes Care (2015) 38(2):271–6.10.2337/dc14-1813
    1. Veijola R, Koskinen M, Helminen O, Hekkala A. Dysregulation of glucose metabolism in preclinical type 1 diabetes. Pediatr Diabetes (2016) 17(Suppl 22):25–30.10.1111/pedi.12392
    1. Xu P, Krischer JP, Behalf of the Type 1 Diabetes TrialNet Study Group Prognostic classification factors associated with development of multiple autoantibodies, dysglycemia, and type 1 diabetes – a recursive partitioning analysis. Diabetes Care (2016) 39(6):1036–44.10.2337/dc15-2292
    1. Bonifacio E, Mathieu C, Nepom GT, Ziegler AG, Anhalt H, Haller MJ, et al. Rebranding asymptomatic type 1 diabetes: the case for autoimmune beta cell disorder as a pathological and diagnostic entity. Diabetologia (2017) 60:35–8.10.1007/s00125-016-4144-8
    1. Jacobsen LM, Anhalt H, Haller MJ. Presymptomatic screening for autoimmune β-cell disorder (ABCD): baby steps towards prevention? Pediatr Diabetes (2018) 19(1):11–3.10.1111/pedi.12620
    1. Becker D, Insel R. Screening, staging, and naming of presymptomatic type 1 diabetes. Pediatr Diabetes (2018) 19:7–10.10.1111/pedi.12613
    1. Meehan C, Fout B, Ashcraft J, Schatz DA, Haller MJ. Screening for type 1 diabetes risk to reduce DKA is not economically viable. Pediatr Diabetes (2015) 16:565–72.10.1111/pedi.12313
    1. Johnson SB, Lynch KF, Roth R, Schatz D, TEDDY Study Group . My child is islet autoantibody positive: impact on parental anxiety. Diabetes Care (2017) 40(9):1167–72.10.2337/dc17-0166
    1. Fr1da. Fr1da Study in Bavaria: Type 1 Diabetes – Early Detection – Early Treatment. (2018). Available from:
    1. Deylami R, Townson J, Mann M, Gregory JW. Systematic review of publicity interventions to increase awareness amongst healthcare professionals and the public to promote earlier diagnosis of type 1 diabetes in children and young people. Pediatr Diabetes (2017):1–8.10.1111/pedi.12565
    1. Buckingham B, Beck RW, Ruedy KJ. Effectiveness of early intensive therapy on β-cell preservation in type 1 diabetes-randomized controlled trial. Diabetes Care (2013) 36(12):4030–5.10.2337/dc13-1074
    1. 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) 346:1685–91.10.1056/NEJMoa012350
    1. Jacobsen L, Schatz D. Current and future efforts toward the prevention of type 1 diabetes. Pediatr Diabetes (2016) 17(Suppl 22):78–86.10.1111/pedi.12333
    1. Writing Group for the TRIGR Study Group. Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes the TRIGR randomized clinical trial. JAMA (2018) 319(1):38–48.10.1001/jama.2017.19826
    1. Ziegler AG, Danne T, Dunger DB, Berner R, Puff R, Kiess W, et al. Primary prevention of beta-cell autoimmunity and type 1 diabetes – the global platform for the prevention of autoimmune diabetes (GPPAD) perspectives. Mol Metab (2016) 5:255–62.10.1016/j.molmet.2016.02.003
    1. Peakman M, von Herrath M. Antigen-specific immunotherapy for type 1 diabetes: maximizing the potential. Diabetes (2010) 59(9):2087–93.10.2337/db10-0630
    1. Tian J, Kaufman DL. Antigen-based therapy for the treatment of type 1 diabetes. Diabetes (2009) 58(9):1939–46.10.2337/db09-0451
    1. Writing Committee for the Type 1 Diabetes Trial Net Oral Insulin Study Group. Krischer JP, Schatz DA, Bundy B, Skyler JS, Greenbaum CJ. Effect of oral insulin on prevention of diabetes in relatives of patients with type 1 diabetes: a randomized clinical trial. JAMA (2017) 318(19):1891–902.10.1001/jama.2017.17070
    1. Simmons KM, Michels AW. Type 1 diabetes: a predictable disease. World J Diabetes (2015) 6(3):380–90.10.4239/wjd.v6.i3.380
    1. Larsson HE, Lundgren M, Jonsdottir B, Cuthbertson D, Krischer J. DiAPREV-IT Study Group. Safety and efficacy of autoantigen-specific therapy with 2 doses of alum-formulated glutamate decarboxylase in children with multiple islet autoantibodies and risk for type 1 diabetes: A randomized clinical trial. Pediatr Diabetes (2017).10.1111/pedi.12611
    1. King’s College London. New Immunotherapy Trial for Type 1 Diabetes. (2018). Available from:
    1. Sherry N, Hagopian W, Ludvigsson J, Jain SM, Wahlen J, Ferry RJ, Jr, et al. Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet (2011) 378(9790):487–97.10.1016/S0140-6736(11)60931-8
    1. Hage MP, Al-Badri MR, Azar ST. A favorable effect of hydroxychloroquine on glucose and lipid metabolism beyond its anti-inflammatory role. Ther Adv Endocrinol Metab (2014) 5(4):77–85.10.1177/2042018814547204

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