Type 1 diabetes Type 1 diabetes accounts for only about 5–10% of all cases of diabetes; however, its incidence continues to increase Lancet 2006; 367: 847–58 worldwide and it has serious short-term and long-term implications. The disorder has a strong genetic component,
See Comment page 795 inherited mainly through the HLA complex, but the factors that trigger onset of clinical disease remain largely Division of Endocrinology, unknown. Management of type 1 diabetes is best undertaken in the context of a multidisciplinary health team and Department of Paediatrics, Hospital for Sick Children and requires continuing attention to many aspects, including insulin administration, blood glucose monitoring, meal University of Toronto, Toronto, planning, and screening for comorbid conditions and diabetes-related complications. These complications consist of ON, Canada M5G 1X8 microvascular and macrovascular disease, which account for the major morbidity and mortality associated with type 1 diabetes. Newer treatment approaches have facilitated improved outcomes in terms of both glycaemic control and firstname.lastname@example.org reduced risks for development of complications. Nonetheless, major challenges remain in the development of approaches to the prevention and management of type 1 diabetes and its complications.
In this age of increasing obesity, the epidemic of type 2
susceptibility, roughly 15% from two other genes—
diabetes threatens both to overwhelm health care
insulin-VNTR (IDDM2) and CTLA-4 (IDDM12)—with
services and to obscure the health care implications and
minor contributions from the other IDDM genes.4–6,9
challenges of type 1 diabetes.1,2 Although type 1 diabetes
Both high risk (eg, DR3/4, DQA1*0301-DQB1*0302,
accounts for only 5–10% of all those with diabetes, it
and DQA1*0501-DQB1*0201) and protective HLA
remains a serious chronic disorder, usually beginning
haplotypes (eg, DQA1*0102-DQB1*0602, associated
earlier in life than type 2 diabetes, but with important
with diabetes resistance, and DR molecules such as
DRB1*1401, associated with protection from diabetes)
In this seminar on type 1 diabetes I emphasise:
have been identiﬁed.4 These susceptibility genes are
(i) current theories of pathogenesis; (ii) epidemiology
thought to be important regulators of the immune
and presentation; (iii) management; (iv) diabetes-related
response. Other genes associated with either rare
complications; (v) psychosocial concomitants; and
syndromes including diabetes (eg, AIRE and Foxp3) or
(vi) the challenges facing diabetes researchers and
other autoimmune conditions (eg, PTPN22) might
health-care professionals. Although not dealt with in this
also provide important insights into the immune
Seminar, issues such as diabetic ketoacidosis and its
prevention and management, and the challenges of
The next step requires exposure to one or more
diabetes in pregnancy for both mother and fetus, should
environmental triggers that alter immune function,
not be overlooked in the comprehensive care of
thereby initiating ␤-cell destruction. Putative triggers
include viruses (eg, enteroviruses, coxsackie, congenital
Pathogenesis Chromosome Candidate genes/markers
Type 1 diabetes is a condition in which pancreatic ␤-celldestruction
HLA DR/DQ regionMajor role in presentation of peptides to T cells
deﬁciency.3–6 Two forms are identiﬁed: type 1A results
Insulin-VNTR Protection associated with greater
from a cell-mediated autoimmune attack on ␤ cells,4–6
whereas type 1B is far less frequent, has no known
CTLA-4, CD28 Related to T-cell activation,
cause, and occurs mostly in individuals of Asian or
African descent, who have varying degrees of insulin
For many of those not listed (IDDM 3-11, 13-17), either the responsible gene remains
deﬁciency between sporadic episodes of ketoacidosis.7
unidentiﬁed or the gene function is uncertain in relation to type 1 diabetes.
In the 1980s Eisenbarth8 proposed the current model
Table 1: Important susceptibility loci for type 1 diabetes
for the development of the immune form of type 1diabetes and although our understanding hasprogressed signiﬁcantly since then, the basic aspects of
Search strategy and selection criteria
this model remain pertinent.4–6 This model postulatesthat everyone is born with a degree of susceptibility to
PubMed and the Cochrane Library database were searched with the terms: “type 1
develop type 1 diabetes: for some this susceptibility is
diabetes”, “insulin-dependent diabetes mellitus”, “juvenile diabetes”, “insulin” and
high, for others very low. Susceptibility is largely
“insulin analogues”, “blood glucose monitoring”, “glycosylated haemoglobin” or
inherited, residing predominantly in the HLA genotypes
“haemoglobin A1c”, “glycaemic index”, “diabetes-related complications”, “diabetic
DR and DQ, and to a lesser extent in a host of other
nephropathy”, “retinopathy”, “neuropathy”; and “macrovascular complications of
genetic loci termed IDDM (insulin-dependent diabetes
diabetes”. Most recent papers, systematic review articles, meta-analyses and evidence-
mellitus) susceptibility genes (table 1). The HLA locus
based guidelines were preferentially selected.
is thought to confer about 50% of the genetic
www.thelancet.com Vol 367 March 11, 2006
rubella),10,11 environmental toxins (eg, nitrosamines),12 or
disorders are less frequent in children in large families or
foods (eg, early exposure to cow’s milk proteins, cereals,
those families receiving day care than in children in
or gluten).13–17 A close relation has been identiﬁed only
small families or those not in day care.29,31,32 Similarities
with congenital rubella.10,11 The results of a 2004 study
exist between these ﬁndings and reports of type 1
did not accord with a causal relation between childhood
diabetes.33 These ﬁndings suggest that children in these
vaccination and type 1 diabetes.18,19 Thus, the search for a
circumstances are less exposed to infections or other
so-called smoking gun trigger continues.
immune challenges early in life that act as protective
The abnormal activation of the T-cell-mediated
environmental inﬂuences. Gale29 has proposed that the
immune system in susceptible individuals leads to an
protective effect is mediated by regulatory T lymphocytes.
inﬂammatory response within the islets (insulitis) as
Although plausible, this hypothesis lacks credible
well as to a humoral (B cell) response with production of
scientiﬁc support in the causation of type 1 diabetes.
antibodies to ␤-cell antigens. Islet cell antibodies were
In the accelerator hypothesis, Wilkin30 postulates that
the ﬁrst described, but have been supplanted by more
diabetes is a single disease, rather than two distinct
speciﬁc autoantibodies to insulin (IAA), glutamic acid
entities, type 1 and type 2 diabetes. He argues that the two
decarboxylase (GADA/GAA), and the protein tyrosine
types of diabetes are distinguished only by the rate of ␤-cell
phosphatase IA2 (IA-2AA), all of which are easily
loss, and the speciﬁc accelerators responsible. Wilkin
detected by sensitive radioimmunoassay.6 The presence
implicates three accelerators: the ﬁrst is the intrinsic
of one or more type of antibody can precede the clinical
potential for a high rate of ␤-cell apoptosis, an essential but
onset of type 1 diabetes by years or even decades. The
insufﬁcient step in the development of diabetes. The
presence and persistence of positivity to multiple
second accelerator is insulin resistance, resulting typically
antibodies increases the likelihood of progression to
from weight gain and physical inactivity, and is central to
clinical disease.20–22 There is no evidence that any of these
the proposed link between the two types of diabetes.
antibodies has an active role in the pathogenesis of this
Insulin resistance puts pressure on a ␤-cell mass already
at risk for accelerated apoptosis, contributing to the
Continuing destruction of ␤ cells leads to progressive
expression of clinical diabetes. The third accelerator is
loss of insulin-secretory reserve with, in order, loss of
present only in those individuals with genetically
ﬁrst phase insulin secretion in response to an
determined predisposition to ␤-cell autoimmunity. The
intravenous glucose tolerance test, then to clinical
metabolically more active ␤ cell, in insulin-resistant
diabetes when insulin secretion falls below a critical
individuals who are genetically biased towards a high rate
amount, and ﬁnally, in most but not all those with type 1
of apoptosis, is at greatest risk for rapid functional
diabetes, to a state of absolute insulin deﬁciency.6,8 The
deterioration and expression of typical type 1 diabetes. In
honeymoon or remission period takes place soon after
the absence of this immune accelerator, apoptosis is
clinical diagnosis and initiation of insulin therapy when
slower and progression is towards type 2 diabetes.
some endogenous insulin secretion is restored to
Proponents of the accelerator hypothesis claim that the
exhausted but not yet destroyed ␤ cells, and when
rise in childhood obesity parallels the rise in both types
insulin resistance associated with initial hyperglycaemia
of diabetes in childhood, and that the decreasing age of
is lessened.23,24 In general, these cells are destroyed more
onset of type 1 diabetes in heavier children lends further
rapidly when onset of clinical diabetes takes place at a
support to their argument.34 Opponents argue that there
young age, when there is also less likelihood of a long
is sufﬁcient evidence to support the Eisenbarth model
remission period.23 Thus, older individuals are more
for type 1 diabetes causation without having to implicate
likely to respond soon after diagnosis to immune
interventions aimed at preserving residual insulinsecretion. Epidemiology and presentation
Supportive evidence for the autoimmune pathogenesis
Past descriptions depict type 1 diabetes as a disease of
of type 1 diabetes comes from the susceptibility of these
childhood and early adulthood, with a sudden, severe
individuals to other autoimmune conditions including
presentation—ie, most people being younger than
Hashimoto’s thyroiditis, Graves’ disease, Addison’s
20 years of age at diagnosis and presenting in diabetic
disease, coeliac disease, myasthenia gravis, and
ketoacidosis. More recent data suggest that only about
vitiligo.25–28 Although recent knowledge has contributed
50–60% of those with type 1 diabetes are younger than
to our understanding of the pathogenesis of type 1
16–18 years at presentation and that such disease
diabetes, there remains no unifying theory of disease
occurs at a low incidence level throughout adulthood.
causation. The hygiene and accelerator hypotheses,
Furthermore, studies of the natural history of type 1
diabetes in ﬁrst-degree relatives with positive islet-
The hygiene hypothesis stems from observations that
related antibodies indicate that there is often a long
atopic disorders such as asthma are more common in
prodrome preceding clinical onset, in which glucose
afﬂuent than in traditional societies, their prevalence
homoeostasis is either normal or only mildly disturbed.6,22
rising with increasing modernisation, and that such
Finally, diabetic ketoacidosis is not universal at disease
www.thelancet.com Vol 367 March 11, 2006
lends support to a strong contribution of environmental
factors in causation. This conclusion is further
supported by reports that the rising incidence of
childhood disease is associated with reduced
contributions from high-risk HLA haplotypes.41
Intensive approaches to management are based on three
sentinel observations highlighted by the extensively
documented cohort of type 1 diabetes subjects enrolled
in the Diabetes Control and Complications Trial
*Polyuria, nocturia, enuresis, polydipsia, polyphagia, weight loss, lethargy, fatigue,
(DCCT) and followed in the Epidemiology of Diabetes
abdominal pain. Data modiﬁed with permission from Booth38 and Curtis and
Interventions and Complications (DCCT/EDIC) study.57–62
First, the DCCT provided unquestionable evidence of a
Table 2: Presentation of type 1 diabetes by age
very close, curvilinear relation between the degree ofglycaemic control (measured by haemoglobin A1c(HbA ) concentrations), maintained over the long term,
onset: in children, rates of 15–67% have been reported,
and the onset or progression of microvascular
inversely correlated with the incidence of type 1 diabetes
(retinopathy, nephropathy, and neuropathy) and likely
in the particular geographic location.36,37 Table 2
also macrovascular (cardiovascular, cerebrovascular,
summarises the presentation of type 1 diabetes
and peripheral vascular disease) complications.57,58
Furthermore, there is no threshold effect: any decrease
The epidemiology of type 1 diabetes has been reported
in HbA concentrations is associated with a similar
in many countries, predominantly in children younger
decline in relative risk of complications. There is also no
than 15–18 years of age. Many important observations
HbA level below which complications are completely
derive from registries: ﬁrst, incidence has been
prevented, nor one above which complications are
increasing at roughly 2–5% per year worldwide. The
certain to develop. These data underscore not only the
increase is steeper in the populations with a lower
pivotal role of glycaemic control, but also the presence of
incidence; however, even in countries with the highest
other factors, such as genes, smoking, obesity,
rates such as Finland, there has been no levelling off
hypertension, and hyperlipidaemia, in the development
since statistics started being recorded in the 1950s.40–42
Second, there is huge geographical variation, with
Second, the DCCT/EDIC cohort has convincingly
countries such as China reporting the lowest incidence
shown that those initially treated intensively, and
rates (about 0·57 cases per 100 000 population younger
achieving reduced HbA concentrations, continue to have
than 18 years of age per year) to rates roughly 30 times
greater protection against development or progression of
higher in the UK (18–20 per 100 000 per year) to almost
complications than those initially receiving conventional
100-fold higher (about 48–49 per 100 000 per year) in
therapy.59–61 This protection arises despite similar levels of
glycaemic control in the 6–10 years after completion of
Third, there is a signiﬁcant trend towards decreasing
the intervention part of the study. This metabolic or
age at presentation, particularly in children younger
hyperglycaemic memory demands that intensive
than 5 years. The Swedish and Belgian data are notable
management be instituted as soon as diabetes is
here.52,53 In Sweden from 1983 to 1998, the overall
incidence of type 1 diabetes did not go up in the
Finally, there is an inverse relation between glycaemic
0–34 year age group, but median age at diagnosis fell.52
control and the risk of severe hypoglycaemic episodes) in
Similar ﬁndings were reported from 1989 to 2000 in
people with type 1 diabetes (panel 1).62 In the DCCT,
Belgium in those younger than 40 years.53 This shift to a
severe hypoglycaemia occurred about 2·5–3 times more
younger age at diagnosis could indicate either exposure
often in those in the intensive therapy groups compared
to heavier doses of environmental triggers or perhaps
with those in conventional therapy groups; adolescents
the increasing weight of the population.54,55
were about 1·5 times more likely to have hypoglycaemia
Finally, migrating populations take on the incidence
than adults in both groups. In the youngest children with
rates of their new countries within a short time. For
the disease, as well as in the older age group with
example, incidence rates for type 1 diabetes in south
enduring disease, repeated episodes of severe
Asian children in the UK are similar to those of white or
hypoglycaemia could lead to cognitive impairment.64–66
other ethnic backgrounds in the same area, which is in
Thus, hypoglycaemia is a major limiting step to
striking contrast to the very low rates reported from
achieving control with present treatment approaches.
Asia.56 This convergence of incidence rates for immigrant
There are two caveats here: ﬁrst, both in the DCCT62 as
populations with those of the background population
well as in a study of almost 3000 children and adolescents
www.thelancet.com Vol 367 March 11, 2006 Panel 1: Severity and treatment of hypoglycaemia Panel 2: Components of management of individuals with type 1 diabetes
● Mild: Autonomic symptoms (trembling, palpitations, sweating, anxiety, hunger,
nausea, tingling) are present; can be self-treated with ingestion of simple sugars
● Appropriate insulin delivery: most regimens include either
multiple daily injections or continuous subcutaneous
● Moderate: Autonomic and neuroglycopenic symptoms (difﬁculty concentrating,
insulin infusions with basal-bolus approach to insulin
confusion, weakness, drowsiness, blurred vision, dizziness, difﬁculty speaking)
symptoms are present, but the individual can still self-treat.
● Self-monitoring of blood glucose concentration:
● Severe: Assistance of another individual is required to reverse hypoglycaemia, usually
frequency of testing correlates with glycaemic outcomes
associated with confusion, convulsion or unconsciousness. Requires intravenous
● Nutritional planning: more ﬂexible programmes, including
glucose (10–25 g) or subcutaneous glucagon (0·5–1·0 mg) injection.
carbohydrate counting, replacing more rigid approaches
● Avoidance or treatment of severe hypoglycaemia and
diabetic ketoacidosis: careful attention to other
with type 1 diabetes from 18 countries,67,68 the risk of
components of management greatly decreases risk of
hypoglycaemia was not evenly spread across all centres
compared with controls. Thus, some therapeutic
● Screening for and treatment of associated disorders:
approaches might foster glycaemic control without the
speciﬁcally thyroid dysfunction (regular measurement of
same risk of severe hypoglycaemia. Second, treatments
thyroid-stimulating hormone) and coeliac disease (speciﬁc
using insulin analogues or continuous subcutaneous
antibodies—eg, tissue transglutaminase)
insulin infusion pumps have a lower incidence of
● Compensation for non-basal conditions—eg, physical
hypoglycaemia than seen with traditional insulins and
● Screening for and treatment of diabetes-related
Individuals should be fully informed about these
rationales for management and provided with realistic
targets for glyceamic control. Tables 3 and 4 provide
glucose and HbA targets established in the evidence-
based 2003 clinical practice guidelines of the Canadian
Macrovascular: detection of hyperlipidaemia and
adolescents. Diabetes self-care requires a high standard
of both initial and continuing education and care, best
● Attention to psychological and psychosocial wellbeing—
provided by a multidisciplinary health care team
eg, awareness of psychosocial stresses of chronic disorder;
consisting of physicians, nurses, dietitians, and
eating disorders; adolescent non-compliance; depression
FPG/preprandial PG 2 h postprandial PG (mmol/L) (mmol/L)
behavioural specialists experienced in the management
of type 1 diabetes.75–79 Panel 2 shows the components of
Treatment targets must be tailored to the patient, with consideration given to
Different centres use various approaches to insulin
individual risk factors. Normal range should be considered for patients in whom it canbe achieved safely. HbA =haemoglobin A1c; FPG=fasting plasma glucose; PG=plasma
management, with increasing numbers of individuals
glucose. Data used with permission from Canadian Diabetes Association.75
using basal-bolus approaches with either multiple dailyinsulin injections or insulin pumps.80 Table 5 details the
Table 3: Glycaemia and HbA targets for adults with diabetes
characteristics of commonly used insulin preparations. Multiple daily injection routines have traditionallyconsisted of isophane (NPH) or ultralente given once or
Plasma glucose HbA Considerations (mmol/L)
twice daily as the basal insulin, with regular humaninsulin boluses before meals. With the availability of
Careful avoidance of hypoglycaemia in this age group due to risk of
both fast-acting and very long-acting insulin analogues,
multiple daily injection routines increasingly use insulin
glargine or detemir as the basal insulin and insulin
lispro or aspart as the boluses before meals.69–74,81–83
Insulin pumps use fast-acting insulin in a continuousbasal rate with boluses before meals.84–87 When basal-
HbA =haemoglobin A . Source: 2003 clinical practice guidelines of the Canadian
bolus routines are fastidiously applied in conjunction
with the other aspects of management, many individuals
Table 4: Glycaemic and HbA targets by age for children and
with type 1 diabetes are able to maintain near-normal
adolescents with type 1 diabetes
www.thelancet.com Vol 367 March 11, 2006
Self-monitoring of blood glucose is fundamental to
Appearance Action characteristics*
diabetes care.75,88,89 Frequent monitoring facilitates
improved glycaemic control, avoidance of hypoglycaemia,
and lifestyle ﬂexibility when the results are used to assist
the individual in their dietary choices, physical activity,
Glucose monitors are now much smaller than
previously, require very small amounts of blood
(2–10 L), are faster at providing a result (5–15 s), and
can be used at sites other than ﬁngertips.89 Veriﬁcation
of accuracy of self-monitoring is achieved by comparing
results obtained from the patient’s meter with a
Very long-acting analogues Detemir
simultaneous specimen sent to the laboratory. A
difference of less than 20% between meter andlaboratory measurements is thought acceptable, which
This list represents the most commonly used insulin preparations and provides averagesfor the action characteristics, but these preparations also show variability within and
might be difﬁcult in concentrations less than 4 mmol/L.
between individuals. In general, there is less variability with insulin analogues than with
Most meters incorporate data management systems;
either animal derived or biosynthetic human insulin preparations. *Shown in hours,
however, keeping a blood glucose logbook is needed to
unless otherwise indicated. †Intermediate-acting and long-acting insulin preparationsneed agitation before use to allow resuspension, whereas very long-acting analogues
detect patterns of glucose control and make appropriate
dose adjustments. Continuous glucose monitoringtechnologies using subcutaneous sensors have become
Table 5: Time course of action of currently available subcutaneously injected insulin preparations
increasingly used in clinical care as a means of accessingmore complete glycaemic data than is available withtraditional self-monitoring.89,93
Both a meta-analysis and the Cochrane Metabolic and
Whereas self-monitoring records daily variations in
Endocrine Disorders Group reviewed randomised
blood glucose concentrations, long-term control is best
controlled trials comparing intensive therapy regimens
measured by HbA concentrations, indicating average
using fast-acting insulin analogues with regimens using
regular insulin.74,81 A small (Ϫ0·1 to Ϫ0·15%) but
90–120 days.94 Each laboratory needs to standardise its
signiﬁcant reduction in HbA was reported with the
analogues, with comparable results between the
internationally recognised reference laboratory since
analogues and regular insulin in terms of overall
there are no universal standards against which individual
hypoglycaemia. Although fast-acting analogues did not
There are few data that lend support to rigid adherence
macrovascular risk by reducing post-prandial glycaemia.
to one particular approach to nutritional therapy in
Quality of life was improved with analogue use, largely
individuals with type 1 diabetes.97 Thus, nutritional
because of the shorter interval between injection and food
planning should be tailored to the individual’s dietary
preferences, age and stage of development, weight,
Several open-label randomised controlled trials as well
culture, and lifestyle.97,98 In general, patients are
as observational studies have assessed insulin glargine or
encouraged to follow guidelines for healthy eating similar
detemir in adults with type 1 diabetes70–73,83 All participants
to the general population—ie, varied consumption from
in these trials used basal–bolus insulin regimens. The
all food groups, maintaining a healthy weight, limiting
results of most trials showed no differences in HbA
total fat to less than about 30% of daily caloric intake, and
concentrations between groups receiving insulin glargine
ensuring adequate intake of carbohydrate, protein,
or detemir, and those receiving isophane insulin. A few
minerals, vitamins, and essential fatty acids. Consistency
in meal planning can assist in reaching glycaemic targets,
glargine was compared with isophane or ultralente. Some
and modiﬁcations in the diet could also be helpful in
studies reported less night time or day time
achieving lipid and lipoprotein proﬁles aimed at reducing
hypoglycaemia or less severe hypoglycaemic events in
macrovascular risk. Nutritional planning in children and
those receiving insulin glargine than in those receiving
adolescents aims to provide adequate energy to promote
Studies in children and adolescents with type 1 diabetes
Although most agree that the quantity of carbohydrate
with insulin analogues show similar ﬁndings to those in
ingested substantially affects glycaemia, disagreement
adults.69,70 Nonetheless, despite advances in insulin
has focused on the importance of the quality of the
therapeutics during the past 25 years, only a few
ingested carbohydrate,98–100 despite the demonstration of
individuals with type 1 diabetes are able to reach the
a ﬁve-fold difference in the effect on glycaemia when
equivalent amounts of carbohydrate from different
www.thelancet.com Vol 367 March 11, 2006
sources are compared by glycaemic index. A meta-analysis of 14 randomised controlled trials (six in type 1
Panel 3: Risk factors for diabetes-related complications
diabetes) shows a small but clinically signiﬁcant
improvement in HbA levels in those receiving low
● Early onset and long duration of type 1 diabetes
versus high glycaemic index diets.99 Thus, individuals
● Genetic predisposition—eg, family history of diabetes-
should be informed about the notion of glycaemic index
and encouraged to incorporate foods that score lower on
the index, such as wholegrain cereals, breads and pastas,
Approaches with carbohydrate counting to the
nutritional management of type 1 diabetes have
developed in parallel with basal-bolus insulin regimens.98Carbohydrate counting allows adjustment of premeal
*No single gene or cluster of genes has been identiﬁed that explains a majorportion of the risk of microvascular or macrovascular complications. Candidate
insulin boluses of fast-acting insulin analogues
genes include those involved in the renin-angiotensin-system in nephropathy
according to both the premeal glucose concentration as
(eg, angiotensin-converting enzyme gene or angiotensin 2 receptor genes);
well as the carbohydrate content of the meal. Calculation
genes related to disruptions in growth factors and cytokines (eg, vascularendothelial growth factor), the polyol pathway (eg, aldose reductase), protein
of insulin to carbohydrate ratios (ie, the amount of
kinase C activation, vascular or platelet function, or the nitric oxide pathway. So
insulin needed to limit glycaemic excursions after
far, the demonstrated interactions between gene polymorphisms and diabetes-related complications have been quite weak.
meals) allows for increased ﬂexibility in meal planningwithout sacriﬁcing glycaemic control. Hypoglycaemia
Despite these efforts, severe hypoglycaemia occurs with
Hypoglycaemia is a major obstacle to glycaemic control
a frequency of about ﬁve to 50 episodes per 100 patient-
for many patients (panel 1). Causes include inadequate
years, dependent both on treatment approach and level
caloric intake, excessive insulin dosage, and inadequate
preparation for physical activity. Often the cause cannotbe determined. Complications and comorbid conditions
Long-term diabetes-related complications are divided
hypoglycaemia often interferes with an individual’s
into microvascular and macrovascular disorders, which
ability to achieve near-normal glycaemic concentrations.101
account for most of the increased morbidity and
This fear might be based on previous experiences with
mortality associated with the disease (panel 3).
hypoglycaemia, or it may be part of wider anxiety aboutdiabetes. Second, hypoglycaemia unawareness—ie, the
occurrence of neuroglycopenia without early warning
Diabetic nephropathy is the most common cause of renal
adrenergic symptoms, can occur in individuals with
failure in the developed world. The proportion of
longstanding disease.102 Finally, an episode of severe
individuals who progress to end-stage renal disease used
hypoglycaemia predisposes that individual to further
to be estimated as 30–40%; however, more recent data
episodes, as a result of downgraded regulatory responses
suggest that this proportion is decreasing, probably as a
to repeated hypoglycaemic events.103 In these situations,
result of intensive efforts to control both glycaemia and
reassessment of glycaemic targets is needed and the
hypertension.108–112 In a cohort of 20 005 individuals from
regimen adjusted to carefully avoid further episodes of
Finland diagnosed younger than 30 years of age between
1965 and 1999, Finne and colleagues111 reported a
Short-term risks of hypoglycaemia include potentially
cumulative prevalence of end-stage renal disease of 2·2%
dangerous circumstances that may arise when someone
at 20 years and 7·7% at 30 years, which are much lower
is hypoglycaemic while, for example, driving a car.104,105
than previously estimated. Diabetic nephropathy
Long-term consequences of severe, longlasting or
progresses through a series of recognisable steps: from
repetitive hypoglycaemia include mild cognitive
subclinical disease, to the earliest detectable phase of
impairments in teenagers with early onset type 1
microalbuminuria (deﬁned as a urinary albumin
diabetes or older adults with longstanding disease.64–66
excretion rate Ͼ20Ͻ200 g per day) to overt nephropathy
Controversy remains about whether cognitive effects in
or macroalbuminuria (Ͼ200 g per day) with renal
young children are a result of severe hypoglycaemia or
dysfunction and eventual end-stage renal disease.
rather due to effect of chronic hyperglycaemia.106
The presence of microalbuminuria has been shown to
Prevention of hyopoglycaemia needs frequent blood
be highly predictive of progression to advanced stages of
glucose monitoring and careful balance between insulin
diabetic nephropathy: a 75–80% probability of
dose, food ingestion, and physical activity. With respect
progression had been reported,108,109 but more recently
to physical activity, the focus should be on adjustment of
Perkins and colleagues110 have suggested that the
therapy to allow safe participation in these activities.107
probability is only 50–66% and that, in a substantial
www.thelancet.com Vol 367 March 11, 2006
proportion, microalbuminuria can regress. These
Diabetic neuropathy refers to a complex group of
investigators showed that the factors predictive of
conditions falling into two major categories: focal and
greater likelihood of regression included younger age,
improvement in metabolic control, reduced cholesterol
example, carpal tunnel syndrome, peroneal nerve and
and triglyceride concentrations, and lowered systolic
third cranial nerve palsies, and diabetic amyotrophy
blood pressure. In adolescents with microalbuminuria,
(proximal nerve conditions). The most common
progression is seen in about 50%, with regression in
generalised neuropathy is sensorimotor polyneuropathy,
many of the others during 3–10 years’ follow-up.63
which often ﬁrst presents as a peripheral neuropathy
Screening of individuals with type 1 diabetes for
alone, but often also affects the autonomic system with
microalbuminuria should be instituted early in the
course of their disorder: the Canadian Diabetes
dysfunction. Peripheral neuropathy, in conjunction with
Association75 suggests annual screening every year, with
peripheral vascular disease, can lead to skin ulceration of
a random urine albumin-creatinine ratio in postpubertal
the lower limbs, poor healing and gangrene, and
individuals with diabetes of duration 5 years or greater.
amputation (the diabetic foot). Good foot care may
Positive screening tests should be conﬁrmed with
greatly lower the risk of these outcomes.75
further random albumin-creatinine ratios or timed urine
Screening for neuropathy should also begin about
collections for 2–3 months. Persistent positive results
5 years after type 1 diabetes diagnosis, with appropriate
require introduction of renoprotective measures,
methods: testing at the great toe with a 10 gauge
including further intensiﬁcation of glycaemic control
monoﬁlament to detect loss of sensitivity, and clinical
and control of hypertension or hyperlipidaemia, or both,
assessment for the other manifestations75 Again,
if present.112,113 First-line drugs of choice include
attention to glycaemic control represents the ﬁrst step in
management; if unsuccessful in controlling symptoms,
angiotensin receptor-blocking agents, both of which are
referral to a specialist is indicated. Attention to preventive
highly effective in slowing progression of renal disease
foot care is an essential component of diabetes
Individuals who reach end-stage renal disease tend to
do less well in dialysis and transplantation programmes
than others with such disease that is unrelated to
Although cardiovascular disease accounts for about 70%
diabetes. The major part of the excessive cardiovascular
of all deaths in people with type 2 diabetes, considerably
morbidity and mortality resides in this group that
less is known about its associations in type 1 diabetes.
develops advanced diabetic nephropathy.
The relative risk of cardiovascular disease in type 1
Diabetic retinopathy is the most common cause of
diabetes can be as much as 10-fold greater than that in
acquired blindness in the western world, with a
non-diabetic individuals. Risk factors for cardiovascular
prevalence rate of proliferative retinopathy of about
disease in type 1 diabetes include the presence of
20–25% in type 1 diabetes.115 It also progresses through
diabetic nephropathy, but also autonomic neuropathy,
recognisable stages: from early non-proliferative
dyslipidaemia, hypertension, and perhaps also speciﬁc
changes, previously called background retinopathy
microvascular cardiac disease. The role of glycaemic
(microaneurysms, exudates, and haemorrhages), which
control has not been easy to deﬁne, although two reports
appear in almost all individuals with type 1 diabetes by
are important: a meta-analysis of randomised controlled
about 20 years’ duration, to preproliferative retinopathy,
trials in type 1 diabetes found that intensive insulin
and then predictably on to proliferative retinopathy (with
therapy may stabilise macrovascular disease or prevent
risk of retinal detachment and vitreous haemorrhage)
progression in those at risk,119 whereas the follow-up
and macular oedema. Unlike early retinopathy, the later
phase of the DCCT/EDIC showed that intensive
stages can be sight-threatening. There is a close
treatment during the active intervention phase of the
association between diabetic retinopathy and diabetic
DCCT led to reduced progression of carotid intima-
media thickness during 6 years’ follow-up.120
Screening for diabetic retinopathy should begin
Reduction of risk of vascular disease includes attention
5 years after diagnosis in individuals of 15 years of age or
to healthy lifestyle (weight control and physical activity),
older and be done yearly by one of the following
smoking avoidance, with optimum glycaemic, blood
methods: seven-ﬁeld stereoscopic fundus photography
pressure (Ͻ130/80 mmHg in adults), and lipid control
interpreted by trained readers (gold standard); direct
(LDL-cholesterol Ͻ2·5 mmol/L and total:HDL-
ophthalmoscopy or indirect slit lamp fundoscopy
cholesterol ratios Ͻ4·0 mmol/L for those at high risk of
through a dilated pupil; or digital fundus photography.75
an event, and Ͻ3·5 mmol/L and Ͻ5·0 mmol/L,
The presence of diabetic retinopathy requires enhanced
respectively, for those at moderate risk75). There has been
attention to glycaemic, blood pressure, and lipid
a steady decline in the recommended targets for lipid
control, with laser therapy in sight-threatening diabetic
control with particular emphasis on control of LDL-
www.thelancet.com Vol 367 March 11, 2006 Comorbid conditions
have shown the usefulness of current prediction models
Clinical automimmune thyroid disease occurs in about
and the feasibility of large-scale multinational studies.127,128
5% and coeliac disease in 3–10% of children with type 1
Second, techniques for islet cell replacement need to
diabetes.25–28 The number of children with positive
be improved, through either islet cell transplantation or
thyroid antibodies is higher than 5% (manifest disease)
islet differentiation from stem cell sources. Initial
and increases with age. Annual screening of individuals
enthusiasm about improved outcomes of islet cell
with thyroid-stimulating hormone measurements will
transplantation, raised by use of the Edmonton
enable early initiation of thyroxine replacement
protocol129,130 for islet harvesting and rejection prevention
therapy.26 The need to screen for coeliac disease has been
has been tempered by the lack of availability of islets, the
debated75 but is now a recommended part of routine
side-effects of the procedure (such as bleeding, mouth
management.27,28 The timing and frequency of screening
ulcers, diarrhoea, anaemia, and ovarian cysts), and the
for coeliac disease have not been deﬁned; however,
increasing reversal of insulin independence in as many
initial screening soon after diagnosis and then every
as 80% of the recipients 5 years after the transplantation,
5 years is a reasonable recommendation. Although more
although some ␤-cell function and hypoglycaemia
common than in the general public, the presence of
awareness seems to persist for longer than 5 years.129,130.
Addison’s disease in individuals with type 1 diabetes is
Stem cell research as a means of developing a potentially
rare and screening cannot be justiﬁed.
inﬁnite source of functional islets is still at a veryfundamental stage.131,132
Research has focused attention on the psychosocial
normoglycaemia are called for. Although insulin
concomitants of type 1 diabetes particularly in children
analogues and insulin pumps help more physiological
and teenagers, but also in adults. For example, children
insulin replacement approaches to be developed, they
from single parent families and low socioeconomic
remain imperfect because of factors other than insulin
status are more likely to present in diabetic ketoacidosis
that affect glycaemia (food intake, activity, stress, etc), the
at disease onset, have more episodes of diabetic
absence of closed loop systems linking insulin infusion to
ketoacidosis during the course of their diabetes, attend
ambient glycaemia, and peripheral rather than portal
clinic less frequently, and are less likely to maintain
insulin delivery. These shortcomings might be partly
good glycaemic control than those from two-parent and
overcome by progress in development of continuous
glucose monitoring systems. Linking of these systems to
colleagues122 showed that over 40% of teenagers had a
sophisticated pump technologies offers the promise of an
period of pervasive non-compliance with major aspects
artiﬁcial endocrine pancreas. Additionally, increasing
of their diabetes routines, and that these individuals
rates of obesity have focused attention on the
were more likely to show serious psychopathology—
development of characteristics of type 2 diabetes in those
most commonly depression—in early adulthood.122
with diagnosed type 1, so-called double diabetes (ie,
Other researchers have also reported an increased
increasing insulin resistance and cardiovascular risk).133
prevalence of depression in adults with type 1 diabetes.123
This double diabetes has prompted the search for
Our research group has reported that nearly a quarter
adjunctive drugs (eg, metformin) that might lessen the
of teenage and young adult women with type 1 diabetes
insulin resistance and improve glycaemic control.134,135
have either a full-blown (about 10%) or sub-threshold
Furthermore, drugs that either suppress glucagon (eg,
(about 14%) eating disorder, and that such disorders are
amylin), or have multiple effects on pathways such as
associated with insulin omission to control weight
appetite regulation, stomach emptying, and continuing
through induced glycosuria, poor glycaemic control, and
␤-cell apoptosis, such as those with activity associated with
early onset of diabetes-related complications.124,125
glucagon-like peptide 1 (eg, exenatide and liraglutide),
Interventions intended to improve the psychological
have potential to beneﬁt individuals not only with type 2
concomitants of diabetes in an effort to enhance
diabetes, but also those with type 1 disease.136–138
glycaemic control have not been very successful.126
Finally, we should deﬁne strategies for complication
prevention or risk factors for development of compli-
cations. Better understanding of pathophysiological
Some of the challenges facing researchers and health-care
mechanisms and susceptibility genes is already leading
professionals are as follows. First, we need to perfect the
to new targets for treatment.139 In the meantime, attention
prediction model for type 1 diabetes in both high risk and
should be focused on how to prevent complications
general populations, and to develop effective and safe
with drugs such as angiotensin-converting enzyme
interventions that reverse the condition either in its
inbibitors or angiotensin receptor blockers, beta-
preclinical or early clinical phase. The multicentre
hydroxy-beta-methylglutaryl-coenzyme A (HMG-CoA)
prevention trials (eg, European Nicotinamide Diabetes
reductase inhibitors (statins), or even aspirin, deserves
Intervention Trial of nicotinamide, and Diabetes
attention.140–142 Evidence-based recommendations about
Prevention Trial Type 1 of insulin), although ineffective,
the prophylactic use of these agents are not available.
www.thelancet.com Vol 367 March 11, 2006 Conclusions
Virtanen SM, Laara E, Hypponen E, et al. Cow’s milk
Type 1 diabetes has transformed from a disease with
consumption, HLA-DQB1 genotype, and type 1 diabetes: a nestedcase-control study of siblings of children with diabetes. Childhood
certain death in the era before the discovery of insulin to
diabetes in Finland study group. Diabetes 2000; 49: 912–17.
one with substantial risk of long-term morbidity and
Vaarala O, Knip M, Paronen J, et al. Cow’s milk formula feeding
mortality.143 For example, a report from the US Centers
induces primary immunization to insulin in infants at genetic riskfor type 1 diabetes.
for Disease Control recently estimated that a 10-year-old
Diabetes 1999; 48: 1389–94.
Thorsdottir I, Ramel A. Dietary intake of 10- to 16-year-old children
boy or girl developing diabetes in the year 2000 would
and adolescents in central and northern Europe and association
lose, on average, 18·7 and 19·0 life-years, respectively,
with the incidence of type 1 diabetes. Ann Nutr Metab 2003; 47: 267–75.
compared with their non-diabetic peers.2 Advances in
Norris JM, Barriga K, Klingensmith G, et al. Timing of initial cereal
treatment have resulted in improved outcomes, which
exposure in infancy and risk of islet autoimmunity. JAMA 2003;
come with increasingly complex and expensive
therapeutic demands on individuals with type 1
Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Childhood vaccination and type 1 diabetes. N Engl J Med 2004; 350:
diabetes.144–146 Furthermore, Gale147 has eloquently pointed
out that, although focused studies show that outcomes
Levitsky LL. Childhood immunizations and chronic illness.
can be improved by better management, there is “no
N Engl J Med 2004; 350: 1380–82.
evidence of this actually happening on a worldwide
Krischer JP, Cuthbertson DD, Yu L, et al. Screening strategies forthe identiﬁcation of multiple antibody-positive relatives of
individuals with type 1 diabetes. J Clin Endocrinol Metab 2003; 88:
A fundamental shift in the management of type 1
diabetes seems unlikely until we are able to close the
Maclaren N, Lan M, Coutant R, et al. Only multiple autoantibodiesto islet cells (ICA), insulin, GAD65, IA-2 and IA-2beta predict
loop through either artiﬁcial endocrine pancreas
immune-mediated (Type 1) diabetes in relatives. J Autoimmun
implantation, or islet replacement by transplantation or
1999; 12: 279–87
stem cell engineering. In the meantime, individuals
Barker JM, Barriga KJ, Yu L, et al. Prediction of autoantibodypositivity and progression to type 1 diabetes: diabetes
with type 1 diabetes and their health providers need to
autoimmunity study in the young (DAISY).
focus their energies on the therapeutic approaches best
J Clin Endocrinol Metab 2004; 89: 3896–902.
capable of maximum risk reduction, including the risks
Sochett EB, Daneman D, Clarson C, Ehrlich RM. Factors affectingand patterns of residual insulin secretion during the ﬁrst year of
of hypoglycaemia and diabetic ketoacidosis in the short
type 1 (insulin-dependent) diabetes mellitus in children.
term, and microvascular and macrovascular disease and
Diabetologia 1987; 30: 453–59.
psychological distress in the longer term.
Yki-Jarvinen H, Koivisto VA. Natural course of insulin resistance in type I diabetes. N Engl J Med 1986; 315: 224–30. Conﬂict of interest statement
Barker JM, Yu J, Yu L, et al. Autoantibody “subspeciﬁcity” in type 1
D Daneman has received research funding from Novo Nordisk, has co-
diabetes: risk for organ-speciﬁc autoimmunity clusters in distinct
organised a continuing education programme sponsored by Lifescan
groups. Diabetes Care 2005; 28: 850–55.
Canada, and has spoken at other continuing education programmes.
Kordonouri O, Hartmann R, Deiss D, Wilms M, Gruters-Kieslich A. Natural course of autoimmune thyroiditis in
type 1 diabetes: association with gender, age, diabetes duration,
Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes:
and puberty. Arch Dis Child 2005; 90: 411–14.
principles of pathogenesis and therapy. Lancet 2005; 365: 1333–46.
Skovbjerg H, Tarnow L, Locht H, Parving HH. The prevalence ofcoeliac disease in adult Danish patients with type 1 diabetes with
Narayan KMV, Boyle JP, Thompson TJ, Sorensen SW,
and without nephropathy. Diabetologia 2005; 48: 1416–17.
Williamson DF. Lifetime risk for diabetes in the United States. JAMA 2003; 290: 1884–90.
Norris JM, Barriga K, Hoffenberg EJ, et al. Risk of celiac diseaseautoimmunity and timing of gluten introduction in the diet of
American Diabetes Association. Clinical practice
infants at increased risk of disease. JAMA 2005; 293: 2343–51.
recommendations. Diabetes Care 2005; 28 (suppl 1): S1–79.
Gale EAM. A missing link in the hygiene hypothesis. Diabetologia
Redondo MJ, Fain PR, Eisenbarth GS. Genetics of type 1A
2002; 45: 588–94.
diabetes. Recent Prog Horm Res 2001; 56: 69–89.
Wilkin TJ. The accelerator hypothesis: weight gain as the missing
Lambert AP, Gillespie KM, Thomson G, et al. Absolute risk of
link between Type I and Type II diabetes. Diabetologia 2001; 44:
childhood-onset type 1 diabetes deﬁned by human leukocyte
antigen class II genotype: a population-based study in the United Kingdom. J Clin Endocrinol Metab 2004; 89: 4037–43.
Ball TM, Castro-Rodriguez JA, Grifﬁth KA, Holberg CJ, Martinez FD, Wright AL. Siblings, day-care attendance, and the
Devendra D, Liu E, Eisenbarth GS. Type 1 diabetes: recent
risk of asthma and wheezing during childhood. N Engl J Med 2000;
developments. BMJ 2004; 328: 750–54. 343: 538–43.
Abiru N, Kawasaki E, Eguch K. Current knowledge of Japanese
von Mutius E, Martinez FD, Fritzsch C, Nicolai T, Reitmeir P,
type 1 diabetic syndrome. Diabetes Metab Res Rev 2002; 18: 357–66.
Thiemann HH. Skin test reactivity and number of siblings. BMJ
Eisenbarth GS. Type I diabetes mellitus. A chronic autoimmune
1994; 308: 692–95.
disease. N Engl J Med 1986; 314: 1360–68.
Kaila B, Taback SP. The effect of day care exposure on the risk of
Anjos S, Polychronakos C. Mechanisms of genetic susceptibility
developing type 1 diabetes: a meta-analysis of case-control studies.
to type 1 diabetes: beyond HLA. Mol Genet Metab 2004; 81: 187–95. Diabetes Care 2001; 24: 1353–58.
Lammi N, Karvonen M, Tuomilehto J. Do microbes have a causal
Betts PR, Mulligan J, Ward P, Smith B, Wilkin TJ. Increasing body
role in type 1 diabetes? Med Sci Monit 2005; 11: RA63–69.
weight predicts the earlier onset of insulin dependent diabetes in
Robles DT, Eisenbarth GS. Type 1A diabetes induced by infection
childhood: Testing the ‘Accelerator Hypothesis’ (2). Diabet Med
and immunization. J Autoimmun 2001; 16: 355–62.
2005; 22: 144–51.
Helgason T, Jonasson MR. Evidence for a food additive as a cause
Daneman D. Is the ‘Accelerator Hypothesis’ worthy of our
of ketosis-prone diabetes. Lancet 1981; 318: 716–20.
attention? Diabet Med 2005; 22: 115–17.
Akerblom HK, Vaarala O, Hyoty H, Ilonen J, Knip M.
Dunger DB, Sperling MA, Acerini CL, et al. ESPE/LWPES
Environmental factors in the etiology of type 1 diabetes.
consensus statement on diabetic ketoacidosis in children and
Am J Med Genet 2002; 115: 18–29
adolescents. Arch Dis Child 2004; 9: 188–94.
www.thelancet.com Vol 367 March 11, 2006
Levy-Marchal C, Patterson CC, Green A; EURODIAB ACE Study
Diabetes Control and Complications Trial/Epidemiology of Diabetes
Group. Geographical variation of presentation at diagnosis of type I
Interventions and Complications Research Group. Retinopathy and
diabetes in children: the EURODIAB study. Diabetologia 2001;
nephropathy in patients with type 1 diabetes four years after a trial of
44 (suppl 3): B75–80.
intensive therapy. N Engl J Med 2000; 342: 381–89.
Booth GL. Short-term clinical consequences of diabetes in adults.
Diabetes control and complications trial/Epidemiology of diabetes
In: Gerstein JC, Haynes RB, eds. Evidence-based diabetes care.
interventions and complications research group. Beneﬁcial effects
Hamilton, ON: BC Decker Inc, 2001: 68–106.
of intensive therapy of diabetes during adolescence: outcomes after
Curtis J, Hamilton J, Beck C, Frank M, Daneman D. Diagnosis and
the conclusion of diabetes control and complications trial. J Pediatr
short-term consequences of diabetes in children and adolescents.
2001; 139: 804–12.
In: Gerstein HC, Haynes RB, eds. Evidence-based diabetes care.
Diabetes Control and Complications Trial/Epidemiology of
Hamilton, ON: BC Decker Inc, 2001: 107–23.
Diabetes Interventions and Complications Research Group. Effect
Onkamo P, Vaananen S, Karvonen M, Tuomilehto J. Worldwide
of intensive therapy on the microvascular complications of type 1
increase in incidence of Type I diabetes—the analysis of the
diabetes mellitus. JAMA 2002; 287: 2563–69.
data on published incidence trends. Diabetologia 1999; 42:
The Diabetes Control and Complication Trial Research Group.
Hypoglycemia in the diabetes control and complication trial
Gillespie KM, Bain SC, Barnett AH, et al. The rising incidence of
research group. Diabetes 1997; 46: 271–86.
childhood type 1 diabetes and reduced contributions of high-risk
Daneman D. Early diabetes-related complications in adolescents:
HLA haplotypes. Lancet 2004; 364: 1699–700.
risk factors and screening. Horm Res 2005; 63: 75–85.
Gale EAM. The rise of childhood type 1 diabetes in the 20th century.
Ryan CM, Geckle MO, Orchard TJ. Cognitive efﬁciency declines
Diabetes 2002; 51: 3353–361.
over time in adults with Type 1 diabetes: effects of micro- and
Tuomilehto J, Karvonen M, Pitkaniemi J, et al. Record-high
macrovascular complications. Diabetologia 2003; 46: 940–48.
incidence of Type I (insulin-dependent) diabetes mellitus in
Ryan C, Vega A, Drash A. Cognitive deﬁcits in adolescents who
Finnish children. The Finnish Childhood Type I Diabetes Registry
developed diabetes early in life. Pediatrics 1985; 75: 921–27.
Group. Diabetologia 1999; 42: 655–60.
Brands AMA, Biessels GJ, de Haan EHF, Kappelle LJ,
Kautiainen S, Rimpela A, Vikat A, Virtanen SM. Secular trends in
Kessels RPC. The effects of type 1 diabetes on cognitive
overweight and obesity among Finnish adolescents in 1977–1999.
performance: a meta-analysis. Diabetes Care 2005; 28: 726–35. Int J Obes Relat Metab Disord 2002; 26: 544–52.
Mortensen HB, Hougaard P. Comparison of metabolic control in a
Karvonen M, Viil-Kajander M, Moltchanova E, Libman I,
cross sectional study of 2873 children and adolescents with insulin-
LaPorte R, Tuomilehto J. Incidence of childhood type 1 diabetes
dependent diabetes from 18 countries. Diabetes Care 1997; 20:
worldwide. Diabetes Care 2000; 23: 1516–26.
Li XH, Li TL, Yang Z, et al. A nine-year prospective study on the
Danne T, Mortensen HB, Hougaard P, et al. Persistent differences
incidence of childhood type 1 diabetes mellitus in China.
among centers over 3 years in glycemic control and hypoglycemia
Biomed Environ Sci 2000; 13: 263–70.
in a study of 3,805 children and adolescents with type 1 diabetes
Tuomilehto J, Karvonen M, Pitkaniemi J, et al. Record-high
from the Hvidore Study Group. Diabetes Care 2001; 24: 1342–47.
incidence of type 1 diabetes mellitus in Finnish children.
Ford-Adams ME, Murphy NP, Moore EJ, et al. Insulin lispro, a
Diabetologia 1999; 42: 655–60.
potential role in preventing nocturnal hypoglycemia in young
Karvonen M, Pitkanemi J, Tuomilehto J; Finnish Childhood
Diabetes Registry Group. The age of onset of type 1 diabetes in
Diabet Med 2003; 20: 656–60.
Finnish children has become younger. Diabetes Care 1999; 22:
Chase HP, Dixon B, Pearson J, et al. Reduced hypoglycemic
episodes and improved glycemic control in children with type 1
Casu A, Pascutto C, Bernardinelli L, Songini M. Type 1 diabetes
diabetes using insulin glargine and neutral protamine hagedorn
among Sardinian children is increasing: the Sardinian diabetes
insulin. J Pediatr 2003; 143: 737–40.
register for children aged 0–14 years (1989–1999). Diabetes Care
Garg SK, Gottlieb PA, Hisatomi ME, et al. Improved glycemic
2004; 27: 1623–29.
control without an increase in severe hypoglycemic episodes in
EURODIAB ACE Study Group. Variation and trends in incidence
intensively treated patients with type 1 diabetes receiving
of childhood diabetes in Europe. Lancet 2000; 355: 873–76.
morning, evening, or split dose insulin glargine. Diabetes Res Clin
Newhook LA, Curtis J, Hagerty D, et al. High incidence of
Pract 2004; 66: 49–56.
childhood type 1 diabetes in the Avalon Peninsula, Newfoundland,
Ratner RE, Hirsh IB, Neiﬁng JL, Mecca TE, Wilson CA. Less
Canada. Diabetes Care 2004; 27: 885–88.
hypoglycemia with insulin glargine in intensive insulin therapy for
Dahlquist G, Mustonen L. Analysis of 20 years of prospective
type 1 diabetes. Diabetes Care 2000; 23: 639–43.
registration of childhood onset diabetes time trends and birth
Vague P, Selam JL, Skeie S, et al. Insulin detemir is associated with
cohort effects. Swedish Childhood Study Group. Acta Paediatr
more predictable glycemic control and reduced risk of
2000; 89: 1231–37.
hypoglycemia than NPH Insulin in patients with type 1 diabetes on
Weets I, De Leeuw IH, Du Caju MV, et al. The incidence of
a basal-bolus regimen with premeal insulin Aspart.
type 1 diabetes in the age group 0–39 years has not increased in
Diabetes Care 2003; 26: 590–96.
Antwerp (Belgium) between 1989 and 2000. Diabetes Care 2002;
Siebenhofer A, Plank J, Berghold A, Narath M, Gferer R,
Pieber TR. Short acting insulin analogues versus regular human
Tremblay MS, Willms JD. Secular trends in the body mass index of
insulin in patients with diabetes mellitus. Cochrane Database Syst
Canadian children. CMAJ 2000; 163: 1429–33. Rev 2004; 2: CD003287.
Chinn S, Hughes JM, Rona RJ. Trends in growth and obesity in
Canadian Diabetes Association 2003: Clinical practice guidelines
ethnic groups in Britain. Arch Dis Child 1998; 19: 162–66.
for the prevention and management of diabetes in Canada. Can J Diab 2003; 27 (suppl 2): S21–23.
Raymond NT, Jones JR, Swift PG, et al. Comparative incidence oftype 1 diabetes in children aged under 15 years from South Asian
Loveman E, Royle P, Waugh N. Specialist nurses in diabetes
and white or other ethnic backgrounds in Leicestershire, UK, 1989
mellitus. Cochrane Database Syst Rev 2003; 2: CD003286.
to 1998. Diabetologia 2001; 44 (suppl 3): B32–6.
Renders CM, Valk GD, Grifﬁn S, Wagner EH, Eijk JT,
The Diabetes Control and Complication Trial Research Group. The
Assendelft WJ. Interventions to improve the management of
effect of intensive treatment of diabetes on the development and
diabetes mellitus in primary care, outpatient and community
progression of long-term complications in insulin-dependent
settings. Cochrane Database Syst Rev 2001; 1: CD001481.
diabetes mellitus. N Engl J Med 1993; 329: 977–86.
Grifﬁn S, Kinmonth AL. Diabetes care: the effectiveness of systems
Diabetes control and complications trial research group. Effect of
for routine surveillance for people with diabetes.
intensive diabetes treatment on the development and progression
Cochrane Database Syst Rev 2000; 2: CD000541.
of long-term complications in adolescents with insulin-dependent
Keers JC, Groen H, Sluiter WJ, Bouma J, Links TP. Cost and
diabetes mellitus: diabetes control and complications trial.
beneﬁts of a multidisciplinary intensive diabetes education
J Pediatr 1994; 125: 177–88.
programme. J Eval Clin Pract 2005; 11: 293–303.
www.thelancet.com Vol 367 March 11, 2006
Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet
101 Nordfeld S, Ludvigsson J. Fear and other disturbances of severe
2001; 358: 739–46.
hypoglycaemia in children and adolescents with type 1 diabetes
Seibenhofer A, Plank J, Berghold A, et al. Meta-analysis of short-
mellitus. J Pediatr Endocrinol Metab 2005; 18: 83–91
acting insulin analogues in adult patients with type 1 diabetes:
102 Smith D, Amiel SA. Hypoglycaemia unawareness and the brain.
continuous subcutaneous insulin infusion versus injection
Diabetologia 2002; 45: 949–58
therapy. Diabetologia 2004; 47: 1895–905.
103 Cryer PE. Diverse causes of hypoglycemia-associated autonomic
Plank J, Siebenhofer A, Berhold A, et al. Systematic review and
failure in diabetes. N Engl J Med 2004; 350: 2272–79.
meta-analysis of short-acting insulin analogues in patients with
104 Draelos MT, Jacobson AM, Weinger K, et al. Cognitive function in
diabetes mellitus. Arch Intern Med 2005; 165: 1337–44.
patients with insulin-dependent diabetes mellitus during
Palmer AJ, Roze S, Valentine WJ, Smith I, Wittrup-Jensen KU.
hyperglycemia and hypoglycemia. Am J Med 1995; 98: 135–44.
Cost-effectiveness of detemir-based basal/bolus therapy versus
105 Ryan CM, Dulay D, Suprasongsin C, Becker DJ. Detection of
NPH-based basal/bolus therapy for type 1 diabetes in a UK setting:
symptoms by adolescents and young adults with type 1 diabetes
an economic analysis based on meta-analysis results of four clinical
during experimental induction of mild hypoglycemia: role of
trials. Curr Med Res Opin 2004; 20: 1729–46.
hormonal and psychological variables. Diabetes Care 2002; 25:
Colquitt J, Royle P, Waugh N. Are analogue insulins better than
soluble in continuous subcutaneous insulin infusion? Results of a
106 Northam EA, Anderson PJ, Jacobs R, Hughes M, Warne GL,
meta-analysis. Diabet Med 2003; 20: 863–66.
Werther GA. Neuropsychological proﬁles of children with type 1
Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N. Clinical
diabetes 6 years after disease onset. Diabetes Care 2001; 24: 1541–46.
and cost-effectiveness of continuous subcutaneous insulin infusion
107 American Diabetes Association. Physical activity/exercise and
for diabetes. Health Technol Assess 2004; 43: 1–171.
diabetes. Diabetes Care 2004; 27 (suppl 1): S58–62.
Retnakaran R, Hochman J, DeVries JH, et al. Continuous
108 Mogensen CE, Chistensen CK. Predicting diabetic nephropathy in
subcutaneous insulin infusion versus multiple daily injections: the
insulin-dependent patients. N Engl J Med 1984; 311: 89–93.
impact of baseline A1c. Diabetes Care 2004; 27: 2590–96.
109 Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U,
Radermecker RP, Scheen AJ. Continuous subcutaneous insulin
Keen H. Microalbuminuria as a predictor of clinical nephropathy
infusion with short-acting insulin analogues or human regular
in insulin-dependent diabetes mellitus. Lancet 1982; 319: 1430–32.
insulin: efﬁcacy, safety, quality of life, and cost-effectiveness.
110 Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH,
Diabetes Metab Res Rev 2004; 20: 178–88.
Krolewski AS. Regression of microalbuminuria in type 1 diabetes.
American Diabetes Association. Standards of medical care in
N Engl J Med 2003; 348: 2285–93.
diabetes. Diabetes Care 2004; 27 (suppl 1): S15–35.
111 Finne P, Reunanen A, Stenman S, Groop PH, Gronhagen-Riska C.
Bui H, Perlman K, Daneman D. Glucose monitoring: future
Incidence of end-stage renal disease in patients with type 1
directions. Self-monitoring of blood glucose in children and teens
diabetes. JAMA 2005; 294: 1782–87.
with diabetes. Pediatric Diabetes 2005; 6: 50–62.
112 DCCT/EDIC Research Group. Sustained effect of intensive
90 Karter AJ, Ackeron LA, Darbinian JA, et al. Self-monitoring of
treatment of type 1 diabetes mellitus on development and
blood glucose levels and glycemic control : the Northern
progression of diabetic nephropathy: the Epidemiology of Diabetes
California Kaiser Permanente Diabetes registry. Am J Med 2001;
Interventions and Complications (EDIC) study. JAMA 2003;
111: 1–9. 290: 2159–67.
Evans JM, Newton RW, Ruta DA, MacDonald TM, Stevenson RJ,
113 Fioretto P, Solini A. Antihypertensive treatment and multifactorial
Morris AD. Frequency of blood glucose monitoring in relation to
approach for renal protection in diabetes. J Am Soc Nephrol 2005;
glycaemic control: observational study with diabetes database.
16 (suppl 1): S18–21. BMJ 1999; 319: 83–86.
114 Lovell HG. Angiotensin converting enzyme inhibitors in
Haller MJ, Stalvey MS, Silverstein JH. Predictors of control of
normotensive diabetic patients with microalbuminuria.
diabetes: monitoring may be the key. J Pediatr 2004;
Cochrane Database Syst Rev 2001; 1: CD002183. 144: 660–61.
115 Fong DS, Aiello LP, Ferris FL 3rd, Klein R. Diabetic retinopathy.
Guerci B, Floriot M, Bohme P, et al. Clinical performance of
Diabetes Care 2004; 27: 2540–53.
CGMS in type 1 diabetic patients treated by continuous
116 Klein R, Zinman B, Gardiner R, et al. The relationship of diabetic
subcutaneous insulin infusion using insulin analogs.
retinopathy to preclinical diabetic glomerulopathy lesions in type 1
Diabetes Care 2003; 26: 582–89.
diabetic patients. Diabetes 2005; 54: 527–33.
Sacks DB; ADA/EASD/IDF working group of the HbA1c assay.
117 Perkins BA, Bril V. Early vascular risk factor modiﬁcation in type 1
Global harmonization of hemoglobin A1c. Clin Chem 2005; 51:
diabetes. N Engl J Med 2005; 352: 408–09.
118 Perkins BA, Bril V. Diagnosis and management of diabetic
Steffes M, Cleary P, Goldstein D, et al. Hemoglobin A1c
neuropathy. Curr Diab Rep 2002; 2: 495–500.
measurements over nearly two decades: sustaining comparable
119 Lawson ML, Gerstein HC, Tsui E, Zinman B. Effect of intensive
values throughout the Diabetes Control and Complications Trial
therapy on early macrovascular disease in young individuals with
and the Epidemiology of Diabetes Interventions and Complications
type 1 diabetes. A systematic review and meta-analysis.
study. Clin Chem 2005; 51: 753–58. Diabetes Care 1999; 22 (suppl 2): B35–39.
Tamborlane WV, Kollman C, Steffes MW, et al; Diabetes Research
120 The Diabetes Control and Complications Trial/Epidemiology of
in Children Network (DirecNet) Study Group. Comparison of
Diabetes Interventions and Complications Research Group.
ﬁngerstick hemoglobin A1c levels assayed by DCA 2000 with the
Intensive diabetes therapy and carotid intima-medial thickness in
DCCT/EDIC central laboratory assay: results of a Diabetes
Research in Children Network (DirecNet) Study.
N Engl J Med 2003; 348: 2294–303.
2005; 6: 13–16.
121 Jacobson AM, Hauser ST, Willett J, Wolfsdorf JI, Herman L.
Consequences of irregular versus continuous medical follow-up in
American Diabetes Association. Nutrition principles and
children and adolescents with insulin-dependent diabetes mellitus.
recommendations in diabetes. Diabetes Care 2004; 27 (suppl 1): S36–46. J Pediatr 1997; 131: 727–33.
122 Kovacs M, Goldston D, Obrosky DS, Iyengar S. Prevalence and
Franz MJ, Bantle JP, Beebe CA, et al. Evidence-based nutrition
predictors of pervasive noncompliance with medical treatment
principles and recommendations for the treatment and prevention
among youths with insulin-dependent diabetes mellitus.
of diabetes and related complications. Diabetes Care 2002; 25: 148–198. J Am Acad Child Adolesc Psychiatry 1992; 31: 1112–19.
123 Jacobson AM, Samson JA, Weinger K, Ryan CM. Diabetes, the
Brand-Miller J, Hayne S, Petocz P, Colagiuri S. Low-glycemic index
brain, and behavior: is there a biological mechanism underlying
diets in the management of diabetes: a meta-analysis of
the association between diabetes and depression?
randomized controlled trials. Diabetes Care 2003; 26: 2261–67. Int Rev Neurobiol 2002; 51: 455–79.
100 Opperman AM, Venter CS, Oosthuizen W, Thompson RL,
124 Jones JM, Lawson ML, Daneman D, Olmsted MP, Rodin G. Eating
Vorster HH. Meta-analysis of the health effects of using the
disorders in adolescent females with and without type 1 diabetes:
glycaemic index in meal-planning. Br J Nutr 2004; 92: 367–81.
cross sectional study. BMJ 2000; 320: 1563–66.
www.thelancet.com Vol 367 March 11, 2006
125 Rydall AC, Rodin GM, Olmsted MP, Devenyi RG, Daneman D.
136 Heptulla RA, Rodriguez LM, Bomgaars L, Haymond MW. The
Disordered eating behavior and microvascular complications in
role of amylin and glucagon in the dampening of glycemic
young women with insulin-dependent diabetes mellitus.
excursions in children with type 1 diabetes. Diabetes 2005; 54: N Engl J Med 1997; 336: 1849–54.
126 Hampson SE, Skinner TC, Hart J, et al. Effects of educational and
137 Bailey CJ. Drugs on the horizon for diabesity. Curr Diab Rep 2005;
psychosocial interventions for adolescents with diabetes mellitus: a
systematic review. Health Technol Assess 2001; 5: 1–79.
138 Nauck MA, Meier JJ. Glucagon-like peptide 1 and its derivatives in
127 Diabetes Prevention Trial-Type 1 Diabetes Study group. Effects of
the treatment of diabetes. Regul Pept 2005; 128: 135–48.
insulin in relatives of patients with type 1 diabetes mellitus.
139 Fukami K, Cooper ME, Forbes JM. Agents in development for the
N Engl J Med 2002; 346: 1685–91.
treatment of diabetic nephropathy. Expert Opin Investig Drugs 2005;
128 Gale EA, Bingley PJ, Emmett CL, Collier T; European
Nicotinamide Diabetes Intervention Trial (ENDIT) Group.
140 McQueen MJ, Lonn E, Gerstein HC, Bosch J, Yusuf S. The HOPE
European Nicotinamide Diabetes Intervention Trial (ENDIT): a
Study and its consequences. Scand J Clin Lab Invest 2005; 240:
randomised controlled trial of intervention before the onset of
type 1 diabetes. Lancet 2004; 363: 925–31.
141 Leiter L. The prevention of diabetic microvascular complications of
129 Ryan EA, Paty BW, Senior PA, Shapiro AM. Risks and side effects
diabetes: is there a role for lipid lowering? Diabetes Res Clin Pract
of islet transplantation. Curr Diab Rep 2004; 4: 304–09.
2005; 68 (suppl 2): S3–14.
130 Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after
142 Davis TM, Bruce DG, Davis WA. Predictors of ﬁrst stroke in Type 1
clinical islet transplantation. Diabetes 2005; 54: 2060–69.
diabetes: The Fremantle Diabetes Study. Diabet Med 2005; 22:
131 Hansson M, Tonning A, Frandsen U, et al. Artifactual insulin release
from differentiated embryonic stem cells. Diabetes 2004; 53: 2603–09.
143 Feudtner C. A disease in motion: diabetes history and the new
132 Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-
paradigm of transmuted disease. Perspect Biol Med 1996; 39:
cells are formed by self-duplication rather than stem-cell
differentiation. Nature 2004; 429: 41–46.
144 Herman WH, Eastman RC. The effects of treatment on the
133 Orchard TJ, Olson JC, Erbey JR, et al. Insulin resistance-related
direct costs of diabetes. Diabetes Care 1998; 21 (suppl 3):
factors, but not glycemia, predict coronary artery disease in type 1
diabetes: 10-year follow-up data from the Pittsburgh Epidemiology
145 DCCT Research Group. Lifetime beneﬁts and costs of intensive
of Diabetes Complications Study. Diabetes Care 2003; 26: 1374–79.
therapy as practiced in the diabetes control and complications trial.
134 Hamilton J, Cummings E, Zdravkovic V, Finegood D, Daneman D. JAMA 1996; 276: 1409–15.
Metformin as an adjunct therapy in adolescents with type 1
146 Laing SP, Jones ME, Swerdlow AJ, Burden AC, Gatling W.
diabetes and insulin resistance: a randomized controlled trial.
Psychosocial and socioeconomic risk factors for premature death
Diabetes Care 2003; 26: 138–43.
in young people with type 1 diabetes. Diabetes Care 2005; 28:
135 Meyer L, Bohme P, Delbachian I, et al. The beneﬁts of metformin
therapy during continuous subcutaneous insulin infusion
147 Gale EAM. Type 1 diabetes in the young: the harvest of sorrow foes
treatment of type 1 diabetic patients. Diabetes Care 2003; 26: 1655.
on. Diabetologia 2005; 48: 1435–38.
www.thelancet.com Vol 367 March 11, 2006
Sexualstörung als kommunikatives Signal in der Paarbeziehung In der systemischen Psychotherapie ist es selbstverständlich, jedes Verhalten, jedes Problem, jede Störung in einem Gesamtkontext zu betrachten. Die Einbettung jedes Menschen in Makrosysteme, z.B: Gesel schaft, Religion, Gesinnungsgemeinschaften, in Mikrosysteme wie Familie, Freunde, Arbeitskontext und in das System im Individu
Phytoestrogens in Soy-Based Infant Foods: Concentrations, Daily Intake and Possible Biological Effects C.H.G. Irvine, M.G. Fitzpatrick† and S.L. Alexander Animal and Veterinary Sciences Group, Lincoln University, New Zealand, and † Chemistry Department, University of Auckland, Auckland, New Zealand Corresponding author : Prof C.H.G. Irvine, Animal & Veterinary Sciences Group,