SEMINAR

Seminar

Type 1 diabetes: new perspectives on disease pathogenesis and

treatment

Mark A Atkinson, George S Eisenbarth

As our knowledge of type 1 (insulin-dependent) diabetes increases, so does our appreciation for the pathogenic
complexity of this disease and the challenges associated with its treatment. Many new concepts about the
pathogenesis of this disorder have arisen. The role of genetics versus environment in disease formation has been
questioned, and the basis on which type 1 diabetes is characterised and diagnosed is the subject of much debate.
Additionally, the care and treatment of patients with type 1 diabetes has seen a rapid evolution; with genetically
engineered insulins, glucose monitoring devices, and algorithms all contributing to a decrease in disease-related
complications. We focus this seminar on these changing views, and offer a new perspective on our understanding of
the pathogenesis of type 1 diabetes and on principles for therapeutic management of patients with this disorder.

In the early to mid 1990s, optimism was high that
knowledge about the pathogenesis of type 1 diabetes
(insulin-dependent) would result in a method for disease
prevention, perhaps by the end of the decade. The disease
was known to result from an immunological destruction
of the insulin-producing islet  cells. An interplay between
genetic susceptibility (polygenic) and a triggering
environmental agent was thought to provide the
fundamental elements for disease formation and,
additionally, form potential targets for both improved
disease prediction and prevention.1,2 The moderate to
long-term symptomless phase of the disorder could
readily be identified through serological markers of anti-
islet immunity (eg, autoantibodies to islet cell cytoplasm
[ICA], insulin [IAA], glutamic acid decarboxylase
[GADA], and ICA512/IA2A). The ability of such markers
to serve as predictive tools provided the opportunity to
undertake clinical trials for testing potential preventive
therapies. Research in animals suggested a fixed natural
history of disease that was subject to an undemanding
preventive intervention with an extensive number of
therapy agents.3
This knowledge fostered long-held opinions that it
would only be a matter of time before scientists found a
prevention or a cure for diabetes. Additionally,
information about the benefits of intensive insulin therapy
generated substantial optimism for improved patient
care.4 Today, however, the pathogenic and therapeutic
complexity of this disorder is better appreciated. The
optimism remains but there is a consensus that much
remains to be learned before radically improved treatment
becomes a reality. The focus of this seminar is to highlight
new perspectives in the pathogenesis and treatment of
type 1 diabetes.
Lancet 2001; 358: 22129
Department of Pathology, Immunology, and Laboratory Medicine,
College of Medicine, University of Florida, Gainesville, FL 32610
0275, USA (M A Atkinson PhD); and Barbara Davis Center for
Childhood Diabetes, University of Colorado Health Sciences
Center, Denver, CO, USA (G S Eisenbarth MD)
Correspondence to: Dr Mark A Atkinson
(e-mail: atkinson@ufl.edu)
Epidemiology and genetics
The incidence of type 1 disease is rapidly increasing in
specific regions and shows a trend towards earlier onset.
The incidence of type 1 diabetes is highly variable among
different ethnic populations.5 The overall age-adjusted
incidence of type 1 diabetes varies from 01/100 000 per
year in the Zunyi region within China to more than
40/100 000 per year in Finland.6,7 This represents more
than a 400-fold variation in the incidence among about
100 populations analysed. Furthermore, the incidence of
type 1 diabetes seems to be increasing in almost all
populations, with the increase particularly high in
nations with a low incidence of this disease. The
incidence of type 1 diabetes will be about 40% higher in
2010 than in 1997.7
However, these data also suggest that the polar-
equatorial gradient (ie, the north-south gradient) described
for disease incidence5,8 is not as strong as previously
thought.9 For example, whereas most populations with
very high incidence rates are of European origin, high
incidence rates have also been noted in Kuwait and Puerto
Rico. The two areas with the highest incidence rates,
Finland and Sardinia, are 3000 km from each other,
whereas Estonia, bordering Finland, has an incidence rate
of about one-quarter of its neighbour.7 Such variations in
disease incidence are increasingly being seen to follow
ethnic and racial distributions, which indicates that we
should not rely on a model that accounts only for
geographic position. The explanation for these wide
disparities in risk within ethnic groups probably lies in
differences in genes or environment.
The EURODIAB collaborative study,6 a registry
consortium involving 44 centres representing most
European countries and Israel, indicates an annual rate of
increase in type 1 diabetes incidence of 34%, but in
some central and eastern European countries (most
notably those of the former communist bloc), the
increase is far more rapid. Furthermore, examination of
the rates of type 1 diabetes as a function of the age at
onset showed rates of increase of 63%, 31%, and 24%
in populations of children aged 04 years, 59 years, and
1014 years, respectively. These findings support the
impressions of health-care professionals that they are
seeing more and more cases of type 1 diabetes, especially
in younger children.

THE LANCET Vol 358 July 21, 2001 221

For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR

Risk HLA
More effective Higher
methods for accuracy in
HLA DRB1 HLA DQA1 HLA DQB1 preventative disease
High risk 0401, 0402, 0405 0301 0302 intervention prediction
0301 0501 0201 Ability to predict
type 1 diabetes
Moderate risk 0801 0401 0402
0101 0101 0501

0901 0301 0303
Weak or moderate 0401 0301 0301
protection 0403 0301 0302
0701 0201 0201
1101 0501 0301
Strong protection 1501 0102 0602
1401 0101 0503
0701 0201 0303
Type 1 diabetes risk associated with HLA-DR and HLA-DQ haplotypes
Genes
Genes for type 1 diabetes provide both susceptibility
towards, and protection from, the disease. Although
many chromosomal loci associated with such activities
have been located, few true genes have been identified.
The genetics of type 1 diabetes cannot be classified
according to a specific model of dominant, recessive, or
intermediate inheritance of a specific set of genes.10 The
most important genes are located within the major
histocompatibility complex (MHC) HLA class II region
on chromosome 6p21, formally termed (IDDMl),
accounting for about 45% of genetic susceptibility for
the disease.11 The function of these genes in terms of an
immune response is well known (ie, presentation of
antigenic peptides to T lymphocytes), yet their specific
contribution to the pathogenesis of type 1 diabetes
remains unclear. The importance of the class II
haplotype not only depends on the well-known risk for
disease associated with HLA-DR3 and HLA-DR4, but
also on additional susceptibility associated with DQ-
chains and DQ-chains. Type 1 diabetes seems
somewhat unique among autoimmune diseases in that in
addition to forming susceptibility, certain MHC
haplotypes provide significant protection, with
protection dominant over susceptibility (table). The
observation that 20% of people from Europe or the USA
carry the protective HLA-DR2 haplotype, yet fewer than
1% of children with type 1 diabetes are DR2
(DQB1*0602) positive, highlights the importance of
genetics in disease developmentie, one HLA allele can
over-ride other genetic or environmental factors which
predispose to disease.10
Type 1 diabetes represents a heterogeneous and
polygenic disorder, with a number (about 20) of non-
HLA loci contributing to disease susceptibility already
identified.12 However, the function of only two non-HLA
loci are known. IDDM2 on chromosome 11p55
contributes about 10% towards disease susceptibility.13
This locus is a polymorphic region that maps to a
variable number of tandem mini-satellite repeats
(VNTR), with short class I VNTR alleles predisposing to
type 1 diabetes, while the longer class III alleles provide
a dominant protective effect. Another locus associated
with type 1 diabetes in some populations is IDDM12 on
chromosome 2q33, which has an apparent action on the
cytotoxic T-lymphocyte-associated protein 4 (CTLA4)
that is responsible for modulating immune
responsiveness.14 Recent technological advances in gene
identification and the formation of cooperative study
groups should enhance the speed at which true genes for
type 1 diabetes are uncovered.
-cell mass
Ability to prevent
Lower Less effective type 1 diabetes
accuracy in methods for
disease preventative
prediction intervention
Onset of
overt type 1
diabetes
Figure 1: Traditional and modern models of the pathogenesis
and natural history of type 1 diabetes
The traditional model provided represents common features cited within
numerous publications and presentations from 198698, many of which
were derived from one schematic of the so-called stages of type 1
diabetes.26 The modern model expands and updates the traditional
model by inclusion of information gained through an improved
understanding of the roles for genetics, immunology, and environment in
the natural history of type 1 diabetes.
Environment
Despite much research, no environmental agent or agents
responsible for triggering type 1 diabetes have been
uncovered. To date, environmental risk determinants
subject to the most widespread investigation can be
classified into three groups: viral infections (eg,
coxsackievirus and cytomegalovirus), early infant diet
(eg, breast feeding versus early introduction of cows milk
components), and toxins (eg, N-nitroso derivatives).1517
Other non-genetic disease-modifying factors include
vaccine administration, psychological stress, and climatic
influences. Prospective studies of infants developing anti-
islet autoantibodies and eventually diabetes could
improve and refine our understanding of potential
environmental-like triggering factors in infancy.
However, to date, the DAISY study18,19 from the USA
and BABYDIAB study20 from Germany have not
documented any effects on disease of early cows milk
exposure, breast feeding, enteroviral infection, and
timing of vaccination. These studies stand in modest
contrast to Finnish reports suggesting the potential for
such associations.21-23 Although still early in their
investigational programmes, the failure of most of these
studies and others to find disease associations with
obvious environmental candidates causes some
pessimism that such agents will soon be identified.24 This
view is supported by the complexity of elucidating and
identifying exposures (qualitatively and quantitatively) to
environmental factors even in the first few years of life,
especially if environmental agents act asynchronously or
multifactorially.25
Environmental agents may serve as modifiers of disease
pathogenesis rather than as triggers. The traditional view
of type 1 diabetes postulates that an environmental agent
triggers the onset of disease in genetically susceptible
individuals.1,2,26 More recent observations (both in human
beings and animal models) support an alternative and
more complex model (figure 1) wherein the penetrance
and expression of heritable immune aberrations (ie,
immune dysregulation), in combination with inherent

222 THE LANCET Vol 358 July 21, 2001

For personal use. Only reproduce with permission from The Lancet Publishing Group.

target organ defects, are part of the life-long influence of
multiple environmental factors such as infectious agents,
dietary factors, and environmental toxins as well as new
classes of influencing variables (eg, sanitation, health-
care access, and vaccinations).
A specific example supporting this model includes the
observation that multiple infections during the first few
years of life are associated with a reduced risk of type 1
diabetes.25,27-29 Similarly, increased risk has been
associated with perinatal infections coupled with a
protective effect of preschool day care; a theory linked to
the age-dependent modifying influence of infections on
the developing immune system. Rather than mere
exposure to one particular agent, environmental
encounters could act to promote and attenuate disease
during different stages of development, with effect
dependent upon both timing and quantity of exposures
(figure 1).30 This newer model may explain, in part, why
the frequency of type 1 diabetes has increased
dramatically during the past three decades as healthcare
and standards of sanitation have improved.
Pathogenesis
Researchers3134 have reported results from investigations
of young children (first-degree relatives of patients with
type 1 diabetes and individuals from the general
population), who were followed from birth to measure
expression of autoantibodies and development of type 1
diabetes. Interestingly, despite wide geographical
differences in the populations studied (eg, Germany,
Finland, Colorado, and USA), the results of the different
populations are highly concordant. Transplacental
autoantibodies disappear slowly (ie, at 69 months of
age), with a small percentage of infants who have
antibodies persisting until 1 year of age. Anti-islet
autoantibodies can be present in the first few months of
life, but commonly develop by age 9 months. Between
ages 9 months and 3 years a greater percentage of
children develop autoantibodies than at any other time.
The first autoantibody for infants is usually, but not
exclusively, IAA, with GADA being the second most
frequent. Most individuals progressing to overt diabetes
express multiple anti-islet autoantibodies by the time of
diabetes onset. The autoantibodies are usually persistent,
though a few individuals lose antibody expression
without progressing to diabetes. Finally, very few
children expressing autoantibodies react with more than
one islet antigen and have only transient expression of
autoantibodies.34 Other studies of immune dysregulation
at the level of cellular immune function also report early
immune dysregulation, most notably that of aberrant
production of prostaglandins, a marker of monocyte
activation.35
Type 1 diabetes is not a disorder limited to young
people, and the rate of disease may be equally prevalent
in adults. Type 1 diabetes has historically been
considered a disorder predominately of children and
young adults (the disease is commonly referred to as
juvenile diabetes because it has peak expression between
ages 1014 years). However, recent studies support a
different model in which the disease can occur at any age.
Specifically, 530% of patients initially diagnosed with
type 2 diabetes actually have type 1 diabetes.36,37 Such
patients are best identified by the expression of anti-islet
autoantibodies, in particular, GADA. Clinically, these
individuals are commonly treated with oral agents, do not
respond to oral hypoglycaemic therapy, and are unable to
maintain adequate glucose control. The slow onset and
protracted disease course has led to the disease
THE LANCET Vol 358 July 21, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
designation of such individuals as latent autoimmune
diabetes of adults (LADA).36 Given the large numbers of
patients diagnosed with type 2 diabetes (estimated to be
ten times greater than type 1 diabetes), patients with
LADA are likely to comprise about half all patients with
type 1 diabetes. Furthermore, in some countries such as
Japan, most cases of type 1 diabetes develop during
adulthood.38
Examination of islet inflammatory infiltrate suggests
Fas-mediated apoptosis may provide one mechanism of
-cell destruction. Mononuclear cell infiltration into the
pancreatic islets (insulitis) and a reduction of insulin-
producing  cells have long been recognised as key
pathological features of the pancreas when obtained at
necropsy from patients with type 1 diabetes.39 For ethical
and technical reasons, only recently have we been able to
extend our knowledge of the insulitis lesion, through
examination of samples obtained from pancreatic biopsy
of prediabetic patients and those with recent-onset type 1
diabetes.40,41 Pancreatic islets obtained in this way have
shown various degrees of reduction in  cell volume in all
patients, yet insulitis could only be identified in about
half patients tested. In the samples in which insulitis was
detected, the infiltrate was composed of CD8 and CD4
T cells, B lymphocytes, and macrophages, with a
predominance of CD8 T cells. Inflamed islet cells
showed hyperexpression of MHC class I molecules.
Furthermore, the degree of insulitis and hyperexpression
of MHC class I moleculars correlated with deteriorating
glycaemic control and GADA.40 In terms of uncovering
potential mechanisms of  cell destruction, Fas was
detected on  cells within inflamed islets, whereas islet-
infiltrating mononuclear cells expressed Fas ligand.41
These results suggest that an interaction between Fas on
 cells and Fas ligand on infiltrating cells might trigger
selective apoptotic -cell death in inflamed islets, leading
to type 1 diabetes. More studies need to be done to
confirm these findings.
Prediction and prospects for disease
prevention
During the past 10 years, much progress has occurred in
determining the biochemical nature of the autoantigens
recognised by anti-islet autoantibodies. Historically, the
gold-standard assay for anti-islet autoantibodies has been
the cytoplasmic islet-cell-antibody test. This assay
measures the degree of binding of immunoglobulin with
islets compared with acinar pancreas, and uses frozen
sections of human pancreas.42 Without question, studies
of this test have greatly aided our knowledge of the
pathophysiology of type 1 diabetes and facilitated a
means for predicting future cases of the disease.
However, quantitative assays with high specificity
and sensitivity for type 1 diabetes are now available for
three major islet autoantigens: insulin, glutamic acid
decarboxylase (in particular GADA65), and
ICA512/IA2A.4345 Determination of autoantibodies
reacting with these three molecules has improved the
islet-cell-antibody assay. Interestingly, the assay can
detect autoantibodies reacting with GAD, ICA512/IA2A,
and gangliosides, yet there are cytoplasmic islet-cell
autoantibodies that are not reactive to these molecules.46
Nevertheless, detection of islet-cell antibody in the
absence of the above three autoantibodies is associated
with a very low risk of progression to diabetes (panel 1).
Finally, despite best efforts, the islet-cell-antibody assay
is hard to standardise and reproduce.47
There is as yet no identified agent capable of preventing
diabetes.48,49 There are many reasons why this is the case,
223
SEMINAR

Panel 1: Caveats of autoantibody determination

Caveat
Assays vary dramatically in sensitivity,
specificity, and ability to standardise
Specific autoantibodies expressed vary, with IAA
most common in young children and GADA more
frequent in adults
Subset of apparent type 1 patients express
no known autoantibody
Autoantibodies can appear at any age, and
often develop sequentially
Antibodies reacting with a single islet autoantigen
do not always indicate impending progression
to type 1 disease
Autoantibodies can disappear, and, in low-risk
populations, serum-sample handling mistakes
may approach true positive rate
Suggestion
Use biochemical autoantibody assays with documented proficiency
testing and specificity >99% for screening
Do not use cytoplasmic islet-cell antibody assay for screening; reserve
for confirmation if needed
Measure multiple biochemical autoantibodies
HLA typing, insulin secretion, and clinical history (eg, autoimmunity)
may aid in diagnosis
Measurement over time is important
Antibodies reacting with multiple epitopes of a single molecule or
multiple islet autoantigens are more likely to be disease associated
Rely on a serum determination of autoantibodies on more than one
occasion

only a few of which will be addressed here. First, although
few would argue that such a discovery would represent a
milestone for type 1 diabetes, controversy has existed as to
whether or not studies aimed at preventing, or at least
delaying, the onset of this disease should be undertaken.
The ability to predict future cases of the disease, although
a major benefit to knowledge about the natural history of
type 1 diabetesin the absence of a preventative agent
has raised ethical considerations related to the induction
of stress, lifestyle changes, and potential effects on
insurability. As a result, participation among some health-
care professionals and acceptance by family members in
screening programmes has, in some cases, been limited.
A second major obstacle facing the diabetes prevention
field has been referred to as the treatment dilemma
(figure 2). A wide body of evidence, both in animal
models of type 1 diabetes and in individuals with
increased risk of the disease, supports the notion that the
most effective interventions will be those that are begun
early in the autoimmune disease process. By contrast, the
process of disease prediction (ie, using immunological,
genetic, and metabolic markers of the disease to identify
risk) is most accurate in the period close to the onset of
overt diabetes. As a result, a conflict (both ethical and
clinical) exists wherein the most effective forms of therapy
might involve the early treatment of individuals in a
period in which disease prediction is less accurate, a
situation that has positioned the need for a safe and
benign form of therapy against treating those who might
never develop type 1 diabetes. The identification of such
an agent has thus far proven extremely difficult to find.
Another challenge relates to properly addressing, in
combination, the questions of whom to treat and what
agent to use. In theory, attempts to prevent type 1
diabetes will most probably address two distinct
populations. The first would involve therapy of high-risk
individuals (eg, islet-autoantibody-positive relatives of a
person with type 1 diabetes). The second would be that of
a general population approach. Both models have
strengths and weaknesses in terms of therapeutic
intervention. In the general population approach, a safe
and benign therapy capable of interrupting adverse
immune events and environmental agents (such as a
vaccine) or alterations in lifestyle providing avoidance of
disease risk factors (eg, diabetogenic dietary components)
would ideally be implemented, although there would be
substantial costs associated with screening general
populations. Yet in terms of doing clinical trials to test
preventive measures within the general population, the
disease frequency and unpredictable time of onset form
major obstacles for design of trials that provide answers in
short time frames. Doing clinical trials in those
populations who are at higher risk might prove more
costeffective (in terms of a trial) and efficient, yet in terms
of humanitarian benefit, the general population approach
may be more important because about 85% of newly-
diagnosed patients have no family history of the disease.
Another issue is the lack of an obvious therapeutic
agent for the next round of large prevention trials. As a
result, a major effort in the type 1 diabetes prevention
field is currently being directed at taking a step back
towards trials as they were done in the 1980s and early
1990s: studies to identify new and perhaps more
promising agents capable of preserving -cell function.
With this model, we propose a new generation of
exploratory pilot studies, and, if a new therapy is shown to
be clinically effective, then a larger preventive trial should
be initiated. Once a promising agent is identified,
prospective randomised controlled studies with
appropriate statistical power and objective endpoints can
be designed, and prevention strategies in different
population groups at different stages of the disease process
can be implemented. Not only will these studies ascertain
potential efficacy and safety, but also should lead to
greater insight into disease pathogenesis.
Despite these challenges, there is still a possibility that
an agent capable of preventing type 1 diabetes could soon
be found. Several studies are currently being done to
address this question, including two large trials aimed at
preventing disease in individuals considered at increased
risk.50,51 The European Nicotinamide Diabetes Inter-
vention Trial (ENDIT)50 has enrolled more than 550
relatives of patients with type 1 diabetes; participants are
randomly assigned nicotinamide or placebo. No major
side-effects have been reported with this agent, and results
are expected within 2 years. In the USA, the Diabetes
Prevention Trial (DPT-1)51 was started in 1994 with the
goal of finding out whether antigen-based therapies with
insulin (ie, low-dose parenteral insulin therapy to high-
risk relatives, or oral insulin vs placebo to intermediate-

224 THE LANCET Vol 358 July 21, 2001

For personal use. Only reproduce with permission from The Lancet Publishing Group.
 SEMINAR

risk relatives) would prevent or Precipitating

Traditional model
delay the onset of diabetes. environmental
Therapy did not provide evidence event
for disease prevention and we Overt immunological
expect the results of the oral insulin abnormalities
therapy to be released with 2 years
outcome data for the low dose Islet-cell antibody
parenteral insulin.

-cell mass
GADA IAA
Genetic Progressive loss of
Diagnosis predisposition insulin release
The diagnostic criteria for different Early
forms of diabetes are being revised. pre-diabetes Glucose intolerance
As our knowledge of the Late C-peptide absence
pathogenesis of a disease increases, pre-diabetes
Overt diabetes
periodic updates of diagnostic
criteria are likely to follow. An
expert committee of the American Time
Diabetes Association (ADA) has
published aetiological diagnostic
criteria.52 These criteria recognise
that most patients with type 1 Immune Environmental
diabetes are not children at onset,53 dysregulation triggers and
and that not all individuals at onset regulators Modern model
are insulin dependent54 or have an
IAA
immune-mediated form of dia-
55
betes. Thus, the terms juvenile GADA ICA512A ICA
onset, or insulin-dependent diabetes
Interactions Loss of first phase
mellitus (IDDM) are no longer between
-cell mass

used. The ADA committee insulin response

genes (IVGTT)
recommended using the term imparting Variable insulitis
type 1A diabetes for immune- susceptibility -cell sensitivity Glucose intolerance
mediated diabetes and type 1B for and resistance to injury Absence of C-peptide
non-immune diabetes with severe
52
insulin deficiency. Type 2 diabetes
is a term to be used for idiopathic Overt diabetes
forms of diabetes with insulin Pre-diabetes
resistance and without severe insulin
deficiency or dramatic loss of Time
 cells. Gestational diabetes was
classified in a separate category. Figure 2: The treatment dilemma for type 1 diabetes
Specific genetic syndromes (eg, Many studies from animal models of type 1 diabetes in combination with a much more limited series of
mutations of the hepatocyte nuclear investigations in human beings suggest that early intervention not only is more effective in terms of
disease prevention, but also often requires more benign forms of therapy. In contrast, the ability to
factor and glucokinase genes) identify an individual who will truly develop type 1 diabetes (among an at-risk population) increases as the
contribute to the final category for individual approaches onset of overt disease. Although this model does not restrict the ability to provide
classification of other specific forms preventative intervention therapy for individuals at or near onset of disease, the degree of residual -cell
of diabetes. mass must be considered when assigning individuals to various therapeutic protocols.
IVGTT=intravenous glucose tolerance test. IAA=insulin autoantibodies. GADA=glutamic acid
The diagnosis of diabetes is made decarboxylase.
on the basis of hyperglycaemia.
Anti-islet autoantibody deter-
mination with specific assays (eg, IAA, GADA, no symptoms.59,60 Screening for autoantibodies to tissue
ICA512A/IA2A), can be used to diagnose type 1A transglutaminase can identify such individuals.61 A high
diabetes.56,57 About 90% of white children will have at least concentration of transglutaminase is predictive of coeliac
one of these autoantibodies at disease diagnosis. As disease on subsequent intestinal biopsy.62 Whether such
previously indicated, as many as 50% of children from individuals are at increased risk for anaemia, intestinal
other ethnic groups with diabetes do not have type 1A cancer, and osteoporosisas are patients with
diabetes, indeed most have type 2 diabetes. 530% of symptomatic diseaseis not yet clearly defined.62 Several
adults with what initially seems to be type 2 diabetes diabetes centres, particularly in Europe, routinely screen
(including overweight non-insulin-treated adults) have for coeliac disease and recommend a gluten-free diet upon
anti-islet autoantibodies and in fact have a variant of type diagnosis. Addisons disease is rare, occurring in about
1A diabetes.36,37 one in 20 000 individuals, but in as many as one in
We know that both the patient with type 1 diabetes and 200500 patients with type 1 diabetes.63,64 Many other
their relatives are at increased risk for other organ-specific autoimmune diseases are associated with type 1 diabetes,
autoimmune diseases, such as thyroid autoimmunity in including characteristic autoimmune syndromes such as
type 1 diabetes and Addisons disease. Graves disease APS-I (autoimmune polyendocrine syndrome) and
and hypothyroidism are so prevalent in type 1 diabetes APS-II.65 Hence, for patients with type 1 diabetes, a high
that routine testing of thyroid-stimulating hormone index of suspicion for other forms of autoimmunity
(TSH) is commonplace.58 Less known, but of increasing should be considered; a practice that will allow for early
significance, are the findings that among patients with diagnosis and therapy of these under-diagnosed and
type 1 diabetes, about one in 20 have coeliac disease with commonly overlooked diseases.

THE LANCET Vol 358 July 21, 2001 225

For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
Contrary to popular beliefs, death at the onset of type 1
diabetes still occurs. Although type 1 diabetes usually
develops slowly, as shown in studies which have
prospectively followed up children, the onset of
hyperglycaemia can often be abrupt. Unfortunately, in
many instances, the first health-care provider to see a
child with type 1 diabetes does not properly diagnose the
disorder; a factor that seems to greatly increase the risk of
subsequent death at presentation. The rate of death at
onset of type 1 diabetes apparently varies between
countries, a factor perhaps related to public awareness of
diabetes within populations.66,67 In the state of Colorado,
USA (with a population of 4 million) about one child dies
at the onset of type 1 diabetes every 2 years, and the
clinical history is almost always associated with delayed
diagnosis. These deaths are characteristically associated
with ketoacidosis and development of cerebral oedema.
Severe metabolic decompensation as well as rapid
bicarbonate administration are risk factors for the
development of cerebral oedema.68 Careful monitoring of
mental status is essential, and early therapy of cerebral
oedema with mannitol might prevent death, although
permanent neurological deficits could remain.69 Bedside
tests for hyperglycaemia are readily available and a high
index for suspicion of diabetes is important, especially for
children with nausea, vomiting, acute illness, and classic
symptoms of diabetes (ie, polyuria, polydipsia, and weight
loss).
Treatment
Insulin
The 1921 discovery of insulin was initially thought to
represent a cure for the disease; a concept that remains
common among those unfamiliar with the disorder.
However, this is not the case. Acute morbidity and
mortality as well as a series of chronic complications still
occurs.66,67 The Diabetes Control and Complications Trial
(DCCT) research group4,70 showed the importance of
strict metabolic control for the delay and prevention of
chronic complications. However, achieving such control
represents a major undertaking for the patient and their
family. The risk of severe hypoglycaemia limits the chance
of the patient achieving euglycaemia with insulin
therapy.71 Nevertheless, there have been improvements in
type 1 diabetes therapy that may bring about advances
during the next decade.
A substantial advance in diabetes care would allow
individuals to have euglycaemia without risk of severe
hypoglycaemia, and with much less effort than is currently
devoted to intensive therapy. The examples of concepts
and devices that might be keys to this evolutionary
progress include improved devices for home blood-
glucose monitoring and routine determination of HbA1c;
development of a series of insulin analogues; introduction
of the first sensors for continuous glucose monitoring; and
development of therapies aimed at delaying or preventing
chronic complications (panel 2).
Most individuals in more-developed countries are now
treated with recombinant human insulin. With the
introduction of human insulin has come the ability to alter
the insulin molecule for improved pharmacokinetics.72
Thus, insulin analogues are now available that can be
absorbed more rapidly and that can decrease the
variability of insulin absorption (eg, Humalogue and
Aspart insulin).73,74 These insulins are rapidly absorbed
after subcutaneous injection due to alterations in the
molecule that interfere with formation of insulin
multimers. A simple example of their use relates to the
care of toddlers with type 1 diabetes.75 Regular insulin
226
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Panel 2: Therapeutic innovations for patients with
established type 1 diabetes
Improved home devices and monitors
Glucose
Fructosamine
HbA1c
Data download to physician via web
Insulin analogues with improved pharmacokinetics
Faster absorption
Reproducible absorption
Pre-packaged insulin mixtures
Improved laboratory services
Point-of-care testing for HbA1c, microalbuminuria
Assessment of endproducts of advanced glycosylation
VEGF measurements for retinopathy
Continuous glucose-monitoring devices
Measurement of real time
Non-invasive or minimally invasive
Drugs for prevention of specific complications
ACE inhibitors for nephropathy
Rigorous control of lipids with new generation statins
Protein kinase C inhibitors
Improved digital retinal-imaging systems
Islet transplantation
Stem cells
Xenoislets
Encapsulation
Improved immunosuppressants
Gene therapy
Tolerance
needs to be given before meals (ie, 30 min to 1 h before),
yet it is common for a toddler to refuse food after insulin
administration. With these new analogues, it is now
possible to administer rapid-acting insulin after the meal,
thereby alleviating parental stress. In many diabetes
centres, it is recommended that rapid-acting insulins be
administered with each meal, either with insulin pens or
with pumps. Alternative routes of insulin administration
(eg, pulmonary) are also being studied. The availability of
rapid-acting insulins has also contributed to the greater
use of insulin pumps.76,77 These pumps, although
expensive, allow for the setting of multiple basal rates of
insulin administration and bolus administration with each
meal. Similar effects can be obtained with multiple daily
injections of rapid-acting insulin combined with long-
acting insulin. Ideally, the long-acting insulin should
provide a peakless basal insulin level and thus not
contribute to erratic insulin therapy. Although even with
the increasing availability of standard human insulins (eg,
ultralente) this has been difficult to achieve, new long-
acting insulin (eg, insulin Glargine) should be an
improvement.78,79 Although these new insulins appear
promising, postmarketing experience will be important to
document whether the altered insulins have any
deleterious effects.
What is likely to represent a major milestone in the
therapy of type 1 diabetes is the discovery that interstitial
glucose reflects blood glucose with a sufficiently short lag
time to be of clinical use.80 The first generation of practical
devices that continuously monitor cutaneous interstitial
glucose are being introduced into practice. These devices
use a number of strategies for sampling interstitial
glucose, including the placement of a subcutaneous
sensor81 or use of an electric current to bring glucose to
the skin surface by iontophoreses.82 One device uses a sub-
THE LANCET Vol 358 July 21, 2001

cutaneous sensor and provides up to 3 days of glucose
monitoring.81 The device that uses an electric current does
not have an alarm nor does it allow the patient to know
glucose concentrations on a real time basis, because data
have to be downloaded at a physicians office. Such a
device can be useful in discovering severe nocturnal
hypoglycaemia or to modify insulin therapy, but there
is a need for devices with real-time information.
Furthermore, these devices do not eliminate the need for
finger-stick testing (or forearm testing with new meters) of
blood glucose, because such values are used to calibrate
the monitors. The ideal is for continuous monitoring with
alarms for high-glucose and low glucose concentrations,
as well as allowing patients to modify their insulin
administration (with multiple injections of rapid-acting
insulins or insulin pumps) in real-time on the basis of
glucose values. Such a therapeutic strategy will come
much closer to the manner in which healthy individuals
secrete insulin, and should provide the added information
needed to implement intensive insulin therapy. The
development of clinical algorithms for such therapies will
require extensive study, and there is likely to be a lag time
in national health systems and insurance companies
funding such new treatments. If the devices live up to
their promise of providing accurate real-time glucose
information, we believe they will revolutionise the therapy
of type 1 diabetes; ameliorating the problems (ie,
morbidity, mortality, and quality-of-life issues) caused by
wide swings in blood glucose concentrations.
Other treatments
Although physicians treating patients with diabetes are
excited about the promise of improved glucose
monitoring and insulin therapy, patients and their families
would obviously prefer the disorder to be cured without
the need for insulin injections. Cures have been
accomplished with both pancreas transplantation83 and
more recently with islet transplantation.84 Despite these
improvements, significant obstacles remain. Limitations
for both forms of transplantation include the relative lack
of organ donors for allogeneic transplantation, and the
need for continuous immunosuppression. Indeed, the
immunosuppression is needed not only to prevent
rejection, but also to block recurrent autoimmune islet
destruction.85 The immunosuppressive regimens for
pancreas transplantation have improved greatly during the
past decade, with drugs such as mycophenolate mofetil
replacing azathioprine, and allowing for much lower doses
of glucocorticoid therapy. Many centres now connect the
pancreas directly to the bowel by anastomosis rather than
using bladder drainage of exocrine secretions.86 These
improvements, as well as 1-year graft survival of more
than 90%, make pancreas transplantation a realistic
consideration for patients with diabetes who require renal
transplantation, or for rare instances where patients have
intractable diabetes-related problems.87 Immediately after
the transplant, hyperglycaemia can be cured, but it may
be at the cost of surgical complications and immuno-
suppression.
From a surgical standpoint, islet transplantation
represents an attractive alternative in that islets can simply
be infused into the liver through a catheter. However,
until the study from the Edmonton group,88 successful
islet transplantation was sporadic at best. The Edmonton
group has introduced a modified immunosuppressive
regimen that involves the use of daclizumab, sirolimus,
and tacrolimus; however, the groups success owes as
much to their ability to procure and isolate islets.
Furthermore, more than one donor pancreas is needed for
THE LANCET Vol 358 July 21, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
each patient, and many islet isolations do not yield usable
islets. Several centres will be implementing the Edmonton
protocol during the next year with great hope for success,
yet, given the constraints, few patients will have their
diabetes cured with islet transplantation. For these
procedures to have a major clinical impact, a new source
of islets will be required (xenogeneic transplants, growth
of islets from stem cells, &c). The basic biological barriers
to using such cells are in the early stages of research.
Additional hopes are high for the development of
tolerance-inducing therapies such that life-long
immunosuppression will not be needed. Experiences with
transplantation have taught researchers that autoimmune
and alloimmune islet destruction can be overcome, and
that isolated islets can cure diabetes. We predict that these
therapies will certainly evolve over the next decade and
should compete with mechanical insulin delivery systems
coupled to real-time glucose monitoring to revolutionise
therapy of type 1 diabetes. Gene therapy might be
promising for promotion of euglycaemia. Two recent
studies,89,90 one using gut K cells and the other involving
liver cells, showed that the insulin gene delivery could be
both glucose responsive and establish euglycaemia.89,90
Even today, many of the chronic complications of
type 1 diabetes can be delayed or prevented, but for many
individuals this does not happen. Meticulous glucose
control is essential, but procedures as simple as yearly
ophthalmologic eye examinations coupled with early
treatment of proliferative retinopathy could prevent the
bulk of diabetes-related blindness.91 Ophthalmological
screening needs to be made more accessible, with non-
mydriatic digital retinal imaging,92 so that all patients are
appropriately screened. Periodic microalbuminuria testing
is a standard of care, and when coupled with early
angiotensin-converting-enzyme therapy can change the
progressive course of diabetic renal disease.93 LDL
cholesterol for patients with diabetes should be
maintained at less than 100 mg/dL (26 mmol/L).
Selective protein kinase C inhibitors may provide a so-
called golden bullet for microvascular disease caused by
glucose toxicity, and may offer a major contribution to the
medical management of diabetic retinopathy and diabetic
neuropathy and nephropathy.94 Finally, all patients with
diabetes should have routine foot examinations and
aggressive therapy of early lesions.95 In short, a strong
commitment to routine procedures by both the patient as
well as the health-care team should lead to prevention or
delay of complications in many patients.
Present and future
More than 2 million individuals have type 1 diabetes
within the European and North American continents and
this number will dramatically increase. At present, the
development of the disorder is a life sentence to an
extremely tedious and only partly effective therapy.
Providing the basics of appropriate care, and the
development of dramatically improved therapy and trials
for diabetes prevention, should be our response to this
devastating disease.
References
1 Castano L, Eisenbarth GS. Type 1 diabetes: a chronic autoimmune
disease of human, mouse, and the rat. Annu Rev Immunol 1990;
8: 64779.
2 Atkinson MA, Maclaren NK. The pathogenesis of insulin dependent
diabetes. N Engl J Med 1994; 331: 142836.
3 Bowman M, Leiter E, Atkinson M. Autoimmune diabetes in NOD
mice: a genetic program interruptible by environmental manipulation.
Immunol Today 1994; 15: 11520.
4 Diabetes Control and Complications Trial Research Group. The
227
SEMINAR
effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes
mellitus. N Engl J Med 1993; 329: 97786.
5 LaPorte RE, Tajima N, Kerblom HK, et al. Geographic differences in
the risk of insulin-dependent diabetes mellitus: the importance of
registries. Diabetes Care 1985; 8 (suppl 1): S10107.
6 Anonymous. EURODIAB ACE Study Group. Variation and trends in
incidence of childhood diabetes in Europe. Lancet 2000; 355:
87376.
7 Onkamo P, Vonnen S, Karvonen M, Tuomilehto J. Worldwide
increase in incidence of Type 1 diabetes - the analysis of the data on
published incidence trends. Diabetologia 1999; 42: 13951403.
8 Green A, Gale EA, Patterson CC, for the EURODIAB ACE study.
Incidence of childhood-onset insulin-dependent diabetes mellitus: the
EURODIAB ACE study. Lancet 1992; 339: 90509.
9 Muntoni S. New insights into the epidemiology of type 1 diabetes in
Mediterranean countries. Diabetes Metab Res Rev 1999; 15:
13340.
10 Todd JA. From genome to aetiology in a multifactorial disease, type 1
diabetes. BioEssays 1999; 21: 16474.
11 Buzzetti R, Quattrocchi CC, Nistico L. Dissecting the genetics of type
1 diabetes: relevance for familial clustering and differences in
incidence. Diabetes Metab Rev 1998; 14: 11128.
12 Lernmark A, Ott J. Sometimes it is hot, sometimes its not. Nat Genet
1998; 19: 21314.
13 Bennett ST. Human type 1 diabetes and the insulin gene: principles
for mapping polygenes. Annu Rev Genet 1996; 30: 34370.
14 Nistico L, Buzzetti R, Pritchard LE, et al. The CTLA-4 gene region
on chromosome 2q33 is linked to and associated with type 1 diabetes.
Hum Mol Genet 1996; 5: 107580.
15 Ellis TM, Atkinson MA. Early infant diets and insulin-dependent
diabetes. Lancet 1996; 347: 146465.
16 Dahlquist GG. Viruses and other perinatal exposures as initiating
events for beta-cell destruction. Ann Med 1997; 29: 41317.
17 Knip M, Akerblom HK. Environmental factors in the pathogenesis of
type 1 diabetes mellitus. Exp Clin Endocrinol Diabetes 1999;
107 (suppl 3): S93100.
18 Norris JM, Beaty B, Klingensmith G, et al. Lack of association
between early exposure to cows milk protein and beta-cell
autoimmunity. Diabetes Autoimmunity Study in the Young. JAMA
1996; 276: 60914.
19 Graves PM, Barriga KJ, Norris JM, et al. Lack of association between
early childhood immunizations and beta-cell autoimmunity. Diabetes
Care 1999; 22: 169497.
20 Hummel M, Fuchtenbusch M, Schenker M, Ziegler AG. No major
association of breast-feeding, vaccinations, and childhood viral
diseases with early islet autoimmunity in the German BABYDIAB
Study. Diabetes Care 2000; 23: 96974.
21 Hypponen E, Kenward MG, Virtanen SM, et al. Infant feeding, early
weight gain, and risk of type 1 diabetes. Childhood Diabetes in
Finland (DiMe) Study Group. Diabetes Care 1999; 22: 196165.
22 Lonnrot M, Salminen K, Knip M, et al. Enterovirus RNA in serum is
a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a
prospective study. Childhood Diabetes in Finland (DiMe) Study
Group. J Med Virol 2000; 61: 21420.
23 Virtanen SM, Laara E, Hypponen E, et al. Cows milk consumption,
HLA-DQB1 genotype, and type 1 diabetes: a nested case-control
study of siblings of children with diabetes. Childhood diabetes in
Finland study group. Diabetes 2000; 49: 91217.
24 Hattersley AT. Genes versus environment in insulin-dependent
diabetes: the phoney war. Lancet 1997; 349: 14748.
25 Wasmuth HE, Hess G, Viergutz C, Henrichs HR, Martin S, Kolb H.
Non-specific viral infections as possible synchronising events of the
manifestation of type 1 diabetes. Diabetes Metab Res Rev 2000;
16 17778.
26 Eisenbarth GS. Type 1 diabetes mellitus. A chronic autoimmune
disease. N Engl J Med 1986; 314: 136068.
27 McKinney PA, Parslow R, Gurney KA, Law GR, Bodansky HJ,
Williams R. Perinatal and neonatal determinants of childhood type 1
diabetes: a case-control study in Yorkshire, U.K. Diabetes Care 1999;
22: 92832.
28 Dahlquist GG, Patterson C, Soltesz G. Infections and vaccinations as
risk factors for childhood type 1 (insulin-dependent) diabetes mellitus:
a multicentre case-control investigation. EURODIAB Substudy 2
Study Group. Diabetologia 2000; 43: 4753.
29 Pundziute-Lycka A, Urbonaite B, Dahlquist G. Infections and risk of
Type I (insulin-dependent) diabetes mellitus in Lithuanian children.
Diabetologia 2000; 43: 122934.
30 Serreze DV, Ottendorfer EW, Ellis TM, Gauntt CJ, Atkinson MA.
Acceleration of type 1 diabetes by a coxsackievirus infection requires a
preexisting critical mass of autoreactive T-cells in pancreatic islets.
Diabetes 2000; 49: 70811.
228
For personal use. Only reproduce with permission from The Lancet Publishing Group.
31 Ziegler A-G, Hummel M, Schenker M, Bonifacio E. 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. Diabetes 1999; 48: 46068.
32 Kimpimaki T, Kulmala P, Savola K, et al. Disease-associated
autoantibodies as surrogate markers of type 1 diabetes in young
children at increased genetic risk. Childhood Diabetes in Finland
Study Group. J Clin Endocrinol Metab 2000; 85: 112632.
33 Yu L, Robles DT, Abiru N, et al. Early expression of antiinsulin
autoantibodies of humans and the NOD mouse: evidence for early
determination of subsequent diabetes. Proc Natl Acad Sci U S A 2000;
97: 170106.
34 Colman PG, Steele C, Couper JJ, et al. Islet autoimmunity in infants
with a Type 1 diabetic relative is common but is frequently restricted
to one autoantibody. Diabetologia 2000; 43: 20309.
35 Litherland SA, Xie XT, Hutson AD, et al. Aberrant prostaglandin
synthase 2 expression defines an antigen-presenting cell defect for
insulin-dependent diabetes mellitus. J Clin Invest 1999 104: 51523.
36 Zimmet PZ, Tuomi T, Mackay IR, et al. Latent autoimmune diabetes
mellitus in adults (LADA): the role of antibodies to glutamic acid
decarboxylase in diagnosis and prediction of insulin dependency.
Diabet Med 1994; 11: 299303.
37 Turner R, Stratton I, Horton V, et al. UKPDS 25: autoantibodies to
islet-cell cytoplasm and glutamic acid decarboxylase for prediction of
insulin requirement in type 2 diabetes. UK Prospective Diabetes
Study Group. Lancet 1997; 350: 128893.
38 Ingawa A, Hanafusa T, Miyagawa JI, Matsuzawa Y. A novel subtype
of Type 1 diabetes mellitus characterized by a rapid onset and an
absence of diabetes-related antibodies. N Engl J Med 2000;
342: 30107.
39 Foulis AK, Liddle CN, Farquharson MA, Richmond JA, Weir RS.
The histopathology of the pancreas in Type 1 (insulin-dependent)
diabetes mellitus: a 25-yr review of deaths in patients under 20 years
of age in the United Kingdom. Diabetologia 1986; 29: 26774.
40 Iwagawa A, Hanafusa T, Itoh N, et al. Immunological abnormalities
in islets at diagnosis paralleled further deterioration of glycaemic
control in patients with recent-onset Type 1 (insulin-dependent)
diabetes mellitus. Diabetologia 1999; 42: 57478.
41 Moriwaki M, Itoh N, Miyagawa J, et al. Fas and Fas ligand expression
in inflamed islets in pancreas sections of patients with recent-onset
type 1 diabetes mellitus. Diabetologia 1999; 42: 133240.
42 Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies
in diabetes mellitus with autoimmune polyendocrine deficiencies.
Lancet 1974; 2: 127983.
43 Verge CF, Stenger D, Bonifacio E, et al. Combined use of
autoantibodies (IA-2 autoantibody, GAD autoantibody, insulin
autoantibody, cytoplasmic islet cell antibodies) in type 1 diabetes:
Combinatorial Islet Autoantibody Workshop. Diabetes 1998;
47: 185766.
44 Hatziagelaki E, Jaeger C, Petzoldt R, et al. The combination of
antibodies to GAD-65 and IA-2ic can replace the islet-cell antibody
assay to identify subjects at risk of type 1 diabetes mellitus. Horm
Metab Res 1999; 31: 56469.
45 Kimpimaki T, Kulmala P, Savola K, et al. Disease-associated
autoantibodies as surrogate markers of type 1 diabetes in young
children at increased genetic risk. Childhood Diabetes in Finland
Study Group. J Clin Endocrinol Metab 2000; 85: 112632.
46 Atkinson MA, Kaufman DL, Tobin AJ, Maclaren NK. Islet cell
autoantibodies reactive to glutamate decarboxylase in insulin
dependent diabetes. J Clin Invest 1992; 91: 35056.
47 Lernmark A, Molenaar JL, van Beers WA, et al. The Fourth
International Serum Exchange Workshop to standardize cytoplasmic
islet cell antibodies. The Immunology and Diabetes Workshops and
Participating Laboratories. Diabetologia 1991; 34: 53435.
48 Rabinovitch A, Skyler JS. Prevention of type 1 diabetes. Med Clin
North Am 1998; 82: 73955.
49 Schatz D, Krischer J, Skyler J. Now is the time to prevent type 1
diabetes. J Clin Endocrinol Metab 2000; 85: 494522.
50 Knip M, Douek IF, Moore et al. Safety of high-dose nicotinamide: a
review. ENDIT Group. European Nicotinamide Diabetes Intervention
Trial. Diabetologia. 2000; 43: 133745.
51 DPT-1 Study Group. The Diabetes Prevention Trial-Type 1 diabetes
(DPT-1): implementation of screening and staging of relatives.
Transplant Proc 1995; 27: 3377.
52 Seissler J, de Sonnaville JJJ, Morgenthaler NG, et al. Immunological
heterogeneity in type 1 diabetes: presence of distinct autoantibody
patterns in patients with acute onset and slowly progressive disease.
Diabetologia 1998; 41: 89197.
53 Horton V, Stratton I, Bottazzo GF, et al. Genetic heterogeneity of
autoimmune diabetes: age of presentation in adults is influenced by
HLA DRB1 and DQB1 genotypes (UKPDS 43). UK Prospective
Diabetes Study (UKPDS) Group. Diabetologia 1999; 42: 60816.
54 Turner R, Stratton I, Horton V, et al. UKPDS 25: autoantibodies to
THE LANCET Vol 358 July 21, 2001

islet-cell cytoplasm and glutamic acid decarboxylase for prediction of
insulin requirement in type 2 diabetes. UK Prospective Diabetes
Study Group. Lancet 1997; 350: 128893.
55 Seissler J, de Sonnaville JJ, Morgenthaler NG, et al. Immunological
heterogeneity in type 1 diabetes: presence of distinct autoantibody
patterns in patients with acute onset and slowly progressive disease.
Diabetologia 1998; 41: 89197.
56 Verge CF, Stenger D, Bonifacio E, et al. Combined use of
autoantibodies (IA-2ab, Gadab, IAA, ICA) in type 1 diabetes:
Combinatorial islet autoantibody workshop. Diabetes 1998;
47: 185766.
57 Leslie RD, Atkinson MA, Notkins AL. Autoantigens IA-2 and GAD
in Type I (insulin-dependent) diabetes. Diabetologia 1999; 42: 314.
58 Riley WJ, Maclaren NK, Lezotte DC, Spillar RP, Rosenbloom AL.
Thyroid autoimmunity in insulin-dependent diabetes mellitus: the
case for routine screening. J Pediatr 1981; 99: 35054.
59 Vitoria JC, Castano L, Rica I, Bilbao JR, Arrieta A, Garcia-Masdevall
MD. Association of insulin-dependent diabetes mellitus and celiac
disease: a study based on serologic markers. J Pediatr Gastroenterol
Nutr 1998; 27: 4752.
60 Savilahti E, Simell O, Koskimies S, Rilva A, Kerblom HK. Celiac
disease in insulin-dependent diabetes mellitus. J Pediatr 1986;
108: 69093.
61 Bao F, Yu L, Babu S, et al. One third of HLA DQ2 homozygous
patients with type 1 diabetes express celiac disease associated
transglutaminase autoantibodies. J Autoimmunity 1999; 13: 14348.
62 Hoffenberg EJ, Bao F, Eisenbarth GS, et al. Silent celiac disease in
children with a genetic risk. J Pediatr 2000; 137: 35660.
63 Nerup J. Addisons disease: serological studies. Acta Endocrinol 1974;
76: 14258.
64 Yu L, Brewer KW, Gates S, et al. DRB1*04 and DQ alleles:
expression of 21-hydroxylase autoantibodies and risk of progression to
Addisons disease. J Clin Endocrinol Metab 1999; 84: 32835.
65 Redondo MJ, Eisenbarth GS. Autoimmune Polyendocrine Syndrome
Type II. In: Eisenbarth GS, ed. Endocrine and Organ Specific
Autoimmunity, O Georgetown: R G Landes Company, 1997:
4161.
66 Matsushima M, LaPorte RE, Maruyama M, et al. Geographic
variation in mortality among individuals with youth-onset diabetes
mellitus across the world. Diabetologia 1997; 40: 21216.
67 Podar T, Solntsey A, Reunanen A, et al. Mortality in patients with
childhood-onset type 1 diabetes in Finland, Estonia, and Lithuania:
follow-up of nationwide cohorts. Diabetes Care 2000; 23: 29094.
68 Glaser N, Barnett P, McCaslin D, et al. Risk factors fir cerebral edema
in children with diabetic ketoacidosis. N Engl J Med 2001;
344: 26469.
69 Franklin B, Liu J, Ginsberg-Fellner F. Cerebral edema and
ophthalmoplegia reversed by mannitol in a new case of insulin-
dependent diabetes mellitus. Pediatrics 1982; 69: 8790.
70 Anon. Retinopathy and nephropathy in patients with type 1 diabetes
four years after a trial of intensive therapy. The Diabetes Control and
Complications Trial/Epidemiology of Diabetes Interventions and
Complications Research Group. N Engl J Med 2000; 342: 38189.
71 Anonymous. Epidemiology of severe hypoglycemia in the diabetes
control and complications trial. The DCCT Research Group. Am J
Med 1991; 90: 45059.
72 Vajo Z, Duckworth WC. Genetically engineered insulin analogs:
diabetes in the new millennium. Pharmacol Rev 2000; 52: 19.
73 Garg SK, Anderson JH, Perry SV, et al. Long-term efficacy of
humalog in subjects with Type 1 diabetes mellitus. Diabet Med 1999;
16: 38487.
74 Mortensen HB, Lindholm A, Olsen BS, Hylleberg B. Rapid
appearance and onset of action of insulin aspart in paediatric subjects
with type 1 diabetes. Eur J Pediatr 2000; 159: 48388.
THE LANCET Vol 358 July 21, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
75 Rutledge KS, Chase HP, Klingensmith GJ, Walravens PA, Slover RH,
Garg SK. Effectiveness of postprandial Humalog in toddlers with
diabetes. Pediatrics 1997; 100: 96872.
76 Catargi B, Breilh D, Roger P, Tabarin A. Glucose profiles in a type 1
diabetic patient successively treated with CSII using regular insulin,
lispro and an implantable insulin pump. Diabetes Metab 2000;
26: 21014.
77 Boland EA, Grey M, Oesterle A, Fredrickson L, Tamborlane WV.
Continuous subcutaneous insulin infusion. A new way to lower risk of
severe hypoglycemia, improve metabolic control, and enhance coping
in adolescents with type 1 diabetes. Diabetes Care 1999; 22: 177984.
78 Ratner RE, Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson CA.
Less hypoglycemia with insulin glargine in intensive insulin therapy for
type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1
Diabetes. Diabetes Care 2000; 23: 63943.
79 Bolli GB, Owens DR. Insulin glargine. Lancet 2000; 356: 44345.
80 Rebrin K, Steil GM, van Antwerp WP, Mastrototaro JJ. Subcutaneous
glucose predicts plasma glucose independent of insulin: implications
for continuous monitoring. Am J Physiol 1999; 277: E561E571
81 Mastrototaro J. The MiniMed Continuous Glucose Monitoring
System (CGMS). J Pediatr Endocrinol Metab 1999; 12 (suppl 3):
S75158.
82 Garg SK, Potts RO, Ackerman NR, Fermi SJ, Tamada JA, Chase HP.
Correlation of fingerstick blood glucose measurements with
GlucoWatch biographer glucose results in young subjects with type 1
diabetes. Diabetes Care 1999; 22: 170814.
83 Robertson RP. Prevention of recurrent hypoglycemia in type 1
diabetes by pancreas transplantation. Acta Diabetol 1999; 36:
39.
84 Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven
patients with type 1 diabetes mellitus using a flucocorticoid-free
immunosuppressive regimen. N Engl J Med 2000; 343: 23038.
85 Sutherland DE, Sibley R, Xu XA, et al. Twin-to-twin pancreas
transplantation: reversal and re-enactment of the pathogenesis of type
I diabetes. Trans Assoc Am Physicians 1984; 97: 8087.
86 Robertson RP, Sutherland DER, Kendall DM, Teuscher AU,
Gruessner RWG, Gruessner A. Metabolic characterization of long-
term successful pancreas transplants in type I diabetes. J Investig Med
1996; 44: 54955.
87 Smets YF, Westendorp RG, van der Pijl JW, et al. Effect of
simultaneous pancreas-kidney transplantation on mortality of patients
with type-1 diabetes mellitus and end-stage renal failure. Lancet 1999;
353: 191519.
88 Berney T, Ricordi C. Islet cell transplantation: the future? Langenbecks
Arch Surg 2000; 385: 37378.
89 Lee HC, Kim SJ, Kim KS, Shin HC, Yoon JW. Remission of type 1
diabetes by gene therapy using a single-chain insulin analogue. Nature
2000; 408: 48388.
90 Cheung AT, Dayanandan B, Lewis JT, et al. Glucose-dependent
insulin release from genetically engineered K cells. Science 2000;
290: 195962
91 Cantrill HL. The diabetic retinopathy study and the early treatment of
diabetic retinopathy study. Int Ophthalmol Clin 1984; 24: 1329.
92 Lin DY, Blumenkranz MS, Brothers R. The role of digital fundus
photography in diabetic retinopathy screening. Diabetes Technol Ther
1999; 1: 47787.
93 Parving H-H. Renoprotection in diabetes: genetic and non-genetic risk
factors and treatment. Diabetologia 1998; 41: 74559.
94 Bursell SE, King GL. Can protein kinase C inhibition and vitamin E
prevent the development of diabetic vascular complications? Diabetes
Res Clin Pract 1999; 45: 16982.
95 Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW,
Karchmer AW. Assessment and management of foot disease in
patients with diabetes. N Engl J Med 1994; 331: 85460.
229