Skip to main content
main-content
Top

08-02-2017 | Diabetes prevention | Review | Article

Understanding and preventing type 1 diabetes through the unique working model of TrialNet

Journal: Diabetologia

Authors: Manuela Battaglia, Mark S. Anderson, Jane H. Buckner, Susan M. Geyer, Peter A. Gottlieb, Thomas W. H. Kay, Åke Lernmark, Sarah Muller, Alberto Pugliese, Bart O. Roep, Carla J. Greenbaum, Mark Peakman

Publisher: Springer Berlin Heidelberg

share
SHARE

Abstract

Type 1 diabetes is an autoimmune disease arising from the destruction of pancreatic insulin-producing beta cells. The disease represents a continuum, progressing sequentially at variable rates through identifiable stages prior to the onset of symptoms, through diagnosis and into the critical periods that follow, culminating in a variable depth of beta cell depletion. The ability to identify the very earliest of these presymptomatic stages has provided a setting in which prevention strategies can be trialled, as well as furnishing an unprecedented opportunity to study disease evolution, including intrinsic and extrinsic initiators and drivers. This niche opportunity is occupied by Type 1 Diabetes TrialNet, an international consortium of clinical trial centres that leads the field in intervention and prevention studies, accompanied by deep longitudinal bio-sampling. In this review, we focus on discoveries arising from this unique bioresource, comprising more than 70,000 samples, and outline the processes and science that have led to new biomarkers and mechanistic insights, as well as identifying new challenges and opportunities. We conclude that via integration of clinical trials and mechanistic studies, drawing in clinicians and scientists and developing partnership with industry, TrialNet embodies an enviable and unique working model for understanding a disease that to date has no cure and for designing new therapeutic approaches.
Literature
1.
Chiang JL, Kirkman MS, Laffel LM, Peters AL (2014) Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Diabetes Care 37:2034–2054 CrossRefPubMed
2.
Bottazzo GF, Florin-Christensen A, Doniach D (1974) Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 2:1279–1283 CrossRefPubMed
3.
Atkinson MA, Eisenbarth GS, Michels AW (2014) Type 1 diabetes. Lancet 383:69–82 CrossRefPubMed
4.
Vehik K, Beam CA, Mahon JL et al (2011) Development of autoantibodies in the TrialNet Natural History Study. Diabetes Care 34:1897–1901 CrossRefPubMedPubMedCentral
5.
Insel RA, Dunne JL, Atkinson MA et al (2015) Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 38:1964–1974 CrossRefPubMedPubMedCentral
6.
Skyler JS, Greenbaum CJ, Lachin JM et al (2008) Type 1 Diabetes TrialNet—an international collaborative clinical trials network. Ann N Y Acad Sci 1150:14–24 CrossRefPubMedPubMedCentral
7.
Nokoff N, Rewers M (2013) Pathogenesis of type 1 diabetes: lessons from natural history studies of high-risk individuals. Ann N Y Acad Sci 1281:1–15 CrossRefPubMedPubMedCentral
8.
Battaglia M, Atkinson MA (2015) The streetlight effect in type 1 diabetes. Diabetes 64:1081–1090 CrossRefPubMedPubMedCentral
9.
Davis AK, DuBose SN, Haller MJ et al (2015) Prevalence of detectable C-peptide according to age at diagnosis and duration of type 1 diabetes. Diabetes Care 38:476–481 CrossRefPubMed
10.
Atkinson MA, von Herrath M, Powers AC, Clare-Salzler M (2015) Current concepts on the pathogenesis of type 1 diabetes--considerations for attempts to prevent and reverse the disease. Diabetes Care 38:979–988 CrossRefPubMedPubMedCentral
11.
Stokes JR, Casale TB (2016) Characterization of asthma endotypes: implications for therapy. Ann Allergy Asthma Immunol 117:121–125 CrossRefPubMed
12.
Arif S, Leete P, Nguyen V et al (2014) Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes. Diabetes 63:3835–3845 CrossRefPubMedPubMedCentral
13.
Akirav EM, Lebastchi J, Galvan EM et al (2011) Detection of beta cell death in diabetes using differentially methylated circulating DNA. Proc Natl Acad Sci U S A 108:19018–19023 CrossRefPubMedPubMedCentral
14.
Herold KC, Usmani-Brown S, Ghazi T et al (2015) Beta cell death and dysfunction during type 1 diabetes development in at-risk individuals. J Clin Invest 125:1163–1173 CrossRefPubMedPubMedCentral
15.
Mirmira RG, Sims EK, Syed F, Evans-Molina C (2016) Biomarkers of beta-cell stress and death in type 1 diabetes. Curr Diab Rep 16:95 CrossRefPubMed
16.
Marre ML, James EA, Piganelli JD (2015) β cell ER stress and the implications for immunogenicity in type 1 diabetes. Front Cell Dev Biol 3:67 CrossRefPubMedPubMedCentral
17.
Evans-Molina C, Hatanaka M, Mirmira RG (2013) Lost in translation: endoplasmic reticulum stress and the decline of β-cell health in diabetes mellitus. Diabetes Obes Metab 15(Suppl 3):159–169 CrossRefPubMedPubMedCentral
18.
Sims EK, Chaudhry Z, Watkins R et al (2016) Elevations in the fasting serum proinsulin-to-C-peptide ratio precede the onset of type 1 diabetes. Diabetes Care 39:1519–1526 CrossRefPubMedPubMedCentral
19.
Rodriguez-Calvo T, Zapardiel-Gonzalo J, Amirian N et al (2017) Increase in pancreatic proinsulin and preservation of beta cell mass in autoantibody positive donors prior to type 1 diabetes onset. Diabetes 66:1334–1345 CrossRefPubMed
20.
Snowhite IV, Allende G, Sosenko J, Pastori RL, Messinger Cayetano S, Pugliese A (2017) Association of serum microRNAs with islet autoimmunity, disease progression and metabolic impairment in relatives at risk of type 1 diabetes. Diabetologia doi: 10.​1007/​s00125-017-4294-3
21.
Orban T, Bundy B, Becker DJ et al (2014) Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment. Diabetes Care 37:1069–1075 CrossRefPubMedPubMedCentral
22.
Orban T, Beam CA, Xu P et al (2014) 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 63:3449–3457 CrossRefPubMedPubMedCentral
23.
Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H et al (2009) Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 361:2143–2152 CrossRefPubMed
24.
Pescovitz MD, Greenbaum CJ, Bundy B et al (2014) B-lymphocyte depletion with rituximab and β-cell function: two-year results. Diabetes Care 37:453–459 CrossRefPubMedPubMedCentral
25.
Chamberlain N, Massad C, Oe T, Cantaert T, Herold KC, Meffre E (2016) Rituximab does not reset defective early B cell tolerance checkpoints. J Clin Invest 126:282–287 CrossRefPubMed
26.
Smith MJ, Packard TA, O’Neill SK et al (2015) Loss of anergic B cells in prediabetic and new-onset type 1 diabetic patients. Diabetes 64:1703–1712 CrossRefPubMed
27.
Valle A, Giamporcaro GM, Scavini M et al (2013) Reduction of circulating neutrophils precedes and accompanies type 1 diabetes. Diabetes 62:2072–2077 CrossRefPubMedPubMedCentral
28.
Bollyky JB, Xu P, Butte AJ, Wilson DM, Beam CA, Greenbaum CJ (2015) Heterogeneity in recent-onset type 1 diabetes—a clinical trial perspective. Diabetes Metab Res Rev 31:588–594 CrossRefPubMedPubMedCentral
29.
Cabrera SM, Chen YG, Hagopian WA, Hessner MJ (2016) Blood-based signatures in type 1 diabetes. Diabetologia 59:414–425 CrossRefPubMed
30.
Chen YG, Cabrera SM, Jia S et al (2014) Molecular signatures differentiate immune states in type 1 diabetic families. Diabetes 63:3960–3973 CrossRefPubMedPubMedCentral

New additions to the Adis Journal Club

A selection of topical peer-reviewed articles from the Adis journals, curated by the editors.

ADA 2022 coverage

Access the latest news and expert insight from the ADA 82nd Scientific Sessions