The novel understanding that the presence of multiple islet autoantibodies, indicating islet autoimmunity, inevitably leads to type 1 diabetes mellitus (T1DM) has necessitated the development of a new staging classification system for the condition. Coupled with an improved understanding of the disease course, the realization that T1DM appears to be more heterogeneous than previously thought has led to unique opportunities to develop more targeted therapies that may be applied even before the onset of dysglycemia or symptoms. To date, several therapies have been trialed to delay or halt disease progression in both presymptomatic and clinical T1DM, each demonstrating varying degrees of effectiveness, toxicity, and utility. Key research supports the eventual implementation of immunotherapy in autoimmune diabetes, potentially calling for a paradigm shift among care providers. It will likely be necessary to develop new approaches to trial design and to address potential barriers to progress before an effective treatment for the disease may be achieved.
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Walsh D, McWilliams D. Mechanisms, impact and management of pain in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10:581–92.
Firestein G, Ravinder N, Romain P. Pathogenesis of rheumatoid arthritis. UpToDate; 2018. https://www-uptodate-com.offcampus.lib.washington.edu/contents/pathogenesis-of-rheumatoid-arthritis?search=pathogenesis%20of%20rheumatoid%20arthritis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Accessed 1 Jan 2018.
group D. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N. Engl. J. Med, 1993. 329(14): p. 977-986.
Group, E.o.D.I.a.C.E.R., Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation, and preliminary results of a long-term follow- up of the Diabetes Control and Complications Trial cohort. Diabetes Care, 1999. 22(1): p. 99-111.
Secrest AM, Washington RE, Orchard TJ. Mortality in Type 1 DIabetes, in Diabetes in America, 3rd Edition. 2016, National Institutes of Health, p. 1–16.
Miller KM, et al. Current state of Type 1 diabetes treatment in the US: updated data from the T1D exchange clinic registry. Diabetes Care. 2015;38(6):971–8.
Eisenbarth GS. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med. 1986;314(21):1360–8.
Sosenko JM, et al. Glucose and C-peptide changes in the perionset period of type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care. 2008;31(11):2188–92.
Greenbaum CJ, et al. Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet data. Diabetes. 2012;61(8):2066–73.
Krogvold L, et al. Function of isolated pancreatic islets from patients at onset of Type 1 diabetes: insulin secretion can be restored after some days in a nondiabetogenic environment in vitro: results from the DiViD Study. Diabetes. 2015;64(7):2506–12.
Keenan HA, et al. Residual insulin production and pancreatic ss-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes. 2010;59(11):2846–53.
Atkinson M, Gianani R. The pancreas in human type 1 diabetes: providing new answers to age-old questions. Curr Opin Endocrinol Diabetes Obes. 2009;16:279–85.
Pugliese A, Yang M, Kusmarteva I. The juvenile diabetes research foundation network for pancreatic organ donors with diabetes (nPOD) program: goals, operational model and emerging findings. Pediatr Diabetes. 2014;15(1):1–9.
Davis AK, et al. Prevalence of detectable C-Peptide according to age at diagnosis and duration of type 1 diabetes. Diabetes Care. 2015;38(3):476–81.
Steffes MW, et al. Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care. 2003;26(3):832–6.
Lachin JM, et al. Impact of C-peptide preservation on metabolic and clinical outcomes in the Diabetes Control and Complications Trial. Diabetes. 2014;63(2):739–48.
Hirshberg B, et al. Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression: the National Institutes of Health experience. Diabetes Care. 2003;26(12):3288–95.
Leitão C, et al. Restoration of hypoglycemia awareness after islet transplantation. Diabetes Care. 2008;31(11):2113–5.
Mahon JL, Sosenko JM, Rafkin-Mervis L, Krause-Steinrauf H, Lachin JM, Thompson C, Bingley PJ, Bonifacio E, Palmer JP, Eisenbarth GS, Wolfsdorf J, Skyler JS. TrialNet Natural History Committee, Type 1 Diabetes TrialNet Study Group. The trialnet natural history study of the development of type 1 diabetes: objectives, design, and initial results. Pediatr Diabetes. 2009;10(2):97–104.
Redondo MJ, et al. Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia. 2001;44:354–62.
Noble JA, Erlich HA. Genetics of type 1 diabetes. Cold Spring Harb Perspect Med. 2012;2(1):a007732.
Noble 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.
Pociot F, et al. Genetics of type 1 diabetes: What’s next? Diabetes. 2010;59:1561–71.
Pugliese A, et al. HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype protects autoantibody-positive relatives from type 1 diabetes throughout the stages of disease progression. Diabetes. 2016;65(4):1109–19.
Jerram S, Leslie RD. The genetic architecture of type 1 diabetes. Genes. 2017;8(8):209.
Ikegami H, et al. Genetics of type 1 diabetes: similarities and differences between Asian and Caucasian populations. Ann N Y Acad Sci. 2006;1079:51–9.
Hagopian WA, et al. Glutamiate decarboxylase, insulin, and islet cell antibodies and HLA typing to detect diabetes in a general population based study of Swedish children. J Clin Invest. 1995;95(4):1505–11.
Rewers M, et al. Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY). Diabetologia. 1996;39(7):807–12.
Winkler C, et al. A strategy for combining minor genetic susceptibility genes to improve prediction of disease in type 1 diabetes. Genes Immun. 2012;13:549–55.
Achenbach P, et al. Natural history of type 1 diabetes. Diabetes. 2005;54(Suppl 2):S25–31.
Wherrett DK, et al. Defining pathways for development of disease-modifying therapies in children with type 1 diabetes: a consensus report. Diabetes Care. 2015;38(10):1975–85.
Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med. 2009;360(16):1646–54.
Insel RA, 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.
Steck AK, 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(5):808–13.
Achenbach P, et al. Characteristics of rapid vs slow progression to type 1 diabetes in mulitple islet autoantibody-positive children. Diabetologia. 2013;56:1615–22.
Ziegler AG, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. J Am Med Assoc. 2013;309(23):2473–9.
Orban T, et al. Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care. 2009;32(12):2269–74.
Parikka V, Nanto-Salonen K, Saarinen M, Simell T, Ilonen J, Hyöty H, Veijola R, Knip M, Simell O. Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk. Diabetologia. 2012;55(7):1926–36.
Krischer JP, et al. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia. 2015;58(5):980–7.
Bosi E, et al. Impact of age and antibody type on progression from single to multiple autoantibodies in type 1 diabetes relatives. J Clin Endocrinol Metab. 2017;102(8):2881–6.
Krischer J, Type 1 Diabetes TrialNet Study Group. The use of intermediate endpoints in the design of type 1 diabetes prevention trials. Diabetologia. 2013;56(9):1919–24.
Krischer JP, 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.
Winkler C, et al. Markedly reduced rate of diabetic ketoacidosis at onset of type 1 diabetes in relatives screened for islet autoantibodies. Pediatr Diabetes. 2012;13(4):308–13.
Elding Larsson H, 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.
Triolo T, et al. Diabetic subjects diagnosed through the Diabetes Prevention Trial-Type 1 (DPT-1) are often asymptomatic with normal A1C at diabetes onset. Diabetes Care. 2009;32:769–73.
Haller MJ, Atkinson MA, Schatz D. Type 1 diabetes mellitus: etiology, presentation, and management. Pediatr Clin North Am. 2005;52(6):1553–78.
American Diabetes Association, I. American Diabetes Association Standards of Medical Care in Diabetes—2017. Diabetes Care. 2017;40((Supplement 1)):S1–134.
Rewers A, et al. Presence of diabetic ketoacidosis at diagnosis of diabetes mellitus in youth: the Search for Diabetes in Youth Study. Pediatrics. 2008;121:e1258–66.
Hagopian WA, et al. The Environmental Determinants of Diabetes in the Young (TEDDY): genetic criteria and international diabetes risk screening of 421 000 infants. Pediatr Diabetes. 2011;12(8):733–43.
Neu A, et al. Ketoacidosis at diabetes onset is still frequent in children and adolescents: a multicenter analysis of 14, 664 patients from 106 institutions. Diabetes Care. 2009;32:1647–8.
Barker J, et al. Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up. Diabetes Care. 2004;27(6):1399–404.
Insel RA, Dunne JL, Ziegler AG. General population screening for type 1 diabetes: has its time come? Curr Opin Endocrinol Diabetes Obes. 2015;22(4):270–6.
Raab J, et al. Capillary blood islet autoantibody screening for identifying pre-type 1 diabetes in the general population: design and initial results of the Fr1da study. BMJ Open. 2016;6(5):e011144.
Zhao Z, et al. A miltiplex assay combining insulin, GAD, IA-2, and transglutaminase autoantibodies to facilitate screening for pre-type 1 diabetes and celiac disease. J Immunol Methods. 2016;430:28–32.
Prevention, C.f.D.C.a, National diabetes statistics report, 2017. 2017, Centers for Disease Control and Prevention, U.S. Dept. of Health and Human Services.: Atlanta, GA.
EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet. 2000;355(9207):873–6.
Veijola R, et al. HLA-DQB1-defined genetic susceptibility, beta cell autoimmunity, and metabolic characteristics in familial and nonfamilial insulin-dependent diabetes mellitus. Childhood Diabetes in Finland (DiMe) Study Group. Vol. 98. 1996. 2489–95.
Diabetes, B.D.C.f. ASK Research Program/Autoimmunity Screening for Kids. 2018 3/16/2018; https://www.askhealth.org/. Accessed 28 Dec 2018.
GPPAD: Global platform for the prevention of autoimmune diabetes. [cited 2018 March 28]; Available from: https://www.gppad.org/en/. Accessed 28 Dec 2018.
Sosenko J, 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(9):2615–20.
Type 1 Diabetes TrialNet. Long-term investigative follow-up in TrialNet (LIFT). Type 1 Diabetes: Stage 3. https://www.trialnet.org/our-research/long-term-follow-up. Accessed 28 Dec 2018.
Ziegler AG, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309(23):2473–9.
Chimel R, et al. Progression from single to multiple islet autoantibodies ofter occurs soon after seroconversion: Implications for early screening. Diabetologia. 2015;58:411–3.
Harjutsalo V, Podar T, Tuomilehto J. Cumulative incidence of type 1 diabetes in 10,168 siblings of Finnish young-onset type 1 diabetic patients. Diabetes. 2005;54(2):563–9.
Hagopian WA, et al. TEDDY–the environmental determinants of diabetes in the young: an observational clinical trial. Ann N Y Acad Sci. 2006;1079:320–6.
Mrena S, et al. Models for predicting type 1 diabetes in siblings of affected children. Diabetes Care. 2006;29(3):662–7.
Steck A, Johnson K, Barriga K. Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes: Diabetes Autoimmunity Study in the Young. Diabetes Care. 2011;34:1397–9.
Bougneres PF, et al. Factors associated with early remission of type I diabetes in children treated with cyclosporine. N Engl J Med. 1988;318(11):663–70.
Vanbuecken D, Lord S, Greenbaum C. Changing the course of disease in type 1 diabetes, in Endotext. South Dartmouth: MDText.com Inc.; 2015.
Ridker P, Everett B, Thuren T. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–31.
Moran A, et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013;381(9881):1905–15.
Mastrandrea L, et al. Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo-controlled, double-blind study. Diabetes Care. 2009;32(7):1244–9.
Clinicaltrials.gov, A Study to Evaluate SIMPONI (Golimumab) Therapy in Children, Adolescents and Young Adults With Pre-Symptomatic Type 1 Diabetes. Last updated March 1, 2018. Accessed March 20, 2018.https://clinicaltrials.gov/ct2/show/NCT03298542.
Clinicaltrials.gov, Study of SIMPONI® to Arrest Beta-cell Loss in Type 1 Diabetes (T1GER); NCT02846545. 2017.
ClinicalTrials.gov, Pilot Clinical Trial of Ustekinumab in Patients With New-onset T1D (USTID). Last updated May 25, 2016. Accessed March 20, 2018.https://clinicaltrials.gov/ct2/show/NCT02117765.
Hundhausen C, et al. Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression. Sci Transl Med. 2016;8(356):356ra119.
Clinicaltrials.gov. Tocilizumab (TCZ) in new-onset type 1 diabetes. https://clinicaltrials.gov/ct2/show/NCT02293837?term=tocilizumab&cond=Type+1+Diabetes&rank=1. Last updated 26 Nov 2018, Accessed 20 Mar 2018.
Lisowska-Myjak B, Pachecka J, Kaczynska B, Miszkurka G, Kadziela K. Serum protease inhibitor concentrations and total antitrypsin activity in diabetic and non-diabetic children during adolescence. Acta Diabetol. 2006;43(4):88–92.
Gottlieb PA, Alkanani A. Michels AW α1-Antitrypsin therapy downregulates toll-like receptor-induced IL-1β responses in monocytes and myeloid dendritic cells and may improve islet function in recently diagnosed patients with type 1 diabetes. J Clin Endocrinol Metab. 2014;99:E1418–26.
Clinicaltrials.gov, Study of the Safety and Efficacy of Intravenous Alpha-1 Antitrypsin in Type 1 Diabetes Mellitus. Last updated June 9, 2016. https://clinicaltrials.gov/ct2/show/NCT01304537. Accessed 20 Mar 2018.
Clinicaltrials.gov, The Effects of Alpha-1 Antitrypsin (AAT) on the Progression of Type 1 Diabetes. Last updated March 24, 2017. https://clinicaltrials.gov/ct2/show/NCT01319331. Accessed 20 Mar 2018.
Louvet C, Szot G, Lang J, Lee MR, Martinier N, Bollag G, Zhu S, Weiss A, Bluestone JA. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci USA. 2008;105(48):18895–900.
Clinicaltrials.gov, Imatinib Treatment in Recent Onset Type 1 Diabetes Mellitus. Last updated June 21, 2017. https://clinicaltrials.gov/ct2/show/NCT01781975. Accessed 20 Mar 2018.
Gitelman S. Imatinib (Gleevec) in New-Onset Type 1 Diabetes—Background and Results. Diabetes, 2017. 66 (suppl 1). https://professional.diabetes.org/webcast/imatinib-gleevec-new-onset-type-1-diabetes%E2%80%94background-and-results. Accessed 23 Mar 2018.
Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, Brough HA, Phippard D, Basting M, Feeney M, Turcanu V, Sever ML, Gomez Lorenzo M, Plaut M, Lack G, LEAP Study Team. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372(9):803–13.
Pescovitz MD, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med. 2009;361(22):2143–52.
Ostrov DA, Alkanani A, McDaniel KA, Case S, Baschal EE, Pyle L, Ellis S, Pöllinger B, Seidl KJ, Shah VN, Garg SK, Atkinson MA, Gottlieb PA, Michels AW. Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes. J Clin Invest. 2018;128(5):1888–902.
Clinicaltrials.gov, Effect of Methyldopa on MHC Class II Antigen Presentation in Type 1 Diabetes. Last updated April 6, 2016. https://clinicaltrials.gov/ct2/show/NCT01883804. Accessed 23 Mar 2018.
Clinicaltrials.gov, Methyldopa for Reduction of DQ8 Antigen Presentation in At-Risk Subjects for Type 1 Diabetes. Last updated March 2, 2018. https://clinicaltrials.gov/ct2/show/NCT03396484. Accessed 20 Mar 2018.
Orban T, 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):412–9.
Clinicaltrials.gov. CTLA4-Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At -Risk for Type 1; NCT01773707. 2017.
Herold KC, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346(22):1692–8.
Herold KC, 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):3766–74.
Clinicaltrials.gov. Teplizumab for prevention of type 1 diabetes in relatives "at-risk". https://clinicaltrials.gov/ct2/show/NCT01030861?term=teplizumab&cond=type+1+diabetes&rank=5. Last updated 9 July 2018, Accessed 26 Dec 2018.
Rigby MR, 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):284–94.
Rigby MR, et al. Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. J Clin Invest. 2015;125(8):3285–96.
Haller MJ, et al. Anti-thymocyte globulin/G-CSF treatment preserves beta cell function in patients with established type 1 diabetes. J Clin Invest. 2015;125(1):448–55.
Haller MJ, et al. Low-Dose Anti-Thymocyte Globulin (ATG) Preserves beta-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes. Diabetes Care. 2018;41(9):1917–25.
Long SA, et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes. 2012;61(9):2340–8.
Clinicaltrials.gov, Low-dose rhIL-2 in Patients With Recently-diagnosed Type 1 Diabetes (DIABIL-2). Last updated Nov 9, 2016. https://clinicaltrials.gov/ct2/show/NCT02411253. Accessed 20 Mar 2016.
Bluestone J, Buckner J, Fitch M, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015;7(315):315ra189.
clinicaltrials.gov, T1DM Immunotherapy Using CD4 + CD127lo/-CD25 + Polyclonal Tregs (Treg). Last updated May 20, 2016. https://clinicaltrials.gov/ct2/show/NCT01210664. Accessed 20 Mar 2018.
Clinicaltrials.gov, T1DM Immunotherapy Using Polyclonal Tregs + IL-2 (TILT), in. In: ClinicalTrialsgov [Internet] Bethesda (MD): National Library of Medicine (US) 2000- [cited 2017 April 13]. http://clinicaltrials.gov/show/NCT02772679NLM Identifier: NCT02772679.
Libman IM, Miller K, DiMeglio LA, et al. Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes: a randomized clinical trial. JAMA. 2015;314(21):2241–50.
Clinicaltrials.gov, Autoimmune Diabetes Accelerator Prevention Trial. Last updated Aug 29, 2016. https://clinicaltrials.gov/ct2/show/NCT02881528. Accessed 20 Mar 2018.
Kielgast U, Asmar M, Madsbad S, Holst JJ. Effect of glucagon-like peptide-1 on alpha- and beta-cell function in C-peptide-negative type 1 diabetic patients. J Clin Endocrinol Metab. 2010;95(5):2492–6.
Htike Z, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ, et al. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017;19(4):524–36.
Zhang J, Tokui Y, Yamagata K, Kozawa J, Sayama K, Iwahashi H, Okita K, Miuchi M, Konya H, Hamaguchi T, Namba M, Shimomura I, Miyagawa JI. Continuous stimulation of human glucagon-like peptide-1 (7-36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes. Diabetologia. 2007;50(9):1900–9.
Rother KI, et al. Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes. Diabetes Care. 2009;32(12):2251–7.
Clinicaltrials.gov, Liraglutide Effect on Beta-cell Function in C-peptide Positive Type 1 Diabetes. Last updated Oct 27, 2017. https://clinicaltrials.gov/ct2/show/NCT02617654. Accessed 20 Mar 2018.
Clinicaltrials.gov, A Clinical Proof-of-principle Trial in Adult Subjects With Newly Diagnosed Type 1 Diabetes Mellitus Investigating the Effect of NNC0114-0006 and Liraglutide on Preservation of Beta-cell Function. Last updated March 9, 2018. https://clinicaltrials.gov/ct2/show/NCT02443155. Accessed 20 Mar 2018.
Clinicaltrials.gov, Incretin-based Therapy in Early Diagnosed Type 1 Diabetes. Last updated Oct 26, 2017. https://clinicaltrials.gov/ct2/show/NCT02908087. Accessed 20 Mar 2018.
Clinicaltrials.gov, Incretin-based Therapy in Late Preclinical Type 1 Diabetes. Last updated Oct 26, 2017. https://clinicaltrials.gov/ct2/show/NCT02898506. Accessed 20 Mar 2018.
Clinicaltrials.gov, Incretin-based Therapy in Preclinical Type 1 Diabetes in Adults. Last updated Oct 26, 2017. https://clinicaltrials.gov/ct2/show/NCT02611232. Accessed 20 Mar 2018.
Rooman I, Lardon J, Bouwens L. Gastrin stimulates β-cell neogenesis and increases islet mass from transdifferentiated but not from normal exocrine pancreas tissue. Diabetes. 2002;51:686–90.
Inci F, Atmaca M, Ozturk M, et al. Pantoprazole may improve beta cell function and diabetes mellitus. J Endocrinol Invest. 2014;37(5):449–54.
Han N, Oh M, Park SM, et al. The effect of proton pump inhibitors on glycated hemoglobin levels in patients with type 2 diabetes mellitus. Can J Diabetes. 2015;39(1):24–8.
Hove KD, Brons C, Færch K, et al. Effects of 12 weeks’ treatment with a proton pump inhibitor on insulin secretion, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind prospective placebo-controlled study. Diabetologia. 2013;56(1):22–30.
Wasko MC, McClure CK, Kelsey SF, et al. Antidiabetogenic effects of hydroxychloroquine on insulin sensitivity and beta cell function: a randomised trial. Diabetologia. 2015;58(10):2336–43.
Clinicaltrials.gov, Hydroxychloroquine in Individuals At-risk for Type 1 Diabetes Mellitus. Last updated Feb 12, 2018. https://clinicaltrials.gov/ct2/show/NCT03428945. Accessed 20 Mar 2018.
Nathan DM, Bayless M, Cleary P, for the DCCT/EDIC Research Group, et al. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: advances and contributions. Diabetes. 2013;62:3976–86.
Lachin JM, Genuth S, Cleary P, Nathan DM, for the EDIC Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342:381–9.
Group ER. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA. 2003;290:2159–67.
Knip M, et al. Hydrolyzed infant formula and early beta-cell autoimmunity: a randomized clinical trial. JAMA. 2014;311(22):2279–87.
Knip M, Writing group for teh TRIGR Study Group. Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes. JAMA. 2018;319(1):38–48.
Norris JM, et al. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA. 2003;290(13):1713–20.
Hummel S, Pfluger M, Hummel M. 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):1302–5.
Gale EA, et al. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet. 2004;363(9413):925–31.
Gibson V, Nikolic T, Pearce V, et al. Proinsulin multi-peptide immunotherapy induces antigen-specific regulatory T cells and limits autoimmunity in a humanized model. Clin Exp Immunol. 2015;182(3):251–60.
Ludvigsson J, et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med. 2012;366(5):433–42.
Wherrett DK, 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):319–27.
Ali MA, Liu Y, Arif S, et al. Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes. Sci Transl Med. 2017;9(402):eaaf7779.
Nanto-Salonen K, 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):1746–55.
Group, D.P.T.S. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med. 2002;346(22):1685–91.
Skyler JS, Krischer J, 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):1068–76.
Skyler J. Update on worldwide efforts to prevent type 1 diabetes. Ann N Y Acad Sci. 2008;1150:190.
Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study, G., et al. 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.
Bonifacio E, 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):1541–9.
Clinicaltrials.gov, Pre-POINT-Early Study: NCT02547519.
Clinicaltrials.gov, Immune Effects of Oral Insulin in Relatives at Risk for Type 1 Diabetes Mellitus. In: ClinicalTrialsgov [Internet] Bethesda (MD): National Library of Medicine (US) 2000- [cited 2018 Nov 26] http://clinicaltrials.gov/show/NCT02580877NLM Identifier: NCT02580877.
Clinicaltrials.gov, Trial of Intranasal Insulin in Children and Young Adults at Risk of Type 1 Diabetes. Last updated Oct 7, 2016. https://clinicaltrials.gov/ct2/show/NCT00336674. Accessed 20 Mar 2018.
Clinicaltrials.gov, Prevention Trial: Immune-tolerance With Alum-GAD (Diamyd) and Vitamin D3 to Children With Multiple Islet Autoantibodies. Last updated August 24, 2017. https://clinicaltrials.gov/ct2/show/NCT02387164. Accessed 20 Mar 2018.
No sources of funding were used to conduct this study or prepare this manuscript.
Conflict of interest
Carla Greenbaum has received personal fees from Lilly, Bristol-Myers Squibb, and Pfizer and grants and personal fees from NovoNordisk and Janssen. Sandra Lord and Dana VanBuecken declare that they have no conflict of interest.
Human and animal rights and informed consent
All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).
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Greenbaum, C., VanBuecken, D. & Lord, S. Disease-Modifying Therapies in Type 1 Diabetes: A Look into the Future of Diabetes Practice. Drugs 79, 43–61 (2019). https://doi.org/10.1007/s40265-018-1035-y