, have been highlighted as: ? Of importance ?? Of major importance 1, Oram RA. Type 1 diabetes. Lancet, vol.391, pp.2449-62, 2018.

D. E. Stanescu, K. Lord, and T. H. Lipman, The epidemiology of type 1 diabetes in children, Endocrinol Metab Clin N Am, vol.41, issue.4, pp.679-94, 2012.

D. M. Maahs, N. A. West, J. M. Lawrence, and M. Ej, Epidemiology of type 1 diabetes, Endocrinol Metab Clin N Am, vol.39, issue.3, pp.481-97, 2010.

E. J. Mayer-davis, J. M. Lawrence, D. Dabelea, J. Divers, S. Isom et al., Incidence trends of type 1 and type 2 diabetes among youths, N Engl J Med, vol.376, issue.15, pp.1419-1448, 2002.

A. Chobot, J. Polanska, A. Brandt, G. Deja, B. Glowinska-olszewska et al., Updated 24-year trend of type 1 diabetes incidence in children in Poland reveals a sinusoidal pattern and sustained increase, Diabet Med, vol.34, issue.9, pp.1252-1260, 2017.

T. H. Lipman, L. Katz, L. E. Ratcliffe, S. J. Murphy, K. M. Aguilar et al., Increasing incidence of type 1 diabetes in youth: twenty years of the Philadelphia pediatric diabetes registry, Diabetes Care, vol.36, issue.6, pp.1597-603, 2013.

A. G. Ziegler, E. Bonifacio, and B. Group, Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes, Diabetologia, vol.55, issue.7, pp.1937-1980, 2012.

J. P. Krischer, K. F. Lynch, A. Lernmark, W. A. Hagopian, M. J. Rewers et al., Genetic and environmental interactions modify the risk of diabetes-related autoimmunity by 6 years of age: the TEDDY study, Diabetes Care, vol.40, issue.9, pp.1194-202, 2017.

J. P. Krischer, X. Liu, A. Lernmark, W. A. Hagopian, M. J. Rewers 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, vol.66, issue.12, pp.3122-3131, 2017.

J. Ilonen, A. Hammais, A. P. Laine, J. Lempainen, O. Vaarala et al., Patterns of beta-cell autoantibody appearance and genetic associations during the first years of life, Diabetes, vol.62, issue.10, pp.3636-3676, 2013.

M. Battaglia, M. S. Anderson, J. H. Buckner, S. M. Geyer, P. A. Gottlieb et al., Understanding and preventing type 1 diabetes through the unique working model of TrialNet, Diabetologia, vol.60, issue.11, pp.2139-2186, 2017.

C. J. Greenbaum, C. Speake, J. Krischer, J. Buckner, P. A. Gottlieb et al., Strength in numbers: opportunities for enhancing the development of effective treatments for type 1 diabetes-the TrialNet experience, Diabetes, vol.67, issue.7, pp.1216-1241, 2018.

J. L. Mahon, J. M. Sosenko, L. Rafkin-mervis, H. Krause-steinrauf, J. M. Lachin et al., The TrialNet natural history study of the development of type 1 diabetes: objectives, design, and initial results, Pediatr Diabetes, vol.10, issue.2, pp.97-104, 2009.

G. Krischer, J. P. Schatz, D. A. Bundy, B. Skyler, J. S. Greenbaum et al., Effect of oral insulin on prevention of diabetes in relatives of patients with type 1 diabetes: a randomized clinical trial, JAMA, vol.318, pp.1891-902, 2017.

J. M. Sosenko, J. P. Palmer, L. Rafkin-mervis, J. P. Krischer, D. Cuthbertson et al., Incident dysglycemia and progression to type 1 diabetes among participants in the diabetes prevention trial-type 1, Diabetes Care, vol.32, issue.9, pp.1603-1610, 2009.

D. K. Wherrett, J. L. Chiang, A. M. Delamater, L. A. Dimeglio, S. E. Gitelman et al., Defining pathways for development of disease-modifying therapies in children with type 1 diabetes: a consensus report, Diabetes Care, vol.38, issue.10, pp.1975-85, 2015.

J. M. Sosenko, J. S. Skyler, J. Mahon, J. P. Krischer, C. A. Beam et al., Validation of the diabetes prevention trial-type 1 risk score in the TrialNet natural history study, Diabetes Care, vol.34, issue.8, pp.1785-1792, 2011.

J. M. Sosenko, J. S. Skyler, J. Mahon, J. P. Krischer, C. A. Beam et al., The application of the diabetes prevention trial-type 1 risk score for identifying a preclinical state of type 1 diabetes, Diabetes Care, vol.35, issue.7, pp.1552-1557, 2012.

J. M. Sosenko, J. P. Palmer, L. E. Rafkin, J. P. Krischer, D. Cuthbertson et al., Trends of earlier and later responses of Cpeptide to oral glucose challenges with progression to type 1 diabetes in diabetes prevention trial-type 1 participants, Diabetes Care, vol.33, issue.3, pp.620-625, 2010.

J. M. Sosenko, J. P. Palmer, C. J. Greenbaum, J. Mahon, C. Cowie et al., Patterns of metabolic progression to type 1 diabetes in the diabetes prevention trial-type 1, Diabetes Care, vol.29, issue.3, pp.643-652, 2006.

C. Evans-molina, E. K. Sims, L. A. Dimeglio, H. M. Ismail, A. K. Steck et al., ? cell dysfunction exists more than 5 years before type 1 diabetes diagnosis, JCI Insight, vol.3, issue.15, p.120877, 2018.

O. Snorgaard, L. H. Lassen, and C. Binder, Homogeneity in pattern of decline of beta-cell function in IDDM. Prospective study of 204 consecutive cases followed for 7.4 yr, Diabetes Care, vol.15, issue.8, pp.1009-1022, 1992.

J. M. Sosenko, S. Geyer, J. S. Skyler, L. E. Rafkin, H. M. Ismail et al., The influence of body mass index and age on C-peptide at the diagnosis of type 1 diabetes in children who participated in the diabetes prevention trial-type 1, Pediatr Diabetes, vol.19, issue.3, pp.403-412, 2018.

C. Steele, W. A. Hagopian, S. Gitelman, U. Masharani, M. Cavaghan et al., Insulin secretion in type 1 diabetes, Diabetes, vol.53, issue.2, pp.426-459, 2004.

M. Rodacki, J. R. Pereira, N. Oliveira, A. M. Barone, B. et al., Ethnicity and young age influence the frequency of diabetic ketoacidosis at the onset of type 1 diabetes, Diabetes Res Clin Pract, vol.78, issue.2, pp.259-62, 2007.

A. Hekkala, A. Reunanen, M. Koski, M. Knip, and R. Veijola, Finnish pediatric diabetes R. Age-related differences in the frequency of ketoacidosis at diagnosis of type 1 diabetes in children and adolescents, Diabetes Care, vol.33, issue.7, pp.1500-1502, 2010.

A. Dost, A. Herbst, K. Kintzel, H. Haberland, C. L. Roth et al., Shorter remission period in young versus older children with diabetes mellitus type 1, Exp Clin Endocrinol Diabetes, vol.115, issue.1, pp.33-40, 2007.

M. J. Redondo, L. M. Rodriguez, M. Escalante, O. Smith, E. Balasubramanyam et al., Beta cell function and BMI in ethnically diverse children with newly diagnosed autoimmune type 1 diabetes, Pediatr Diabetes, vol.13, issue.7, pp.564-71, 2012.

C. J. Greenbaum, C. A. Beam, D. Boulware, S. E. Gitelman, P. A. Gottlieb 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, vol.61, issue.8, pp.2066-73, 2012.

W. Hao, S. Gitelman, L. A. Dimeglio, D. Boulware, and C. J. Greenbaum, Type 1 diabetes TrialNet study G. Fall in C-peptide during first 4 years from diagnosis of type 1 diabetes: variable relation to age, HbA1c, and insulin dose, Diabetes Care, vol.39, issue.10, pp.1664-70, 2016.

B. M. Shields, T. J. Mcdonald, R. Oram, A. Hill, M. Hudson et al., C-peptide decline in type 1 diabetes has two phases: an initial exponential fall and a subsequent stable phase, Diabetes Care, vol.41, issue.7, pp.1486-92, 2018.

M. Wallensteen, G. Dahlquist, B. Persson, M. Landin-olsson, A. Lernmark et al., Factors influencing the magnitude, duration, and rate of fall of B-cell function in type 1 (insulindependent) diabetic children followed for two years from their clinical diagnosis, Diabetologia, vol.31, issue.9, pp.664-673, 1988.

A. K. Foulis, C. N. Liddle, M. A. Farquharson, J. A. Richmond, and R. S. Weir, The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom, Diabetologia, vol.29, issue.5, pp.267-74, 1986.

M. Campbell-thompson, C. Wasserfall, J. Kaddis, A. Neill, A. Staeva et al., Network for pancreatic organ donors with diabetes (nPOD): developing a tissue biobank for type 1 diabetes, Diabetes Metab Res Rev, vol.28, issue.7, pp.608-625, 2012.

L. Krogvold, B. Edwin, T. Buanes, J. Ludvigsson, O. Korsgren et al., Pancreatic biopsy by minimal tail resection in live adult patients at the onset of type 1 diabetes: experiences from the DiViD study, Diabetologia, vol.57, issue.4, pp.841-844, 2014.

Y. Saisho, A. E. Butler, E. Manesso, D. Elashoff, R. A. Rizza et al., Beta-cell mass and turnover in humans: effects of obesity and aging, Diabetes Care, vol.36, issue.1, pp.111-118, 2013.

J. J. Meier, A. E. Butler, Y. Saisho, T. Monchamp, R. Galasso et al., Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans, Diabetes, vol.57, issue.6, pp.1584-94, 2008.

C. J. Lam, D. R. Jacobson, M. M. Rankin, A. R. Cox, and J. A. Kushner, This study examines the persistence of pancreatic ? cells in donors with longstanding Type 1 diabetes donors from the nPOD collection and suggests that this is not due to ? cell regeneration, J Clin Endocrinol Metab, vol.102, issue.8, pp.2647-59, 2017.

B. E. Gregg, P. C. Moore, D. Demozay, B. A. Hall, M. Li et al., Formation of a human beta-cell population within pancreatic islets is set early in life, J Clin Endocrinol Metab, vol.97, issue.9, pp.3197-206, 2012.

D. A. Striegel, M. Hara, and V. Periwal, Adaptation of pancreatic islet cytoarchitecture during development, Phys Biol, vol.13, issue.2, p.25004, 2016.

O. Cabrera, D. M. Berman, N. S. Kenyon, C. Ricordi, P. O. Berggren et al., The unique cytoarchitecture of human pancreatic islets has implications for islet cell function, Proc Natl Acad Sci, vol.103, issue.7, pp.2334-2343, 2006.

G. Kilimnik, J. J. Periwal, V. Zielinski, M. C. Hara, and M. , Quantification of islet size and architecture, Islets, vol.4, issue.2, pp.167-72, 2012.

, Insulitis in human type 1 diabetes: the quest for an elusive lesion, Islets, vol.3, issue.4, pp.131-139, 2011.

M. Campbell-thompson, A. Fu, J. S. Kaddis, C. Wasserfall, D. A. Schatz et al., Insulitis and beta-cell mass in the natural history of type 1 diabetes, Diabetes, vol.65, issue.3, pp.719-750, 2016.

S. Arif, P. Leete, V. Nguyen, K. Marks, N. M. Nor et al., Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes, Diabetes, vol.63, issue.11, pp.3835-3880, 2014.

?. ?-leete, P. Willcox, A. Krogvold, L. Dahl-jørgensen, K. Foulis et al., This study demonstrates that age of onset of Type 1 diabetes (in recent-onset cases) is associated with different insulitic islet immune cell profiles and extent of pancreatic ?-cell destruction, Diabetes, vol.65, issue.6, pp.1362-1371, 2016.

. Klinke, Extent of beta cell destruction is important but insufficient to predict the onset of type 1 diabetes mellitus, PLoS One, vol.3, issue.1, p.1374, 2008.

H. A. Keenan, J. K. Sun, J. Levine, A. Doria, L. P. Aiello et al., Residual insulin production and pancreatic beta-cell turnover after 50 years of diabetes: Joslin medalist study, Diabetes, vol.59, issue.11, pp.2846-53, 2010.

L. Krogvold, O. Skog, G. Sundstrom, B. Edwin, T. Buanes 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 non-diabetogenic environment in vitro. Results from the DiViD study, Diabetes, vol.64, issue.7, pp.2506-2518, 2015.

A. Willcox, S. J. Richardson, A. J. Bone, A. K. Foulis, and N. G. Morgan, Analysis of islet inflammation in human type 1 diabetes, Clin Exp Immunol, vol.155, issue.2, pp.173-81, 2009.

M. L. Campbell-thompson, M. A. Atkinson, A. E. Butler, N. M. Chapman, G. Frisk et al., The diagnosis of insulitis in human type 1 diabetes, Diabetologia, vol.56, issue.11, pp.2541-2544, 2013.

M. L. Campbell-thompson, M. A. Atkinson, A. E. Butler, B. N. Giepmans, V. Herrath et al., Re-addressing the 2013 consensus guidelines for the diagnosis of insulitis in human type 1 diabetes: is change necessary?, Diabetologia, vol.60, issue.4, pp.753-758, 2017.

?. Culina, S. Lalanne, A. I. Afonso, G. Cerosaletti, K. Pinto et al., ):eaao4013. This paper proposes that a universal state of 'benign' autoimmunity is present in all individuals. The key difference between the islet-reactive CD8+ T cells of T1D and healthy donors is not in their circulating frequency or history of antigen encounter, Sci Immunol, vol.3, issue.20, 2018.

S. Gonzalez-duque, M. E. Azoury, M. L. Colli, G. Afonso, J. V. Turatsinze et al., Conventional and neo-antigenic peptides presented by beta cells are targeted by circulating naïve CD8+ T cells in type 1 diabetic and healthy donors, Cell Metab, 2018.

S. Arif, T. I. Tree, T. P. Astill, J. M. Tremble, A. J. Bishop et al.,

, Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health, J Clin Invest, vol.113, issue.3, pp.451-63, 2004.

T. M. Brusko, C. H. Wasserfall, C. -. Salzler, M. J. Schatz, D. A. Atkinson et al., Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes, Diabetes, vol.54, issue.5, pp.1407-1421, 2005.

F. P. Legoux, J. B. Lim, A. W. Cauley, S. Dikiy, J. Ertelt et al., CD4+ T cell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion, Immunity, vol.43, issue.5, pp.896-908, 2015.

D. Malhotra, J. L. Linehan, T. Dileepan, Y. J. Lee, W. E. Purtha et al., Tolerance is established in polyclonal CD4(+) T cells by distinct mechanisms, according to self-peptide expression patterns, Nat Immunol, vol.17, issue.2, pp.187-95, 2016.

E. K. Sims, Z. Chaudhry, R. Watkins, F. Syed, J. Blum et al., Elevations in the fasting serum Proinsulin-to-C-peptide ratio precede the onset of type 1 diabetes, Diabetes Care, vol.39, issue.9, pp.1519-1545, 2016.

D. Fava, S. Gardner, D. Pyke, and R. D. Leslie, Evidence that the age at diagnosis of IDDM is genetically determined, Diabetes Care, vol.21, issue.6, pp.925-934, 1998.

M. J. Redondo, L. Yu, M. Hawa, T. Mackenzie, D. A. Pyke et al., Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States, Diabetologia, vol.44, issue.3, pp.354-62, 2001.

J. M. Howson, J. D. Cooper, D. J. Smyth, N. M. Walker, H. Stevens et al., Evidence of gene-gene interaction and age-at-diagnosis effects in type 1 diabetes, Diabetes, vol.61, issue.11, pp.3012-3019, 2012.

?. Inshaw, J. Walker, N. M. Wallace, C. Bottolo, L. Todd et al., The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age, Diabetologia, vol.61, issue.1, pp.147-57, 2018.

F. Cerutti, G. Bruno, F. Chiarelli, R. Lorini, F. Meschi et al., Younger age at onset and sex predict celiac disease in children and adolescents with type 1 diabetes: an Italian multicenter study, Diabetes Care, vol.27, issue.6, pp.1294-1302, 2004.
DOI : 10.2337/diacare.27.6.1294

URL : http://care.diabetesjournals.org/content/27/6/1294.full.pdf

J. M. Howson, S. Rosinger, D. J. Smyth, B. O. Boehm, A. Group et al., Genetic analysis of adult-onset autoimmune diabetes, Diabetes, vol.60, issue.10, pp.2645-53, 2011.

B. I. Frohnert, L. Ide, F. Dong, A. E. Baron, A. K. Steck et al., Late-onset islet autoimmunity in childhood: the diabetes autoimmunity study in the young (DAISY), Diabetologia, vol.60, issue.6, pp.998-1006, 2017.

R. Mishra, A. Chesi, D. L. Cousminer, M. I. Hawa, J. P. Bradfield et al., Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes, BMC Med, vol.15, issue.1, p.88, 2017.

M. J. Redondo, R. A. Oram, and A. K. Steck, Genetic risk scores for type 1 diabetes prediction and diagnosis, Curr Diab Rep, vol.17, issue.12, p.129, 2017.
DOI : 10.1007/s11892-017-0961-5

M. J. Redondo, S. Geyer, A. K. Steck, S. Sharp, J. M. Wentworth 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, vol.41, issue.9, pp.1887-94, 2018.

M. J. Redondo, S. F. Grant, A. Davis, C. Greenbaum, and T. Biobank, Dissecting heterogeneity in paediatric type 1 diabetes: association of TCF7L2 rs7903146 TT and low-risk human leukocyte antigen (HLA) genotypes, Diabet Med, vol.34, issue.2, pp.286-90, 2016.

M. J. Redondo, J. Muniz, L. M. Rodriguez, D. Iyer, F. Vaziri-sani et al., Association of TCF7L2 variation with single islet autoantibody expression in children with type 1 diabetes, BMJ Open Diabetes Res Care, vol.2, issue.1, p.8, 2014.

M. J. Redondo, S. Geyer, A. K. Steck, J. Sosenko, M. Anderson et al., TCF7L2 genetic variants contribute to phenotypic heterogeneity of type 1 diabetes, Diabetes Care, vol.41, issue.2, pp.311-318, 2018.
DOI : 10.2337/dc17-0961

URL : http://care.diabetesjournals.org/content/diacare/41/2/311.full.pdf

B. Keymeulen, M. Walter, C. Mathieu, L. Kaufman, F. Gorus et al., Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass, Diabetologia, vol.53, issue.4, pp.614-637, 2010.

W. Hagopian, R. J. Ferry, N. Sherry, D. Carlin, E. Bonvini et al., Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebocontrolled Protege trial, Diabetes, vol.62, issue.11, pp.3901-3909, 2013.
DOI : 10.2337/db13-0236

URL : http://diabetes.diabetesjournals.org/content/62/11/3901.full.pdf

M. R. Rigby, L. A. Dimeglio, M. S. Rendell, E. I. Felner, J. M. Dostou 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, vol.1, issue.4, pp.284-94, 2013.

M. R. Rigby, K. M. Harris, A. Pinckney, L. A. Dimeglio, M. S. Rendell et al., Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients, J Clin Invest, vol.125, issue.8, pp.3285-96, 2015.
DOI : 10.1172/jci81722

URL : http://www.jci.org/articles/view/81722/files/pdf

M. D. Pescovitz, C. J. Greenbaum, H. Krause-steinrauf, D. J. Becker, S. E. Gitelman et al., B-lymphocyte depletion, and preservation of beta-cell function, N Engl J Med, vol.361, issue.22, pp.2143-52, 2009.

T. Orban, B. Bundy, D. J. Becker, L. A. Dimeglio, S. E. Gitelman et al., Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebocontrolled trial, Lancet, vol.378, issue.9789, pp.412-421, 2011.
DOI : 10.1016/s0140-6736(11)60886-6

URL : http://europepmc.org/articles/pmc3462593?pdf=render