trating the islets.1The disease accounts for about 10% of all
cases of diabetes, occurs most commonly in people of Euro-
pean descent and affects 2 million people in Europe and
North America. There is a marked geographic variation in
incidence, with a child in Finland being about 400 times
more likely than a child in Venezuela to acquire the disease
(Fig. 1). The current global increase in incidence of 3% per
year is well reported,2and it is predicted that the incidence
of type 1 diabetes will be 40% higher in 2010 than in 1998.3
This rapid rise strongly suggests that the action of the envi-
ronment on susceptibility genes contributes to the evolving
epidemiology of type 1 diabetes.
Before safe and rational therapies can be offered in a clini-
cal setting, a detailed understanding of the immune-mediated
process that results in type 1 diabetes is required, as is the ac-
ype 1 diabetes is characterized by autoimmune de-
struction of insulin-producing β cells in the pancreas
by CD4+ and CD8+ T cells and macrophages infil-
curate identification of those at risk of the disease. The im-
munogenetics of type 1 diabetes has become the model upon
which other complex disorders are studied, and in this article
we review the importance of recent insights into the patho-
genesis and natural history of type 1 diabetes and consider
current therapeutic strategies.
Genes: How important are they?
Like other organ-specific autoimmune diseases, type 1 dia-
betes has human leukocyte antigen (HLA) associations, but
how well are they understood? The HLA on chromosome 6
was the first locus shown to be associated with the disease by
candidate gene studies4,5and is considered to contribute
about half of the familial basis of type 1 diabetes.6,7Two
combinations of HLA genes (or haplotypes) are of particular
importance: DR4-DQ8 and DR3-DQ2 are present in 90% of
children with type 1 diabetes.8A third haplotype, DR15-DQ6,
is found in less than 1% of children with type 1 diabetes,
compared with more than 20% of the general population,
and is considered to be protective.9The genotype combining
the 2 susceptibility haplotypes (DR4-DQ8/DR3-DQ2) con-
tributes the greatest risk of the disease and is most common
in children in whom the disease develops very early in life.10
First-degree relatives of these children are themselves at
greater risk of type 1 diabetes than are the relatives of chil-
dren in whom the disease develops later.11
Candidate gene studies also identified the insulin gene on
chromosome 11 as the second most important genetic sus-
ceptibility factor, contributing 10% of genetic susceptibility to
type 1 diabetes.12Shorter forms of a variable number tandem
repeat in the insulin promoter are associated with susceptibil-
ity to the disease, whereas longer forms are associated with
protection.13Demonstration of increased expression of in-
sulin (mRNA) in the thymus of people with “long” or protec-
tive repeats — which suggests more efficient deletion of in-
sulin-specific T cells during induction of central tolerance —
provides an attractive potential mechanism for the role of the
insulin gene in type 1 diabetes.14,15
Over the last decade, whole genome screens have indi-
cated that there are at least 15 other loci associated with type 1
diabetes,16–18and of those, another 2 genes intimately associ-
ated with T-cell activation have been identified recently. An al-
lele of the gene for a negative regulator of T-cell activation,
cytotoxic T lymphocyte antigen 4 (CTLA-4), found on chro-
mosmone 2q33, is considered to be the third susceptibility lo-
© 2006 CMA Media Inc. or its licensors
• July 18, 2006 • 175(2) | 165
Kathleen M. Gillespie
Type 1 diabetes: pathogenesis and prevention
Type 1 diabetes results from the autoimmune destruction of
insulin-producing β cells in the pancreas. Genetic and, as
yet undefined, environmental factors act together to precipi-
tate the disease. The excess mortality associated with the
complications of type 1 diabetes and the increasing inci-
dence of childhood type 1 diabetes emphasize the impor-
tance of therapeutic strategies to prevent this chronic dis-
order. Why is it considered that type 1 diabetes might be
preventable? Different strands of diabetes research are com-
ing together to suggest therapeutic targets. Islet cell auto-
antibody assays make it possible to accurately identify peo-
ple at risk of future disease. In most cases, a long prodrome
provides a window of opportunity to reverse the autoim-
mune process. Although no current “cure” exists, recent ge-
netic data and preliminary trial results suggest T cells as a
target for preventive strategies. Another potentially attain-
able target is induction of tolerance to the β-cell proteins
such as insulin that are inappropriately recognized. Other
strategies involve β-cell replacement, but currently there are
insufficient donor cells available. This may be overcome as
the processes controlling the differentiation of pancreatic
and nonpancreatic progenitors as well as replication of exist-
ing islet βcells are unravelled.
cus for type 1 diabetes and has been associated with increased
levels of soluble CTLA-419and the frequency of regulatory T
cells.20A variant of PTPN22, the gene encoding LYP, also a
suppressor of T-cell activation, has been deemed the fourth
susceptibility factor.21,22The observation that the 4 most im-
portant susceptibility genes for type 1 diabetes can all be rep-
resented on a single diagram of antigen presentation to T
cells (Fig. 2) emphasizes the potential importance of current
therapeutic strategies targeting this interaction. It is also
worth noting that the HLA, CTLA-4 and PTPN22 have all
been implicated in autoimmune thyroid disease and other au-
toimmune diseases,23which supports the premise that simi-
lar or overlapping biological pathways contribute to different
Genetic studies have highlighted the importance of large,
well-characterized populations in the identification of sus-
ceptibility genes for type 1 diabetes. Recruitment of increas-
ingly large populations of patients with type 1 diabetes and
their families is underway (www.t1dgc.org) to provide statis-
tically powerful cohorts in which to identify other disease-
associated genes. Some genes will have a relatively minor
individual impact on susceptibility to disease but could never-
theless provide more clues to future preventive therapies. The
genes for intercellular adhesion molecule (ICAM) and vitamin
D are candidates. Some epidemiologic observations support a
protective role for vitamin D in type 1 diabetes. Maternal in-
take of vitamin D in pregnancy and high doses of vitamin D
supplements early in life have been shown to protect against
islet autoimmunity in offspring,25,26whereas children with a
diagnosis of rickets in the first year of life have been found to
have a 3-fold increased risk of type 1 diabetes later in life.27
Further safety studies of vitamin D doses in pregnancy are re-
quired.28Genetic data on type 1 diabetes and vitamin D re-
main controversial.29,30The gene for ICAM-1, associated with
an increased risk of type 1 diabetes, may contribute to the
homing and activation of mononuclear cells in the islets dur-
ing infection and an early autoimmune response, although
confirmatory studies are required.31
Genetic and environmental interactions
Studies in most populations confirm an increase in the inci-
dence of type 1 diabetes, particularly among young children,
with the greatest increase occurring in the previously low-
incidence countries of eastern Europe. Some studies,32,33how-
ever, have shown convincingly that the increases among
young children are occurring because of a shift to lower age at
onset rather than an overall increase in incidence in all age
groups. These changes are too rapid to be caused by alter-
ations in the genetic background and are likely the result of
environmental changes. This is confirmed by recent experi-
ments showing that the increase in type 1 diabetes has been
accompanied by a concomitant widening of the HLA risk pro-
file, which suggests increased environmental pressure on sus-
Identification of such environmental factors has proved
frustratingly difficult. The most popular candidates are
viruses, with enteroviruses,36rotavirus37and rubella being
suspects. The strongest data to date have supported a role
for rubella. Infants infected with congenital rubella syn-
drome are said to be at increased risk of type 1 diabetes.38
Yet Finland, where vaccination has effectively eradicated
rubella, still has one of the highest incidences of type 1 dia-
betes.39There is also evidence that some enteroviruses
(e.g., Coxsackie B viruses) are less prevalent in countries
with high incidences of type 1 diabetes (e.g., Finland) than
in countries with low incidences but geographically similar
populations (e.g., Russian Karelia).40This observation may
be in keeping with the concept of the hygiene hypothe-
sis,41,42which proposes that environmental exposure to mi-
crobes, other pathogens and their products early in life
promotes innate immune responses that suppress atopy
and perhaps autoimmunity. In Western cultures, the devel-
oping immune system of the infant is no longer exposed to
widespread infection, which may contribute to the current
increases in incidence observed in atopic and autoimmune
Large studies are required to address the role of environ-
mental factors in susceptibility to type 1 diabetes. An interna-
tional consortium — the Environmental Determinants of
Diabetes in the Young (TEDDY; www.niddk.nih.gov/patient
/TEDDY/TEDDY.htm) — has been established to follow sev-
eral thousand babies with high-risk HLA genotypes from
birth until adolescence to identify infectious agents, dietary
factors or other environmental factors that trigger islet au-
toimmunity in genetically susceptible people.
Do we know who is at greatest risk?
More than 30 years ago, it was recognized that antibodies in
sera from patients with type 1 diabetes could bind to sections
of pancreatic islets. These antibodies were termed islet cell an-
• July 18, 2006 • 175(2) | 166
0 10 20 3040
Annual incidence per 100 000
Fig 1:Geographic variation in annual incidence of type 1 diabetes.
tibodies. The 3 principal autoantigens identified were glu-
tamic acid decarboxylase (GAD 65),43a protein tyrosine phos-
phatase-like molecule (IA-2)44and insulin.45Studies involving
first-degree relatives gave insight into the potential usefulness
of islet cell antibodies as predictors of future disease, but the
immunoflourescence assay proved difficult to standardize. In-
ternational workshops to standardize assays for antibodies to
GAD, IA-2 and insulin have been more successful,46,47and it is
now clear that about 90% of people with newly diagnosed type
1 diabetes have autoantibodies to at least 1 of these 3 antigens.
There is variability in the pattern of humoural immunity, how-
ever: insulin autoantibodies are more prevalent in young chil-
dren,48IA-2 antibodies often decrease after diagnosis,49and
antibodies to GAD tend to persist.50It is in the pre-diabetes
phase that islet autoantibodies have been most useful. They
appear to be already present in most cases of future diabetes
by the age of 5 years.51This indicates that the autoimmune
process “smoulders” subclinically for many years in the ma-
jority of patients and that clinical symptoms do not appear un-
til up to 80% of βcells have been destroyed.
The observations that islet cell autoantibodies predict au-
toimmune diabetes in first-degree relatives,52that the pres-
ence of 2 or more autoantibodies in people in the general
population is highly predictive of future disease53and that
recent reports have shown that people who have IA-2 anti-
bodies are at very high risk54,55have opened the way for inter-
vention strategies to delay or slow the autoimmune process.
Identification of appropriate agents to reverse or delay the
autoimmune process in people found to have 2 or more islet
cell autoantibodies is one of the main targets of diabetes
Prevention of the disease process before the appearance
of islet cell autoantibodies would be ideal, but the accuracy
of prediction based on the presence of genes associated with
type 1 diabetes is limited. In a study involving patients with
islet cell autoantibodies in Belguim, HLA class II genotyping
identified a subgroup who represented less than 10% of the
Belgian population but who accounted for the majority of
future cases of type 1 diabetes in childhood or early adult-
hood.56Targeting 10% of the population for therapeutic
intervention, however, when the vast majority will not go on
to have type 1 diabetes would require a highly effective and
safe intervention. Population screening strategies for islet
cell autoantibodies can be aided by HLA screening strategies,
• July 18, 2006 • 175(2) | 167
Fig 2: Representation of the process whereby antigen (in this case peptides of proinsulin) is presented to
CD4 T cells by human leukocyte antigen (HLA) class II molecules on the antigen presenting cell. This re-
sults in T-cell activation. In this diagram the 4 major genes associated with type 1 diabetes are present.
CTLA-4is an inhibitor of T-cell activation, as is lymphoid tyrosine phosphatase (LYP), which is encoded by
the gene PTPN22. The complex of LYP–C-terminal Src kinase (CSK) inhibits Lck signalling after engage-
ment of the T-cell antigen receptor (TCR).
Lianne Friesen and Nicholas Woolridge
since 90% of people in whom type I diabetes will later de-
velop are found to be positive for one or both of the HLA sus-
ceptibility haplotypes (DR3-DQ2 and DR4-DQ8) and nega-
tive for the protective haplotype (DR2-DQ6). This strategy is
being used by the type 1 Diabetes Prediction and Prevention
Study (DIPP)57to test the effectiveness of intranasally applied
insulin as an antigen-specific therapy.
Two major trials of ways to prevent or delay the onset of type 1
diabetes are complete.
The European Nicotinamide Diabetes Intervention Trial
(ENDIT), a randomized double-blind placebo-controlled
trial of high-dose nicotinamide therapy, recruited first-
degree relatives of people who were less than 20 years old
when their type 1 diabetes was diagnosed, were ICA positive,
were less than 40 and had a nondiabetic oral glucose toler-
ance test. Although nicotinamide had proved protective in
animal studies, no effect was observed in the ENDIT study
during the 5-year test period.58
A trial that ran concurrently with ENDIT, the Diabetes
Prevention Trial – type 1 (DPT-1), studied the efficacy of low-
dose insulin injections in high-risk (> 50%) first-degree rela-
tives of patients with type 1 diabetes. In addition, oral insulin
capsules were compared with placebo capsules in relatives
with a 25%–50% risk of type 1 diabetes. Overall, the insulin
treatments had no effect,59but in a subset of participants in
the oral insulin group (those with high levels of insulin au-
toantibodies), a delay and perhaps a reduction in the inci-
dence of type 1 diabetes was observed.60Recent data suggest-
ing that insulin is a primary autoantigen in type 1 diabetes61,62
strengthen the case for a therapeutic focus on insulin.
Both the ENDIT and DPT-1 trials, although reporting
largely negative findings, have set the standard for future tri-
als and emphasized the requirement for international collab-
oration to facilitate well-designed trials. To this end, TrialNet
(www.diabetestrialnet.org) has been established. TrialNet is a
network of 18 clinical centres working in cooperation with
screening sites throughout the United States, Canada, Fin-
land, the United Kingdom, Italy, Germany, Australia and
Other studies are examining anti–T-cell strategies. Early
studies of cyclosporin in the 1980s provided a proof of prin-
cipal for the usefulness of immunomodulators in the treat-
ment of type 1 diabetes; the adverse effects of cyclosporin,
however, were incompatible with their widespread use.63,64
More sophisticated anti–T-cell strategies have been devel-
oped more recently. In one study, hOKT3γ1(Ala-Ala), a hu-
manized, modified anti-CD3 monoclonal antibody, was
given to 21 patients within 6 weeks of type 1 diabetes diag-
nosis; patients in the treatment group had improved C-pep-
tide responses, with effects lasting more than 1 year after a
single course of treatment and without chronic immuno-
suppression.65In another study, 80 patients with newly di-
agnosed type 1 diabetes were randomly assigned to receive
either an anti-CD3 monoclonal antibody (ChAglyCD3) or
placebo; results indicated that residual β-cell function was
maintained for at least 18 months and that the effect was
strongest in those with the greatest residual β-cell function
at study entry.66
In the hOKT3γ1(Ala-Ala) trial, analysis of peripheral blood
samples demonstrated an increase in the CD8/CD4 ratio and
in particular an increase in CD8+CD25+ regulatory T cells.67
Most studies of regulatory T cells have focused on a subset of
naturally occurring CD4+ cells that have the capacity to con-
trol self-reactive T cells,68and their depletion results in au-
toimmunity.69Strategies that target the action of regulatory T
cells in vivo offer one of the most attractive options for ther-
apy in type 1 diabetes and other autoimmune diseases.
• July 18, 2006 • 175(2) | 168
Appearance of islet
• Renewable sources
• β-cell regeneration
Identify and remove
Diagnosis of type 1 diabetes
(< 20% β cells remaining)
• Islet transplantation
• Gene therapy to generate
• Anti-T-cell strategies
• Induction of tolerance
• T-cell regulation
Fig 3: Potential targets for therapeutic intervention of type 1 diabetes.
Pancreatic transplantation has offered a successful thera-
peutic approach for many years.70,71However, as with all
whole-organ transplants, lifelong immunosuppression is
required and donor organs are in short supply. An alter-
native strategy, injection of donor islets into the liver,
although less invasive, was found to have mixed success
until researchers in Edmonton presented the so-called “Ed-
monton protocol.”72With the use of a combination of da-
clizumab, sirolimus and tacrolimus and islets from more
than 1 donor pancreas per recipient, success rates of 80%
at 1 year and 20% at 5 years have been reported.73One of
the variables that must be standardized is the crucial islet
isolation step.74Both the quality and the number of islets
affect success rates. A prospective multicentre trial coordi-
nated by the Immune Tolerance Network has been estab-
lished to replicate this success. Like pancreatic transplanta-
tion, the procedure is currently limited by availability of
donor islets. New sources of functional islets will be re-
quired for islet transplantation to make a significant impact
on type 1 diabetes.
Regeneration of β β cells
The presence of β cells in patients with long-standing type 1
diabetes, despite ongoing autoimmunity, implies that new
formation of β cells may be occurring.75Although an ambi-
tious aim currently, targeted regeneration of such β cells of-
fers another strategy to prevent type 1 diabetes. Regeneration
of β cells is therefore an area of major active investigation,
with recent studies reporting differentiation of pancreatic
and nonpancreatic progenitors as well as replication of exist-
ing islet β cells. One study has shown that a single, murine,
adult pancreatic precursor exists that can differentiate into
cells with the characteristics of islet β cells.76Another study
has shown that pre-existing β cells, rather than pluripotent
stem cells, are the main source of new β cells during adult
life and after pancreatectomy in mice.77
We are still some way from developing a pill to prevent type 1
diabetes, but all the divergent strands of ongoing research,
from epidemiology to molecular biology, immunology to
clinical trials, appear to be converging to provide clear per-
spectives on the therapeutic interventions that are most likely
to be successful. Two strategies are open to physicians who
have patients with type 1 diabetes: the first is to prevent initi-
ation of autoimmunity; the second is to reverse the effects of
ongoing autoimmunity coupled with β-cell regeneration
(Fig. 3). Although highly ambitious, the prevention of type 1
diabetes could be possible by identifying and eliminating en-
vironmental risk factors. The next line of defence would be
to re-educate the immune system through exposure to β-cell
antigens with the use of oral or nasal tolerance strategies.
The observation that insulin may be the primary autoantigen
provides support for therapies using insulin to induce toler-
ance. The potential to re-educate the immune system, or to
divert it using regulatory T cells, and the rapidly expanding
field of islet β-cell differentiation give hope that improved
strategies to manage this chronic disease are on the horizon.
1. Foulis AK, McGill M, Farquharson MA. Insulitis in type 1 (insulin-dependent) dia-
betes mellitus in man — macrophages, lymphocytes, and interferon-gamma con-
taining cells. J Pathol1991;165:97-103.
2. EURODIAB ACE Study Group. Variation and trends in incidence of childhood dia-
betes in Europe. Lancet2000;355:873-6.
3. Onkamo P, Vaananen S, Karvonen M, et al. Worldwide increase in incidence of
type I diabetes — the analysis of the data on published incidence trends. Dia-
4. Cudworth AG, Woodrow JC. HLA system and diabetes mellitus. Diabetes 1975;24:
5. Nerup J, Platz P, Andersen OO, et al. HLA antigens and diabetes mellitus. Lancet
6. Risch N. Assessing the role of HLA-linked and unlinked determinants of disease.
Am J Hum Genet1987;40:1-14.
7. Todd JA. Genetic analysis of type 1 diabetes using whole genome approaches. Proc
Natl Acad Sci U S A1995;92:8560-6.
8. Devendra D, Eisenbarth GS. Immunologic endocrine disorders. J Allergy Clin Im-
9. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med
10.Caillat-Zucman S, Garchon HJ, Timsit J, et al. Age-dependent HLA genetic hetero-
geneity of type 1 insulin-dependent diabetes mellitus. J Clin Invest1992;90:2242-50.
11.Gillespie KM, Gale EAM, Bingley PJ. High familial risk and genetic susceptibility in
early onset childhood diabetes. Diabetes2002;51:210-4.
12.Bell GI, Horita S, Karam JH. A polymorphic locus near the insulin gene is associ-
ated with insulin-dependent diabetes mellitus. Diabetes1984;33:176-83.
13.Bennett ST, Lucassen AM, Gough SCL, et al. Susceptibility to human type 1 dia-
betes at IDDM2 is determined by tandem repeat variation at the insulin gene min-
isatellite locus. Nat Genet1995;9:284-92.
14.Vafiadis P, Bennett ST, Todd JA, et al. Insulin expression in human thymus is mod-
ulated by INS VNTR alleles at the IDDM2 locus. Nat Genet1997;15:289-92.
15.Pugliese A, Zeller M, Fernandez A Jr, et al. The insulin gene is transcribed in the
human thymus and transcription levels correlated with allelic variation at the INS
VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet1997;15:293-7.
16.Mein CA, Esposito L, Dunn MG, et al. A search for type 1 diabetes susceptibility
genes in families from the United Kingdom. Nat Genet1998;19:297-300.
17.Concannon P, Gogolin-Ewens KJ, Hinds DA, et al. A second-generation screen of
the human genome for susceptibility to insulin-dependent diabetes mellitus. Nat
18.Cox NJ, Wapelhorst B, Morrison VA, et al. Seven regions of the genome show evi-
dence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex fami-
lies. Am J Hum Genet2001;69:820-30.
19. Ueda H, Howson JM, Esposito L, et al. Association of the T-cell regulatory gene
CTLA4 with susceptibility to autoimmune disease. Nature2003;423:506-11.
20. Atabani SF, Thio CL, Divanovic S, et al. Association of CTLA4 polymorphism with
regulatory T cell frequency. Eur J Immunol2005;35:2157-62.
21.Bottini N, Musumeci L, Alonso A, et al. A functional variant of lymphoid tyrosine
phosphatase is associated with type I diabetes. Nat Genet2004;36:337-8.
22. Smyth D, Cooper JD, Collins JE, et al. Replication of an association between the
lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evi-
dence for its role as a general autoimmunity locus. Diabetes2004;53:3020-3.
23. Gregersen PK. Gaining insight into PTPN22 and autoimmunity. Nat Genet 2005;
24. Becker KG. Comparative genetics of type 1 diabetes and autoimmune disease:
Common loci, common pathways? Diabetes1999;48:1353-8.
25. Fronczak CM, Baron AE, Chase HP, et al. In utero dietary exposures and risk of
islet autoimmunity in children. Diabetes Care2003;26:3237-42.
26. Hyppönen E, Läärä E, Reunanen A, et al. Intake of vitamin D and risk of type 1 dia-
betes: a birth cohort study. Lancet2001;358:1500-3.
27. Mathieu C, Badenhoop K. Vitamin D and type 1 diabetes mellitus: state of the art.
Trends Endocrinol Metab2005;16:261-6.
28. Mahomed K, Gulmezoglu AM. Vitamin D supplementation in pregnancy [review].
Cochrane Database Syst Rev2000;(2):CD000228.
29. Nejentsev S, Cooper JD, Godfrey L, et al. Analysis of the vitamin D receptor gene
sequence variants in type 1 diabetes. Diabetes2004;53:2709-12.
• July 18, 2006 • 175(2) | 169
This article has been peer reviewed.
Kathleen Gillespie is a lecturer with the Department of Clinical Science at
North Bristol, University of Bristol, UK.
Competing interests:None declared.
30. Pani MA, Knapp M, Donner H, et al. Vitamin D receptor allele combinations influ-
ence genetic susceptibility to type 1 diabetes in Germans. Diabetes2000;49:504-7.
31. Nejentsev S, Guja C, McCormack R, et al. Association of intercellular adhesion
molecule-1 gene with type 1 diabetes. Lancet2003;362:1723-4.
32. Pundziute-Lycka A, Dahlquist G, Nystrom L, et al. Incidence of type I diabetes has
not increased but shifted to a younger age at diagnosis in the 34 years group in
Sweden 1983–1998. Diabetologia2002;45:783-91.
33. Weets I, De Leeuw IH, Du Caju MV, et al. The incidence of type 1 diabetes in the
age group 0–39 years has not increased in Antwerp (Belgium) between 1989 and
2000: evidence for earlier disease manifestation. Diabetes Care2002;25:840-6.
34. Hermann R, Knip M, Veijola R, et al. Temporal changes in the frequencies of HLA
genotypes in patients with type 1 diabetes — Indication of an increased environ-
mental pressure? Diabetologia2003;46:420-5.
35. Gillespie KM, Bain SC, Barnett AH, et al. The rising incidence of childhood type 1
diabetes and reduced contribution of high-risk HLA haplotypes. Lancet 2004;364:
36. Hyoty H. Enterovirus infections and type 1 diabetes. Ann Med2002;34:138-47.
37. Honeyman MC, Coulson BS, Stone NL, et al. Association between rotavirus infec-
tion and pancreatic islet autoimmunity in children at risk of developing type 1 dia-
38.Ginsberg-Fellner F, Witt ME, Fedun B, et al. Diabetes mellitus and autoimmunity in
patients with the congenital rubella syndrome. Rev Infect Dis1985;7(Suppl 1):S170-6.
39. Peltola H, Davidkin I, Paunio M, et al. Mumps and rubella eliminated from Fin-
40. Viskari H, Ludvigsson J, Uibo R, et al. Relationship between the incidence of type 1
diabetes and maternal enterovirus antibodies: time trends and geographical varia-
41.Gale EA. A missing link in the hygiene hypothesis? Diabetologia2002;45:588-94.
42. Bach JF. Infections and autoimmune diseases. J Autoimmun2005;25:74-80.
43. Baekkeskov S, Warnock G, Christie M, et al. Revelation of specificity of 64K au-
toantibodies in IDDM serums by high-resolution 2-D gel electrophoresis. Unam-
biguous identification of 64K target antigen. Diabetes1989;38:1133-41.
44. Lan MS, Wasserfall C, Maclaren NK et al. IA-2, a transmembrane protein of the
protein tyrosine phosphatase family, is a major autoantigen in insulin-dependent
diabetes mellitus. Proc Natl Acad Sci U S A. 1996 25; 93:6367-70.
45. Palmer JP. Insulin autoantibodies: their role in the pathogenesis of IDDM. Dia-
betes Metab Rev1987;3:1005-15.
46. Verge CF, Stenger D, Bonifacio E, et al. Combined use of autoantibodies (IA-2 au-
toantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell anti-
bodies) in type 1 diabetes: Combinatorial Islet Autoantibody Workshop. Diabetes
47. Bingley PJ, Bonifacio E, Mueller PW. Diabetes Antibody Standardization Program:
first assay proficiency evaluation. Diabetes2003;52:1128-36.
48. Vandewalle CL, Decraene T, Schuit FC, et al. Insulin autoantibodies and high titre
islet cell antibodies are preferentially associated with the HLA DQA1*0301-
DQB1*0302 haplotype at clinical type 1 (insulin-dependent) diabetes mellitus be-
fore age 10 years, but not at onset between age 10 and 40 years. The Belgian Dia-
betes Registry. Diabetologia1993;36:1155-62.
49. Gorus FK, Goubert P, Semakula C, et al. IA-2-autoantibodies complement GAD65-
autoantibodies in new-onset IDDM patients and help predict impending diabetes
in their siblings. The Belgian Diabetes Registry. Diabetologia1997;40:95-9.
50. Decochez K, Tits J, Coolens JL. High frequency of persisting or increasing islet-
specific autoantibody levels after diagnosis of type 1 diabetes presenting before 40
years of age. The Belgian Diabetes Registry. Diabetes Care2000;23:838-44.
51.Ziegler A.G., Hummel M., Schenker M., et al. Autoantibody appearance and risk
for development of childhood diabetes in offspring of parents with type 1 diabetes:
the 2-year analysis of the German BABYDIAB Study. Diabetes1999;48:460-8.
52. Bingley PJ, Williams AJK, Gale EAM. Optimized autoantibody-based risk assess-
ment in family members. Diabetes Care1999;22:1796-801.
53. Bingley PJ, Bonifacio E, Williams AJK, et al. Prediction of IDDM in the general
population. Strategies based on combinations of autoantibody markers. Diabetes
54. Decochez K, Truyen I, van der Auwera B, et al. Combined positivity for HLA
DQ2/DQ8 and IA-2 antibodies defines populations at high risk of developing type
1 diabetes. Diabetologia2005;48:687-94.
55. Achenbach P, Warncke K, Reiter J, et al. Stratification of type 1 diabetes risk on the
basis of islet autoantibody characteristics. Diabetes2004;53:384-9.
56. Van der Auwera BJ, Schuit FC, Weets I, et al. Relative and absolute HLA-DQA1-
DQB1 linked risk for developing type I diabetes before 40 years of age in the Bel-
gian population: implications for future prevention studies. Hum Immunol 2002;
57. Nejentsev 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 mark-
ers in the HLA-DQB1, HLA-DQA1 and HLA-DRB1 loci. Diabet Med1999;16:985-92.
58. Gale EA, Bingley PJ, Emmett CL, et al. European Nicotinamide Diabetes Interven-
tion Trial (ENDIT): a randomised controlled trial of intervention before the onset
of type 1 diabetes. Lancet2004;363:925-31.
59. Diabetes Prevention Trial–Type 1 Diabetes Study Group: Effects of insulin in rela-
tives of patients with type 1 diabetes mellitus. N Engl J Med2002;346:1685-91.
60. Skyler JS, Krischer JP, Wolfsdorf J, et al. Effects of oral insulin in relatives of pa-
tients with type 1 diabetes: the Diabetes Prevention Trial–Type 1. Diabetes Care
61.Kent SC, Chen Y, Bregoli L, et al. Expanded T cells from pancreatic lymph nodes of
type 1 diabetic subjects recognize an insulin epitope. Nature2005;435:224-8.
62. Nakayama M, Abiru N, Moriyama H, et al. Prime role for an insulin epitope in the
development of type 1 diabetes in NOD mice. Nature2005;435:220-3.
63. Feutren G, Papoz L, Assan R, et al. Cyclosporin increases the rate and length of re-
missions in insulin-dependent diabetes of recent onset. Results of a multicentre
double-blind trial. Lancet1986;2:119-24.
64. Canadian–European Randomized Control Trial Group. Cyclosporin-induced re-
mission of IDDM after early intervention. Association of 1 yr of cyclosporin treat-
ment with enhanced insulin secretion. Diabetes1988;37:1574-82.
65. Herold KC, Gitelman SE, Masharani U, et al. A single course of anti-CD3 mono-
clonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide re-
sponses and clinical parameters for at least 2 years after onset of type 1 diabetes.
66. Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-
antibody therapy in new-onset type 1 diabetes. N Engl J Med2005;352:2598-608.
67. Bisikirska B, Colgan J, Luban J, et al. TCR stimulation with modified anti-CD3
mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs. J Clin In-
68. Sakaguchi S. Regulatory T cells: key controllers of immunologic self-tolerance.
69. DiPaolo RJ, Glass DD, Bijwaard KE, et al. CD4+CD25+ T cells prevent the develop-
ment of organ-specific autoimmune disease by inhibiting the differentiation of au-
toreactive effector T cells. J Immunol2005;175:7135-42.
70. Burke GW, Ciancio G, Sollinger HW. Advances in pancreas transplantation.
71. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United States
(US) and non-US cases as reported to the United Network for Organ Sharing
(UNOS) and the International Pancreas Transplant Registry (IPTR) as of June
2004. Clin Transplant2005;19:433-55.
72. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with
type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen.
N Engl J Med2000;343:230-8.
73. Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after clinical islet trans-
74. Ricordi C. Islet transplantation: a brave new world. Diabetes2003;52:1595-603.
75. Meier JJ, Bhushan A, Butler AE. Sustained beta cell apoptosis in patients with long-
standing type 1 diabetes: Indirect evidence for islet regeneration? Diabetologia
76. Seaberg RM, Smukler SR, Kieffer TJ. Clonal identification of multipotent precur-
sors from adult mouse pancreas that generate neural and pancreatic lineages. Nat
77. Dor Y, Brown J, Martinez OI. Adult pancreatic beat-cells are formed by self-dupli-
cation rather than stem-cell differentiation. Nature2004;429:41-6.
• July 18, 2006 • 175(2) | 170
Correspondence to: Dr. Kathleen M. Gillespie, Medical School
Unit, Southmead Hospital, Bristol BS10 5NB, UK;
fax +44 117 959 5336; firstname.lastname@example.org