Management of diabetes mellitus in infants



Management of diabetes mellitus in infants
Management of diabetes mellitus in infants
Beate Karges, Thomas Meissner, Andrea Icks, Thomas Kapellen and Reinhard W. Holl
Abstract | Diabetes mellitus diagnosed during the first 2 years of life differs from the disease in older
children regarding its causes, clinical characteristics, treatment options and needs in terms of education
and psychosocial support. Over the past decade, new genetic causes of neonatal diabetes mellitus have
been elucidated, including monogenic β‑cell defects and chromosome 6q24 abnormalities. In patients with
KCNJ11 or ABCC8 mutations and diabetes mellitus, oral sulfonylurea offers an easy and effective treatment
option. Type 1 diabetes mellitus in infants is characterized by a more rapid disease onset, poorer residual
β‑cell function and lower rate of partial remission than in older children. Insulin therapy in infants with type 1
diabetes mellitus or other monogenic causes of diabetes mellitus is a challenge, and novel data highlight the
value of continuous subcutaneous insulin infusion in this very young patient population. Infants are entirely
dependent on caregivers for insulin therapy, nutrition and glucose monitoring, which emphasizes the need for
appropriate education and psychosocial support of parents. To achieve optimal long-term metabolic control
with low rates of acute and chronic complications, continuous and structured diabetes care should be provided
by a multidisciplinary health-care team.
Karges, B. et al. Nat. Rev. Endocrinol. 8, 201–211 (2012); published online 29 November 2011; doi:10.1038/nrendo.2011.204
The diagnosis of diabetes mellitus in an infant aged
≤2 years constitutes a diagnostic and therapeutic challenge to patients, their families, caregivers and professional diabetes health-care teams. Although clinically
distinct from diabetes mellitus with an onset during
childhood, the complexity of this disorder in infancy
has frequently not received adequate emphasis. Infants
aged ≤2 years represent approximately 4–5% of all pediatric diabetes patients (Table 1).1,2 Identification of the
underlying defect facilitates adequate medical treatment and family counseling. In this Review, we will
dis­cuss the clinical management of diabetes mellitus in
infants, including diagnostic and therapeutic approaches,
ongoing diabetes care and quality control.
Forms of diabetes mellitus in infancy
Several specific etiologies of diabetes mellitus have to
be considered in infants, including monogenic permanent or transient forms of neonatal diabetes mellitus
(NDM), developmental disorders of the pancreas and
auto­immune diabetes mellitus, that is, type 1 diabetes
mellitus (T1DM).
Neonatal diabetes mellitus
Two types of NDM exist, which exhibit a different clinical course. Patients with transient NDM (TNDM) show
spontaneous remission at least before 18 months of age,
whereas those with permanent NDM (PNDM) require
Competing interests
T. Kapellen declares an association with the following
companies: Medtronic, Roche. See the article online for
details of the relationships. The other authors declare no
competing interests.
lifelong medical therapy. TNDM is more frequent than
PNDM (57% versus 43%).3 Multiple genetic abnormalities have been identified as causes of NDM (Figure 1),
some of which also affect the function of the exocrine
pancreas and other organ systems (Table 2).
Transient neonatal diabetes mellitus
TNDM is caused by overexpression of an imprinted gene
region in chromosome 6q24 in about 70% of cases.4,5
Activating mutations of one of the two subunits of the
pancreatic β‑cell ATP-sensitive inward rectifier potassium
(KATP) channel, Kir6.2 (encoded by KCNJ11) and sulfonylurea receptor 1 (SUR1; encoded by ABCC8),6,7 are found
in approximately 25% of patients, whereas pre-proinsulin
(INS) gene mutations are even rarer.3,8,9 Further causes
of TNDM are mutations in the zinc finger transcription
factor ZFP57, which result in hypo­methylation of multiple
imprinted loci.10
In addition to diabetes mellitus, individuals with
TNDM can exhibit neurological symptoms and congenital heart disease (Table 2). TNDM is often accompanied
by severe intrauterine growth retardation that requires
hospitalization, which leads to an early diagnosis of diabetes mellitus. Patients with 6q24 anomalies have lower
birth weight and are, therefore, usually diagnosed at an
earlier age than individuals with KCNJ11 or ABCC8 mutations.7 After clinical remission, diabetes mellitus recurs in
adolescence or early adulthood in approximately 50% of
patients with TNDM.4,9,11
Permanent neonatal diabetes mellitus
PNDM is most often caused by activating mutations of
KCNJ11 or ABCC8,6,12–15 which lead to channel overactivity
Endocrinology and
Diabetes, RWTH
Aachen University,
Pauwelsstraße 30,
D‑52074 Aachen,
Germany (B. Karges).
Department of General
Pediatrics and
Neonatology, University
Children’s Hospital
(T. Meissner),
Department of Public
Health and German
Diabetes Center
(A. Icks), Heinrich Heine
University of
Moorenstraße 5,
D‑40225 Düsseldorf,
Germany. Department
of Pediatrics, University
of Leipzig, Liebigstraße
20a, D‑04103 Leipzig,
Germany (T. Kapellen).
Institute of
Epidemiology and
Medical Biometry,
University of Ulm,
Albert-Einstein-Allee 41,
D‑89081 Ulm, Germany
(R. W. Holl).
Correspondence to:
B. Karges
[email protected]
VOLUME 8 | APRIL 2012 | 201
© 2012 Macmillan Publishers Limited. All rights reserved
Key points
■■ Diabetes mellitus in infants and children differs in etiology, clinical presentation
and therapeutic options; heterogeneous etiologies of diabetes mellitus in infancy
include genetic abnormalities, developmental defects and autoimmune disease
■■ Monogenic forms of neonatal diabetes mellitus almost always occur in the first
6 months of life and very rarely after 12 months; onset of diabetes mellitus in
infants aged >6 months is mostly due to type 1 diabetes mellitus (T1DM)
■■ Infants with T1DM exhibit rapid disease onset, poor residual β‑cell function
and a low rate of transient recovery
■■ Insulin is preferentially provided by continuous subcutaneous infusion
■■ Treatment with sulfonylurea is possible in most patients with mutations in the
genes that encode the ATP-sensitive inward rectifier potassium (KATP) channel
■■ Special needs of infants with diabetes mellitus include comprehensive
education of caregivers and provision of ongoing diabetes care
Table 1 | Comparison of infant-onset and childhood-onset diabetes mellitus*
diabetes mellitus
Childhood-onset diabetes
Age (years)
≤2 years
>2–11 years
>11–18 years
Male sex (%)
Duration of symptoms before
diagnosis (weeks)
Diabetic ketoacidosis at
diagnosis, pH <7.3 (%)
Severe diabetic ketoacidosis at
diagnosis, pH <7.1 (%)
Blood glucose at diagnosis
HbA1c at diagnosis (%)
Duration of diabetes
remission (years)‡
β-cell autoantibody positive (%)§
Celiac disease antibody
positive (%)||
Celiac disease (%)¶
*Data of 21,539 patients from the prospective DPV documentation system (period of 1995–2010).
Remission is defined as HbA1c level <7.5% and a total insulin dose of <0.5 IU/kg per day. §At least one
positive autoantibody against ICA, GAD2, insulin or ICA512. ||At least one positive autoantibody against
endomysium or tissue transglutaminase. ¶Clinical diagnosis of celiac disease.
with impaired insulin secretion (Figure 2).16,17 Activated
KATP channels cause diabetes mellitus, whereas loss-offunction mutations lead to congenital hyper­insulinism.18
An overlap exists between activating KCNJ11 and ABCC8
mutations that cause TNDM and those that result in
PNDM.3 It has been hypothesized that ‘more active’
PNDM mutations completely suppress insulin release and
induce β‑cell apoptosis, whereas ‘less active’ TNDM mutations allow some insulin release and postnatal increase in
β‑cell mass sufficient for diabetes remission.3 The most
important clinical feature of indivi­duals with activating
KATP channel mutations is their responsiveness to oral
sulfonylurea therapy, which allows for discontinuation
of insulin therapy.6,19,20 DEND (develop­mental delay, epilepsy, neonatal diabetes) syndrome occurs in some cases,
as these genes are also expressed in the brain. Patients with
DEND respond to sulfonylurea therapy with neuro­logical
202 | APRIL 2012 | VOLUME 8
improvement.3,19,21 A milder variant without epilepsy and
less severe developmental delay, intermediate DEND
(iDEND), is more frequent than DEND.22 Other monogenic causes of PNDM include INS mutations8,12,23–25 and
homozygous GCK mutations.12,26,27
Wollcott–Rallison syndrome is a common cause of
PNDM in consanguineous families and is associated with
skeletal abnormalities and liver dysfunction.28 Further
clinical findings include cardiac and renal abnormalities,
mental retardation, epilepsy and neutropenia, with poor
prognosis and often early death.28,29 The syndrome results
from mutations in EIF2AK3, which encodes eukaryotic
translation initiation factor 2α kinase 3. Mutations in the
gene FOXP3, which encodes a fork-winged helix family
of transcription factors, cause the IPEX (immune dysregulation, polyendocrinopathy enteropathy, X‑linked)
syndrome.30 This disorder is often fatal, but a milder
pheno­t ype with PNDM and hypothyroidism, auto­
immune enteropathy or nephritic syndrome has been
reported and accounts for about 4% of male cases of
PNDM.31 Intractable diarrhea and NDM are also found
in indivi­duals with biallelic NEUROD1 or NEUROG3
mutations, which cause a lack of enteroendocrine
cells.32–34 Other causes of PNDM associated with complex
clinical phenotypes include mutations that affect the zinc
finger protein GLIS3 (encoded by GLIS3),35,36 transcription factor PAX6 (encoded by PAX6),37,38 a thiamine
transporter (encoded by SLC19A2)39,40 and the glucose
transporter GLUT-2 (encoded by SLC2A2)41–43 (Table 2).
Developmental disorders of the pancreas
PNDM due to pancreatic hypoplasia can be caused by
different genetic defects of transcription factors involved
in pancreas development. In this case, different clinical pheno­types have been described in relation to the
mutated gene and the functional consequences of the
mutation. The effects can be limited to the pancreas, but
can also affect other organs (Table 2). The pancreatic and
duo­denal homeobox 1 transcription factor PDX1 (previously known as IPF1) is expressed in all pan­creatic epithelial precursor cells. As a result, homozygous PDX1
mutations result in pancreatic agenesis associated with
exocrine deficiency.44,45 PTF1A is another transcription factor involved in early pancreas develop­ment and
cerebellar neurogenesis. Hypoplasia of the pancreas
and cerebellum result from PTF1A mutations, which
cause a reduction in transactivation of PDX1 protein
expres­sion.46 Other transcription factors such as RFX6
are involved in the more distal process of endocrine
speci­f ication. Hypoplasia of the pancreas and gall­
bladder, intestinal atresia and intract­able diarrhea are
features of RFX6 mutations.47 However, in several cases
of PNDM, extended molecular genetic analyses could
not identify the underlying cause of pancreas hypoplasia
or agenesis.48,49
Type 1 diabetes mellitus
T1DM is a chronic T‑cell-mediated disease that leads to
destruction of the β cells within the pancreas. Infiltration
of pancreatic islets by lymphocytes causes a variable rate
© 2012 Macmillan Publishers Limited. All rights reserved
of insulitis, with progressive loss of β‑cell function. The
presence of immunologic abnormalities induces loss of
tolerance to self-antigens, but the precise mechanisms
of how the immune system initiates β‑cell destruction
are not known. The disease process is thought to begin
months to years before the onset of hyperglycemia, and
clinical symptoms become apparent when approximately
≥90% of pancreatic β cells are destroyed. Disease markers
for the chronic autoimmune process are serum anti­
bodies against islet antigens, including glutamate decarb­
oxylase 2 (GAD2; also known as GAD65), receptor-type
tyrosine-protein phosphatase-like N (also known as islet
cell antigen 512; ICA512), insulin and zinc transporter 8
(ZnT8), with a particularly strong humoral autoimmunity
response in infants.1,50
Genetic predisposition contributes about half of disease
risk in families with T1DM.51 Increased genetic susceptibility to autoimmune diabetes mellitus in infants is
afforded mainly by the HLA genotype, but more than 40
distinct genomic risk loci have been identified in genomewide studies.52,53 Several environmental factors, such as
short-term exclusive breastfeeding and early introduction
of cows’ milk54 or cereals,55–57 enterovirus infections,58
vitamin D deficiency 59 or rapid postnatal weight gain,60
seem to contribute to autoimmune β‑cell destruction
in genetically predisposed individuals. After the clinical onset of T1DM, a partial transient recovery (honeymoon phase) is observed in most children, but duration
is shorter in infants (Table 1). The higher prevalence of
celiac disease and IgA deficiency in infants with diabetes
mellitus compared with older children points to environmental factors predisposing to β‑cell auto­immunity in the
context of a leaky intestinal mucosal barrier and altered
intestinal immune responsiveness.2,61
NDM is diagnosed during the first 6 months of life with
an incidence of 1:89,000 live births when both TNDM
and PNDM are considered49 and with an incidence from
1:210,000 to 1:260,000 for PNDM alone.22,27 The increased
frequency of newly diagnosed NDM over the past
decade might partially reflect increased survival or
investi­g ation rates. Several distinct causes of NDM
have been identified in about half of the infants aged
≤6 months in an unselected population-based cohort
(Figure 1). Pancreatic hypoplasia or agenesis account
for approximately 10% of NDM cases.49
By contrast, onset of diabetes mellitus between
6 months and 24 months is highly suggestive of T1DM,
which is found with increasing incidence in very young
children.3,9,27,62–64 The average age at T1DM onset has
decreased over the past two decades.62,63 The annual
increase of T1DM cases between 1989 and 2003 was 5.4%
in children aged 0–4 years, and incidence trends predict
doubling of new cases in this age group until 2020.63
However, a reverse trend in children born after 2000
has been observed in Sweden.65 These incidence trends
suggest a critical role for exo­genous factors in the development of β‑cell auto­immunity, effective before birth or in
early postnatal life.
Autoimmune diabetes 6%
UPD6/transient diabetes 6%
KATP channel
mutations 13%
Unclassified 53%
Other monogenic
diabetes forms 8%
Pancreatic dysplasia
or other disorder 10%
Other defined causes 3%
Figure 1 | Causes of neonatal diabetes mellitus with onset ≤6 months of age
(in percent of total) in 225 infants from the DPV cohort (period of 2000–2010).
Transient neonatal diabetes mellitus includes uniparental disomy of chromosome 6
(UDP6). Monogenic causes include KATP channel mutations (n = 16 KCNJ11, n = 14
ABCC8 mutations) and mutations in the genes GCK (n = 4), INSR (n = 1), INS (n = 2),
HNF1α (n = 1) and IPF1 (n = 2), or IPEX syndrome (n = 4) and Wollcott–Rallison
syndrome (n = 3). Other defined causes include cytomegaly virus infection (n = 1),
preterm birth (n = 3), Noonan syndrome (n = 1) and Down syndrome (n = 1).
Diabetes-related direct medical costs for health
in­surances range between $1,700 and $4,730 in the
USA66,67 and from €2,250 to €3,930 in Europe per child
and year.68,69 Costs are higher in socially deprived patients,
mainly due to hospitalization. Main cost categories were
hospitalization, glucose self-monitoring and insulin.
In a German study, mean diabetes-associated costs in
2007 were about 35% higher than in 2000, and costs of
insulin pump therapy had increased to 20% of total cost.70
Children <4 years of age had 30–40% higher costs than
older children, mainly due to hospitalization and more
frequent blood glucose measurements. Genetic testing in
NDM is considered cost-effective, given that classification
of the underlying defect allows specific treatment and can
improve quality of life and lower costs.71
The clinical approach
Symptoms and signs
The clinical presentation of diabetes mellitus in infants
ranges from incidentally detected asymptomatic hyperglycemia to polydipsia, failure to thrive, vomiting and
irritability or acute symptoms with severe dehydration,
ketoacidosis, hypotension or loss of consciousness. Infants
<2 years of age at disease onset present more often with
vomiting, diarrhea, fever and impaired consciousness than
older children.1,2 Similarly, infants with dia­betes mellitus
have a higher rate of diabetic ketoacidosis at diagnosis and
more often have severe diabetic keto­acidosis (pH <7.1)
than those aged >2 years (Table 1).1,2,72 The higher morbidity and mortality of infants with dia­betes mellitus should
be prevented by an earlier diagnosis.73 Monogenic forms of
NDM almost always present within the first 6 months
of life and almost never after the age of 12 months.27,64,74
© 2012 Macmillan Publishers Limited. All rights reserved
Table 2 | Genetic causes of neonatal diabetes mellitus
Diabetes phenotype
Associated clinical features
Imprinting disorder, paternal
uniparental disomy, duplication
or methylation defect
Diagnosed week 1–4
Diabetic ketoacidosis rare
IUGR, macroglossia, umbilical hernia, cardiac
abnormalities, dysmorphy, bone dysplasia and
delayed maturation
Autosomal recessive;
imprinting disorder, mosaicism
of hypomethylation
Diagnosed week 1–4
Diabetic ketoacidosis rare
Similar to 6q24, developmental delay,
hypotonia, hypoplasia of corpus callosum,
impaired vision and hearing
Autosomal dominant
Diagnosed month 1–2
DEND or iDEND syndrome
Autosomal dominant,
autosomal recessive
Diagnosed week 4–16
DEND or iDEND syndrome
IUGR rare
Autosomal dominant,
autosomal recessive
Onset month 6–12 rare
Autosomal recessive
Autosomal recessive
Wollcott–Rallison syndrome
X-linked recessive,
male limited
IPEX syndrome, enteropathy, eczema, thyroiditis,
Autosomal recessive
Intractable diarrhea
Autosomal recessive
IUGR, diarrhea
Autosomal recessive
Hypothyroidism, cholestasis, glaucoma,
polycystic kidneys, recurrent infections, deafness
Autosomal recessive
Eye and brain anomalies
Autosomal recessive
PNDM or late-onset
Megaloblastic anemia, deafness, heart defects,
visual impairment
Autosomal recessive
Neonatal onset rare
Fanconi–Bickel syndrome, renal dysfunction,
Autosomal recessive
Exocrine pancreas deficiency
Autosomal recessive
Hypoplasia of cerebellum
Autosomal recessive
Intestinal atresia, gallbladder aplasia,
intractable diarrhea
Abbreviations: DEND, developmental delay, epilepsy, neonatal diabetes; iDEND, intermediate DEND; IPEX, immune dysregulation, polyendocrinopathy
enteropathy, X‑linked; IUGR, intrauterine growth retardation, PNDM, permanent neonatal diabetes mellitus; TNDM, transient diabetes mellitus.
Dysmorphic features can indicate rare types of NDM,
and additional clinical findings can direct the evaluation
to specific genetic defects (Table 2).
Diagnostic criteria and procedures
Diabetes mellitus comprises a group of metabolic dis­
orders characterized by chronic hyperglycemia,75 predominantly caused by insulin deficiency in infants.
Criteria for the diagnosis of diabetes mellitus in childhood are based on blood glucose measurements, defined
as random plasma glucose concentrations ≥11.1 mmol/l
plus symptoms of diabetes mellitus, or fasting plasma
glucose ≥7.0 mmol/l, or 2 h post-load glucose levels
≥11.1 mmol/l during an oral glucose challenge test.75
Detection of ketones in blood or urine requires urgent
insulin treatment, as ketoacidosis can occur rapidly.
An HbA1c level ≥6.5% has been accepted as a diagnostic criterion for diabetes mellitus.75 However, neonatal
blood contains a high proportion of fetal hemoglobin
(HbF), whereas hemoglobin A (HbA) accounts for only
10–20%. During the first 6 months of life, HbF is gradually replaced by HbA. Therefore, HbA1c is not suitable
to diagnose diabetes mellitus in infants aged <6 months.
Once the diagnosis of diabetes mellitus has been
established in an infant, specific diagnostic procedures
204 | APRIL 2012 | VOLUME 8
are proposed to elucidate the underlying defect (Box 1).
Careful investigation of associated clinical findings
and target-oriented genetic analysis are helpful to classify diabetes mellitus in many patients (Table 2).12,27
Genetic screening should be advised in all individuals
with onset of diabetes mellitus within the first 6 months
of life because of potential consequences for medical
treatment.64,74,76 If TNDM is suspected, analysis of 6q24
anoma­lies is performed. 74 For those with suspected
PNDM, sequencing of KCNJ11 is recom­mended, followed by analysis of INS and ABCC8.64,76 As a novel tool,
whole-exome sequencing might become useful for further
molecular diag­nosis in NDM cases that are negative for
known genetic abnormalities.77
Differences between infants and children
Infants with diabetes mellitus differ in their clinical
features from children aged >2 years at disease onset
(Table 1). The time from initial presentation of symptoms
to diagnosis is shorter in infants than in older children.2
At time of diagnosis, infants have higher blood glucose
and lower HbA1c and C‑peptide levels than children
aged >2 years, which suggests a faster process of β‑cell
destruction in younger patients.1,2 Infants with type 1
diabetes mellitus (T1DM) have increased genetic disease
© 2012 Macmillan Publishers Limited. All rights reserved
susceptibility and a strong humoral auto­immunity against
islet cells and antigens, with poorly preserved residual
β‑cell function and a lower rate of partial remission,
compared with patients aged >2 years.1,2 These observations might explain why metabolic control during the
first 6 months after diagnosis is poorer in infants than in
older children.1
β cell
with ER
Treatment and management
Insulin treatment is acutely required in most infants with
newly diagnosed diabetes mellitus to treat or prevent
ketoacidosis and dehydration and to allow weight gain.
Rarely, spontaneous normalization of blood glucose in
asymptomatic ketone-negative neonates with TNDM can
occur that justifies withholding insulin therapy. In familial
PNDM due to activating KATP channel mutations, sulfonyl­
urea therapy has been successfully initiated in an insulinnaive neonate.78 The majority of children diagnosed with
diabetes mellitus during infancy will have T1DM, requiring permanent insulin substitution, which presents a particular challenge in these very young children with respect
to precise and flexible dosage.
Insulin injection and subcutaneous infusion
Insulin replacement therapy in infants is provided by
multiple daily insulin injections (MDI) or continuous
subcutaneous insulin infusion (CSII). To accommodate
meal-dependent insulin requirements, regular insulin
and the rapid-acting insulin analogues aspart, glulisine
or lispro are available. Mealtime insulin dose is calculated based on carbohydrate intake. Rapid-acting insulin
analogues for meals are more convenient for parents of
young children, as they allow prandial injections of shortacting insulin instead of preprandial regular insulin in
the context of unpredictable food intake.79,80 Basal insulin
is substituted in infants by intermediate-acting NPH
(neutral protamine Hagedorn) insulin, or by the basal
insulin analogues detemir or glargine—although these
two agents are not formally approved for infants—and
mainly by CSII using rapid-acting insulin analogues
(Figure 3). In infants, basal insulin accounts for 10–30%
of total daily insulin with CSII81,82 and for 30–50% with
MDI.83 The very low insulin demand is difficult to obtain
by (diluted) NPH or regular insulin injections, bearing
in mind the risk of hypoglycemia.48 At low doses, NPH
insulin has a shorter action profile than at high doses,
requiring more frequent injections.
In neonates with total parenteral nutrition or continuous enteral feeding, only basal insulin substitution
with CSII is sufficient.84 When breast or bottle feeding
is started, basal insulin typically accounts for about 30%
and mealtime insulin for 70% of daily insulin doses. The
total daily insulin requirement can vary from 0.29 U/kg
to 1.4 U/kg per day.84 In the case of very low insulin
requirements (≤0.02 U/h or bolus ≤0.2 U), CSII of diluted
insulin (5 or 10 U/ml) is the treatment of choice, as this
approach reduces the risk of hypoglycemia. 48,84 CSII
administered by insulin pumps provides close to physio­
logic insulin de­livery due to its variable low-dose basal
insulin administra­tion and mealtime insulin bolus, which
β cell
with ER
ER toxicity
Figure 2 | Pathogenesis of decreased insulin secretion in neonatal diabetes
mellitus. a | Mechanisms of normal insulin secretion. Glucose is transported into
the β cell by GLUT-2. Glucokinase phosphorylates glucose to glucose‑6-phosphate
as the rate-limiting enzyme in glucose metabolism. Glycolysis increases the ATP/
ADP ratio, sensed by the KATP channels. Increase of the ATP/ADP ratio leads to
KATP channel closure, followed by membrane depolarization resulting in opening of
VDCC. Influx of calcium triggers exocytosis of insulin. Within the nucleus, different
transcription factors regulating insulin synthesis are shown. b | Localization of
genetic defects within the β cell and their effect on impaired insulin release.
Defective GLUT-2 results in decreased glucose influx into the β cell. Glucokinase
deficiency leads to impaired glucose phosphorylation, which reduces the
generation of ATP. Activating mutations of the genes encoding the two subunits
SUR1 and Kir6.2 of the pancreatic KATP channel result in channel opening.
Increased potassium outflow leads to hyperpolarization and stabilization of the
membrane potential, thus blocking insulin exocytosis. Mutations in the INS gene
cause abnormal proinsulin processing within the endoplasmic reticulum, leading
to β‑cell toxicity. Mutations in genes encoding transcription factors PDX1, PTF1A,
RFX6, GLIS3, PAX6, NEUROD1 and NEUROG3 cause abnormal development of
pancreas or endocrine cells. Abbreviations: ER, endoplasmic reticulum; GLUT-2,
solute carrier family 2 facilitated glucose transporter member 2; KATP, ATPsensitive inward rectifier potassium; VDCC, voltage-dependent calcium channels.
© 2012 Macmillan Publishers Limited. All rights reserved
Box 1 | Diagnostic procedures in infants with diabetes at initial diagnosis
■■ Detailed family history including consanguinity, gestational diabetes mellitus
and early-onset type 2 diabetes mellitus
■■ Evaluation for associated clinical features including birth weight, dysmorphic
features, umbilical hernia, macroglossia and skeletal dysplasia
■■ Ultrasonography of abdomen (pancreas agenesis, renal abnormalities) and brain
(structural abnormalities)
■■ Determination of chymotrypsin-like elastase family member 3B or chymotrypsin
(to detect exocrine pancreatic insufficiency)
■■ In patients aged ≤6 months: target-oriented molecular analysis starting with
the most probable entities (for example, 6q24 anomalies, KCNJ11, ABCC8, INS)
and evaluation of first-degree relatives by oral glucose challenge test
■■ Analysis of autoantibodies to GAD2, ICA512, islet cells, insulin and ZnT8
■■ In antibody-negative infants with disease onset between 6 and 12 months of age
consider analysis of KCNJ11 and ABCC8 because of therapeutic implications
100 –
Insulin pump (CSII)
4+ injections
90 –
3 injections
Proportion of patients (%)
80 –
1–2 injections
70 –
60 –
50 –
40 –
30 –
20 –
10 –
Age (years)
Figure 3 | Proportion of different insulin therapeutic strategies
in infants ≤2 years of age (n = 176) and older children
(>2–11 years, n = 8,866, and >11–18 years, n = 15,833)
with diabetes mellitus from the DPV initiative (period of
2009–2010). Abbreviation: CSII, continuous subcutaneous
insulin infusion.
allows for a flexible food intake. The fastest action profile
of CSII is reached with rapid-acting insulin analogues,
used by almost 90% of patients.85 The automatic calculation of meal or correction boluses based on insulin to
carbohydrate ratios and insulin sensitivity factors, as well
as the option of remote-controlled insulin delivery, make
this treatment modality an appealing option for care­
givers. In very young children with diabetes mellitus,
CSII has been shown to be safe and effective,86,87 and it is
currently the predominant treatment for this age group
in many countries (Figure 3).
The total amount of daily insulin is approximately
10–30% lower with CSII than with MDI in children. 88
The rate of severe hypoglycemia was significantly lower in
young children with diabetes mellitus if they were treated
with CSII rather than with MDI therapy (6.5 versus 24.1
episodes in 100 patient-years),89 whereas two randomized controlled trials of insulin pump therapy in young
206 | APRIL 2012 | VOLUME 8
children with T1DM found no differences in metabolic
control between CSII and MDI.86,90 Infants starting CSII
treatment at diabetes onset had better long-term metabolic
control with less frequent hypoglycemic events than those
on MDI therapy over 5 years.91 Basal insulin sub­stitution
with CSII depends on age, body weight and duration of
diabetes mellitus in pediatric patients, calculated for children aged 0–5 years as 0.25 IU/kg, for 6–12 year-olds as
0.33 IU/kg, and for those aged >12–18 years as 0.43 IU/kg
with age-specific circadian variation.81
Identification of an activating KATP channel mutation in
an infant with diabetes mellitus enables switching from
insulin injections to oral sulfonylurea treatment in >90%
of affected patients.19,20 Gain-of-function in the poreforming Kir6.2 subunits or regulatory SUR1 subunits of
the KATP channel induces hyperglycemia due to impaired
insulin secretion (Figures 4a,b). Binding of sulfonylurea
to SUR1 induces ATP-independent channel closure in
response to high glucose, resulting in insulin secretion
(Figure 4c). Sulfonylurea compounds also alleviate extrapancreatic glucose-lowering effects.92 A transfer protocol
to switch patients with activated KATP channel mutations
from insulin to sulfonylurea has been proposed.93 The
initial dose of sulfonylurea compounds for patients
with KCNJ11 mutations is higher than that of patients with
ABCC8 mutations,3,19,20 with dose reductions required
over time irrespective of the mutation. Different types
of sulfonylureas have been used for treatment in infants,
including glibenclamide, glipizide and gliclazide, with
similar efficacy and safety. 19,20 Long-term follow-up
shows efficacy and safety of this treatment in children
with PNDM.94 Patients with TNDM due to chromosome 6 abnormalities also respond to sulfonylurea
during infancy and at diabetes recurrence.11
Glucose monitoring
Frequent monitoring of blood glucose is a cornerstone
of optimized insulin therapy, which allows for immediate recognition of hyperglycemia and hypoglycemia and
thus enables adjustment of treatment. Monitoring of blood
glucose should be conducted by parents at least four to
six times daily. Frequency of blood glucose monitoring
per day is highest in very young children and correlates
with glycemic control.95 In children using MDI, more
than five glucose measurements per day did not further
improve HbA1c, whereas children with CSII showed an
HbA1c reduction of 0.27% for any additional blood glucose
measure­ment per day.95 Because of their fear of hypo­
glycemia, parents of infants with diabetes mellitus tend to
monitor blood glucose also frequently during the night.
Continuous glucose monitoring (CGM) with subcutaneous sensors that measure interstitial glucose offers
enhanced insight into glycemic variation. Glucose
sensors placed for 5–6 days give real-time information
on interstitial glucose and can be analyzed retrospectively. CGM informs about trends and can alert to the
presence of high or low glucose levels, thereby gaining
particular prominence in combination with CSII.96
© 2012 Macmillan Publishers Limited. All rights reserved
Differences between sensor and blood glucose are caused
by the distinct compartments used for glucose measurement, and rapid changes of blood glucose are detected by
sensors with time lags. CGM in very young children can
reduce the rate of hypoglycemia and parents’ anxiety and
has helped uncover unsuspected hypoglycemia.97 Due to
the limited body surface to place an additional subcu­
taneous glucose sensor in infants wearing an insulin
pump, CGM is inconvenient for permanent use. CGM
systems are costly and frequently not covered by many
insurance companies.
Future treatment directions
To optimize insulin replacement, closing the loop
between insulin delivery and CGM on the route to an
arti­ficial pancreas is a major field in diabetes research.
Several studies have shown that sensor-augmented
pump therapy can improve metabolic control and reduce
hypoglycemia in children,96,98 but continued sensor use
is critical for effectiveness.99 Novel technologies have
combined CGM, CSII and computerized algorithms to
improve overnight glucose control that reduces the risk
of hypoglycemia,100 but these technologies have so far not
been approved in infants. In eight children with T1DM
aged 6–13 years, an automated overnight closed-loop
glucose control and insulin delivery system has been
found to be technically feasible to control glucose levels
and avoid hypoglycemia.101
In patients with T1DM, various immunological interventions have been performed to preserve β‑cell function after disease manifestation or in individuals at
increased diabetes risk. T‑cell directed CD3 antibodies,
TNF-blocking etanercept or GAD vaccination demonstrated a partial102–104 or no105 effect on the preservation
of β‑cell function in children with diabetes mellitus aged
3–18 years. Administration of nasal insulin, initiated soon
after detection of autoantibodies, did not prevent or delay
T1DM in children aged >1 year.106 Dietary intervention
in infancy with hydrolysate formula reduced β‑cell autoimmunity and disease onset in the genetically at risk.107
Experimental autologous stem cell transplantation in
patients with diabetes mellitus aged 13–31 years resulted
in transient insulin independence in some patients,108 but
immune suppression can cause severe adverse effects that
do not legitimate this therapy.
Nutritional management
Infants with diabetes mellitus have the same basic nutritional requirements as nondiabetic children and need
regular, balanced meals. Breast feeding is recommended
as in other children.109 The amount of a breast-fed meal
is commonly estimated by weighing the child before
and after a meal; carbohydrate content of breast milk
is calculated at about 6–7 g per 100 ml.110 In neonates,
insulin requirement depends on the frequency of breast
feeds.48 With more than six breast feeds per day, a very
smooth blood glucose profile can be obtained by high
basal insulin substitution and very low mealtime boluses
such as 0.05 U per 12 g of carbohydrates.48 Families of
an infant with diabetes mellitus should be encouraged
a Normal
b Overactive
c Sulfonyurea restores
insulin secretion
insulin secretion
insulin secretion
Figure 4
| Molecular mechanism of Hyperglycemia
sulfonylurea therapy in neonatal
mellitus. a | Normal β‑cell KATP channels respond to hyperglycemia with an ATP
increase that leads to channel closure and insulin secretion. b | The overactive KATP
channel due to activating ABCC8 or KCNJ11 mutations remains open in the presence
of hyperglycemia, attenuating insulin release. c | Sulfonylurea restores KATP channel
function with closure in response to high glucose, resulting in insulin secretion.
to develop a good working knowledge of nutrition and
how it affects glucose control. Carbohydrate counting
and pre-meal blood glucose tests are necessary to calculate mealtime insulin doses. Frequent small meals are
more favorable to achieve good glycemic control, and
feeding patterns should be matched with the duration
of action of injected insulins.109 In infants with CSII, the
insulin bolus can be given after the meal.90 Alternatively,
a prolonged insulin bolus during the meal might be
advantageous to avoid postprandial hyper­glycemia or
hypoglycemia. Food refusal by the child causes distress
and anxiety in caregivers, who should be guided to deal
with this situation, for example, by substituting milk as
an alternative.109 To prevent nocturnal hypoglycemia in
infants, extra-slowly-absorbed complex carbohydrates,
such as corn starch, may be required at bedtime.111
Education and psychosocial support
Diabetes education
Continued diabetes education is a main component of
diabetes therapy, conveying knowledge to the families
necessary for adequate self-management. Infants are
completely dependent on caregivers for insulin injections, food availability, glucose monitoring and other
treatment aspects. Limited verbal communication
skills, variable appetite with unforeseeable eating, fluctuating activity, frequent infections and fear of hypo­
glycemia or hyper­glycemia are potential limitations and
can contribute to inferior metabolic control in infants
with diabetes mellitus.1 Education on prevention, recog­
nition and manage­ment of dys­glycemia is particularly
important in this age group. Specific programs, including age-appropriate, demand-oriented and individualized practical information and skills training for parents
of affected children have been effective in improving
metabolic control.112,113 Apart from teaching diabetes
© 2012 Macmillan Publishers Limited. All rights reserved
treatment according to current guidelines, translating
this knowledge into everyday self-­management behavior
and emotional coping with the chronic disease is part of
educational interventions.112,113
Signs of hypoglycemia in infants can be more difficult to recognize and may be expressed by behavioral
changes, including irritability and inconsolable crying.114
Hypo­g lycemia is more common in children aged
<5 years with diabetes mellitus115,116 and may be more
detri­mental than in older children. Partial cognitive deficits in children with early-onset diabetes mellitus have
been explained by frequent and early exposure to severe
hypoglycemia,115 whereas another study found associ­
ations between cognitive function and the degree of diabetic ketoacidosis at diagnosis and elevated long-term
HbA1c levels but not with hypoglycemia.117 In general,
hyperglycemia and hypoglycemia are linked to adverse
neurological outcomes.118,119
Clinical management during acute infections (sick day
management) in infants with diabetes mellitus requires
frequent blood glucose monitoring, regular intake of easily
digestible food or sugar-containing fluids, and insulin
dose adjustments to prevent ketoacidosis, dehydration
and hyperglycemia or hypoglycemia.120 Determination
of blood 3‑hydroxybutyrate using test strips might be
superi­or to urine ketone sticks for the detection and treatment of diabetic ketosis.121 Parents should be trained to
manage sick days and, therefore, clinicians should provide
them with written information, adequate amounts of
glucose and ketone or 3‑­hydroxybutyrate test strips, a
gluca­gon kit to treat severe hypoglycemia, and aroundthe-clock access to the diabetes care team.120 To achieve
social integration of the infant with diabetes mellitus
within a nursery, comprehensive information on the
disease should be offered to all care providers.
Psychosocial support
The diagnosis of diabetes mellitus in an infant is often
associated with massive changes of everyday life for the
entire family. Parents should be advised to make regular
meal plans with carbohydrate counting, glucose readings and insulin injections. Instructions are needed for
handling of unforeseen situations, for example, when
infants reject blood glucose measurements and insulin
injections. It may be difficult to distinguish normal
infant behavior from diabetes-related mood changes.122
Glucose measurements and insulin injections admini­
stered by parents and caregivers might be perceived
as painful.122,123 Parents often feel increased emotional
stress, anxiety and depression.124,125
High levels of family functioning improve treatment adherence and glycemic control, whereas family
conflicts, single parenthood, lower income, migration
background and psychological maladjustment predict
poor metabolic control.68,126 The psychosocial resources
of the family should be continuously evaluated from
disease onset, to provide sufficient support, especially
for mothers. 127 Given that socioemotional support
and psycho­logical interventions can improve glycemic
control in young children with diabetes mellitus,128,129
208 | APRIL 2012 | VOLUME 8
psychological care by mental-health professionals should
be offered to caregivers.
Ongoing diabetes care
Programs and structures
To maintain optimal glucose control and quality of care,
ongoing consultations in specialized outpatient clinics
are advised every 3 months. During the visits, insulin
or other medication, blood glucose records, history of
hypo­glycemia or ketoacidosis, nutrition, intercurrent
health problems, developmental milestones and dia­betesspecific knowledge of parents are assessed. 130 Physical
examination includes weight, height, blood pressure
and inspection of insulin injection and blood glucose
monitor­ing sites. Measurement of HbA1c levels is suitable
to monitor glycemic control in infants aged >6 months
but does not necessarily reflect average blood glucose in
infants <6 months. Diabetes-associated diseases including hypothyroidism and celiac disease131,132 and lipid
parameters are typically screened. Microvascular and
macrovascular diabetes complications are uncommon
in infants, and general agreement exists that eye or renal
examinations are not required during the first 5 years
after diagnosis.
Continuous up-to-date advice provided by the dia­
betes care team to the family provides a basis for skilled
self-management. The specialized multidisciplinary
dia­b etes care team for infants with diabetes mellitus
involves a pediatrician, diabetes nurse or educator, dietician, social worker and/or psychologist in partnership
with the patient and the family.112,130 Beside ambulatory
dia­b etes care, hospitalization can be necessary in the
case of meta­bolic deteriora­tion. Additional tools and
resources of diabetes teams include telecommunication
and computer interfacing with blood glucose meters,
CGM sensors and insulin pumps, which enable direct
interaction between visits.130,133
Quality control
To investigate outcomes of care in infant-onset diabetes
mellitus, prospective data systems have been established
by national networks.134–136 Major differences in metabolic
outcome have been demonstrated between international
pediatric diabetes centers.137 Including more than 38,000
children with diabetes aged 0–18 years, the prospective
diabetes documentation initiative (DPV), which contains
data from Germany and Austria, is one of the largest data
documentation systems for childhood diabetes mellitus
worldwide.131,132,138 This and other national initiatives have
been used to evaluate indicators of childhood diabetes
care, including the frequency of out-patient visits, hospitalization, rates of severe hypoglycemia and diabetic
ketoacidosis and other outcomes.134–136 The DPV has
been pivotal to characterize common and rare forms of
neonatal diabetes mellitus at the population level.49 The
design and conductance of research initiatives in pedi­
atric diabetology, focusing on questions specific to infants
with diabetes mellitus and taking into account the ethical
implications of research in young children, is a highly
rele­vant challenge for the future.
© 2012 Macmillan Publishers Limited. All rights reserved
Diabetes mellitus in infants is different from diabetes in
older children in terms of underlying causes, clinical signs
and treatment options. The heterogeneous etiologies of
infant-onset diabetes mellitus include several genetic
abnormalities, developmental disorders of the pancreas
and autoimmune disease. Infants aged ≤6 months of age
frequently have monogenic diabetes mellitus, whereas
infants aged >6 months most probably have T1DM.
Infants with T1DM exhibit a rapid disease onset and poor
residual β‑cell function, with a low rate of partial remission. Insulin therapy is frequently given as CSII in many
countries. In most patients with activating KATP channel
mutations, treatment with oral sulfonyl­ureas is possible.
Considering the special needs of infants, comprehensive
education and support of caregivers is an integral part of
Komulainen, J. et al. Clinical, autoimmune, and
genetic characteristics of very young children
with type 1 diabetes. Childhood Diabetes in
Finland (DiMe) Study Group. Diabetes Care 22,
1950–1955 (1999).
Nimri, R., Phillip, M. & Shalitin, S. Children
diagnosed with diabetes during infancy have
unique clinical characteristics. Horm. Res. 67,
263–267 (2007).
Aguilar-Bryan, L. & Bryan, J. Neonatal diabetes
mellitus. Endocr. Rev. 29, 265–291 (2008).
Metz, C. et al. Neonatal diabetes mellitus:
chromosomal analysis in transient and
permanent cases. J. Pediatr. 141, 483–489
Temple, I. K. et al. Transient neonatal diabetes:
widening the understanding of the
etiopathogenesis of diabetes. Diabetes 49,
1359–1366 (2000).
Babenko, A. P. et al. Activating mutations in the
ABCC8 gene in neonatal diabetes mellitus.
N. Engl. J. Med. 355, 456–466 (2006).
Flanagan, S. E. et al. Mutations in ATP-sensitive
K+ channel genes cause transient neonatal
diabetes and permanent diabetes in childhood
or adulthood. Diabetes 56, 1930–1937 (2007).
Garin, I. et al. Recessive mutations in the INS
gene result in neonatal diabetes through
reduced insulin biosynthesis. Proc. Natl Acad.
Sci. USA 107, 3105–3110 (2010).
Mackay, D. J. & Temple, I. K. Transient neonatal
diabetes mellitus type 1. Am. J. Med. Genet. C
Semin. Med. Genet. 154C, 335–342 (2010).
Mackay, D. J. et al. Hypomethylation of multiple
imprinted loci in individuals with transient
neonatal diabetes is associated with mutations
in ZFP57. Nat. Genet. 40, 949–951 (2008).
Søvik, O. et al. Familial occurrence of neonatal
diabetes with duplications in chromosome
6q24: treatment with sulfonylurea and 40-yr
follow-up. Pediatr. Diabetes
Edghill, E. L. et al. Insulin mutation screening in
1,044 patients with diabetes: mutations in the
INS gene are a common cause of neonatal
diabetes but a rare cause of diabetes diagnosed
in childhood or adulthood. Diabetes 57,
1034–1042 (2008).
Ellard, S. et al. Permanent neonatal diabetes
caused by dominant, recessive, or compound
heterozygous SUR1 mutations with opposite
functional effects. Am. J. Hum. Genet. 81,
375–382 (2007).
Gloyn, A. L. et al. Activating mutations
in the gene encoding the ATP-sensitive
diabetes management. Future research will focus on facilitation of long-term insulin treatment and preservation of
β‑cell function. Population-based networks of childhood
diabetes documentation systems may serve to further
investigate quality indicators of diabetes care in infants.
Review criteria
References were searched using PubMed for original
articles in English published from 1995 to 2011. The
search terms used (either alone or in combination) were
“neonatal diabetes”, “infant diabetes”, “congenital
diabetes”, “type 1 diabetes”, “insulin”, “sulfonylurea”,
“glucose monitoring”, “therapy”, “diabetes care”,
“education”, “nutrition”, “psychosocial support”, “cost”,
“quality control”. In addition, relevant articles were retrieved
by searching the reference lists of identified articles.
potassium-channel subunit Kir6.2 and
permanent neonatal diabetes. N. Engl. J. Med.
350, 1838–1849 (2004).
Sagen, J. V. et al. Permanent neonatal diabetes
due to mutations in KCNJ11 encoding Kir6.2:
patient characteristics and initial response to
sulfonylurea therapy. Diabetes 53, 2713–2718
de Wet, H. et al. Increased ATPase activity
produced by mutations at arginine-1380 in
nucleotide-binding domain 2 of ABCC8 causes
neonatal diabetes. Proc. Natl Acad. Sci. USA
104, 18988–18992 (2007).
Proks, P. et al. A heterozygous activating
mutation in the sulphonylurea receptor SUR1
(ABCC8) causes neonatal diabetes. Hum. Mol.
Genet. 15, 1793–1800 (2006).
Thomas, P. M. et al. Mutations in the
sulfonylurea receptor gene in familial persistent
hyperinsulinemic hypoglycemia of infancy.
Science 268, 426–429 (1995).
Pearson, E. R. et al. Switching from insulin to
oral sulfonylureas in patients with diabetes due
to Kir6.2 mutations. N. Engl. J. Med. 355,
467–477 (2006).
Rafiq, M. et al. Effective treatment with oral
sulfonylureas in patients with diabetes due to
sulfonylurea receptor 1 (SUR1) mutations.
Diabetes Care 31, 204–209 (2008).
Zwaveling-Soonawala, N. et al. Successful transfer
to sulfonylurea therapy in an infant with
developmental delay, epilepsy and neonatal
diabetes (DEND) syndrome and a novel ABCC8
gene mutation. Diabetologia 54, 469–471 (2011).
Slingerland, A. S. et al. Referral rates for
diagnostic testing support an incidence of
permanent neonatal diabetes in three European
countries of at least 1 in 260,000 live births.
Diabetologia 52, 1683–1685 (2009).
Colombo, C. et al. Seven mutations in the human
insulin gene linked to permanent neonatal/
infancy-onset diabetes mellitus. J. Clin. Invest.
118, 2148–2156 (2008).
Polak, M. et al. Heterozygous missense
mutations in the insulin gene are linked to
permanent diabetes appearing in the neonatal
period or in early infancy: a report from the
French ND (Neonatal Diabetes) Study Group.
Diabetes 57, 1115–1119 (2008).
Støy, J. et al. Insulin gene mutations as a cause
of permanent neonatal diabetes. Proc. Natl
Acad. Sci. USA 104, 15040–15044 (2007).
Njølstad, P. R. et al. Neonatal diabetes mellitus
due to complete glucokinase deficiency. N. Engl.
J. Med. 344, 1588–1592 (2001).
NATURE REVIEWS | ENDOCRINOLOGY 27. Russo, L. et al. Permanent diabetes during the
first year of life: multiple gene screening in 54
patients. Diabetologia 54, 1693–1701 (2011).
28. Rubio-Cabezas, O. et al. Wolcott–Rallison
syndrome is the most common genetic cause of
permanent neonatal diabetes in
consanguineous families. J. Clin. Endocrinol.
Metab. 94, 4162–4170 (2009).
29. Senée, V. et al. Wolcott-Rallison syndrome:
clinical, genetic, and functional study of EIF2AK3
mutations and suggestion of genetic
heterogeneity. Diabetes 53, 1876–1883 (2004).
30. Bennett, C. L. et al. The immune dysregulation,
polyendocrinopathy, enteropathy, X-linked
syndrome (IPEX) is caused by mutations of
FOXP3. Nat. Genet. 27, 20–21 (2001).
31. Rubio-Cabezas, O. et al. Clinical heterogeneity in
patients with FOXP3 mutations presenting with
permanent neonatal diabetes. Diabetes Care 32,
111–116 (2009).
32. Rubio-Cabezas, O. et al. Permanent neonatal
diabetes and enteric anendocrinosis associated
with biallelic mutations in NEUROG3. Diabetes
60, 1349–1353 (2011).
33. Rubio-Cabezas, O. et al. Homozygous mutations
in NEUROD1 are responsible for a novel
syndrome of permanent neonatal diabetes and
neurological abnormalities. Diabetes 59,
2326–2331 (2011).
34. Wang, J. et al. Mutant neurogenin-3 in congenital
malabsorptive diarrhea. N. Engl. J. Med. 355,
270–280 (2006).
35. Dimitri, P. et al. Novel GLIS3 mutations
demonstrate an extended multisystem
phenotype. Eur. J. Endocrinol. 164, 437–443
36. Senée, V. et al. Mutations in GLIS3 are
responsible for a rare syndrome with neonatal
diabetes mellitus and congenital hypothyroidism.
Nat. Genet. 38, 682–687 (2006).
37. Solomon, B. D. et al. Compound heterozygosity
for mutations in PAX6 in a patient with complex
brain anomaly, neonatal diabetes mellitus, and
microophthalmia. Am. J. Med. Genet. A 149A,
2543–2546 (2009).
38. Wen, J. H. et al. Paired box 6 (PAX6) regulates
glucose metabolism via proinsulin processing
mediated by prohormone convertase 1/3
(PC1/3). Diabetologia 52, 504–513 (2009).
39. Bergmann, A. K. et al. Thiamine-responsive
megaloblastic anemia: identification of novel
compound heterozygotes and mutation update.
J. Pediatr. 155, 888–892 e1 (2009).
40. Labay, V. et al. Mutations in SLC19A2 cause
thiamine-responsive megaloblastic anaemia
VOLUME 8 | APRIL 2012 | 209
© 2012 Macmillan Publishers Limited. All rights reserved
associated with diabetes mellitus and deafness.
Nat. Genet. 22, 300–304 (1999).
Kentrup, H., Altmüller, J., Pfäffle, R. &
Heimann, G. Neonatal diabetes mellitus with
hypergalactosemia. Eur. J. Endocrinol. 141,
379–381 (1999).
Santer, R. et al. Mutations in GLUT2, the gene for
the liver-type glucose transporter, in patients
with Fanconi–Bickel syndrome. Nat. Genet. 17,
324–326 (1997).
Yoo, H. W., Shin, Y. L., Seo, E. J. & Kim, G. H.
Identification of a novel mutation in the GLUT2
gene in a patient with Fanconi–Bickel syndrome
presenting with neonatal diabetes mellitus and
galactosaemia. Eur. J. Pediatr. 161, 351–353
Nicolino, M. et al. A novel hypomorphic PDX1
mutation responsible for permanent neonatal
diabetes with subclinical exocrine deficiency.
Diabetes 59, 733–740 (2010).
Stoffers, D. A., Zinkin, N. T., Stanojevic, V.,
Clarke, W. L. & Habener, J. F. Pancreatic
agenesis attributable to a single nucleotide
deletion in the human IPF1 gene coding
sequence. Nat. Genet. 15, 106–110 (1997).
Sellick, G. S. et al. Mutations in PTF1A cause
pancreatic and cerebellar agenesis. Nat. Genet.
36, 1301–1305 (2004).
Smith, S. B. et al. Rfx6 directs islet formation
and insulin production in mice and humans.
Nature 463, 775–780 (2010).
Beardsall, K., Pesterfield, C. L. & Acerini, C. L.
Neonatal diabetes and insulin pump therapy.
Arch. Dis. Child. Fetal Neonatal Ed. 96,
F223–F224 (2011).
Grulich-Henn, J. et al. Entities and frequency of
neonatal diabetes: data from the diabetes
documentation and quality management system
(DPV). Diabet. Med. 27, 709–712 (2010).
Vaziri-Sani, F. et al. ZnT8 autoantibody titers in
type 1 diabetes patients decline rapidly after
clinical onset. Autoimmunity 43, 598–606
Erlich, H. et al. HLA DR-DQ haplotypes and
genotypes and type 1 diabetes risk: analysis of
the type 1 diabetes genetics consortium
families. Diabetes 57, 1084–1092 (2008).
Barrett, J. C. et al. Genome-wide association
study and meta-analysis find that over 40 loci
affect risk of type 1 diabetes. Nat. Genet. 41,
703–707 (2009).
Concannon, P. et al. Genome-wide scan for
linkage to type 1 diabetes in 2,496 multiplex
families from the Type 1 Diabetes Genetics
Consortium. Diabetes 58, 1018–1022 (2009).
Holmberg, H., Wahlberg, J., Vaarala, O. &
Ludvigsson, J. Short duration of breast-feeding
as a risk-factor for beta-cell autoantibodies in
5‑year‑old children from the general population.
Br. J. Nutr. 97, 111–116 (2007).
Norris, J. M. et al. Timing of initial cereal
exposure in infancy and risk of islet
autoimmunity. JAMA 290, 1713–1720 (2003).
Virtanen, S. M. et al. Early introduction of root
vegetables in infancy associated with advanced
ss-cell autoimmunity in young children with
human leukocyte antigen-conferred susceptibility
to type 1 diabetes. Diabet. Med. 28, 965–971
Ziegler, A. G., Schmid, S., Huber, D., Hummel, M.
& Bonifacio, E. Early infant feeding and risk of
developing type 1 diabetes-associated
autoantibodies. JAMA 290, 1721–1728 (2003).
Yeung, W. C., Rawlinson, W. D. & Craig, M. E.
Enterovirus infection and type 1 diabetes
mellitus: systematic review and meta-analysis of
observational molecular studies. BMJ 342, d35
210 | APRIL 2012 | VOLUME 8
59. Zipitis, C. S. & Akobeng, A. K. Vitamin D
supplementation in early childhood and risk
of type 1 diabetes: a systematic review and
meta-analysis. Arch. Dis. Child. 93, 512–517
60. Harder, T. et al. Birth weight, early weight gain,
and subsequent risk of type 1 diabetes:
systematic review and meta-analysis. Am. J.
Epidemiol. 169, 1428–1436 (2009).
61. Vaarala, O., Atkinson, M. A. & Neu, J. The
“perfect storm” for type 1 diabetes: the complex
interplay between intestinal microbiota, gut
permeability, and mucosal immunity. Diabetes
57, 2555–2562 (2008).
62. Dahlquist, G. G., Nyström, L. & Patterson, C. C.
Incidence of type 1 diabetes in Sweden among
individuals aged 0–34 years, 1983–2007:
an analysis of time trends. Diabetes Care 34,
1754–1759 (2011).
63. Patterson, C. C., Dahlquist, G. G., Gyürüs, E.,
Green, A. & Soltész, G. Incidence trends for
childhood type 1 diabetes in Europe during
1989–2003 and predicted new cases 2005–20:
a multicentre prospective registration study.
Lancet 373, 2027–2033 (2009).
64. Rubio-Cabezas, O., Klupa, T. & Malecki, M. T.
Permanent neonatal diabetes mellitus--the
importance of diabetes differential diagnosis in
neonates and infants. Eur. J. Clin. Invest. 41,
323–333 (2011).
65. Berhan, Y., Waernbaum, I., Lind, T., Möllsten, A.
& Dahlquist, G. Thirty years of prospective
nationwide incidence of childhood type 1
diabetes: the accelerating increase by time
tends to level off in Sweden. Diabetes 60,
577–581 (2011).
66. Altamirano-Bustamante, N. et al. Economic
family burden of metabolic control in children
and adolescents with type 1 diabetes mellitus.
J. Pediatr. Endocrinol. Metab. 21, 1163–1168
67. Ying, A. K. et al. Predictors of direct costs of
diabetes care in pediatric patients with type 1
diabetes. Pediatr. Diabetes 12, 177–182 (2011).
68. Icks, A. et al. Direct costs of pediatric diabetes
care in Germany and their predictors. Exp. Clin.
Endocrinol. Diabetes 112, 302–309 (2004).
69. Wiréhn, A. B., Andersson, A., Ostgren, C. J. &
Carstensen, J. Age-specific direct healthcare
costs attributable to diabetes in a Swedish
population: a register-based analysis. Diabet.
Med. 25, 732–737 (2008).
70. Bächle, C. et al. Direct diabetes-related costs in
young patients with early onset and long-lasting
type 1 diabetes [a864]. Diabetologia 54
(Suppl. 1), S353 (2011).
71. Greeley, S. A. et al. The cost-effectiveness of
personalized genetic medicine: the case of
genetic testing in neonatal diabetes. Diabetes
Care 34, 622–627 (2011).
72. Hekkala, A., Reunanen, A., Koski, M., Knip, M. &
Veijola, R. Age-related differences in the
frequency of ketoacidosis at diagnosis of type 1
diabetes in children and adolescents. Diabetes
Care 33, 1500–1502 (2010).
73. Dahlquist, G. & Källén, B. Mortality in childhoodonset type 1 diabetes: a population-based study.
Diabetes Care 28, 2384–2387 (2005).
74. Temple, I. K. & Shield, J. P. 6q24 transient
neonatal diabetes. Rev. Endocr. Metab. Disord.
11, 199–204 (2010).
75. American Diabetes Association. Diagnosis and
classification of diabetes mellitus. Diabetes Care
33 (Suppl. 1), S62–S69 (2010).
76. Edghill, E. L., Flanagan, S. E. & Ellard, S.
Permanent neonatal diabetes due to activating
mutations in ABCC8 and KCNJ11. Rev. Endocr.
Metab. Disord. 11, 193–198 (2010).
77. Bonnefond, A. et al. Molecular diagnosis of
neonatal diabetes mellitus using next-generation
sequencing of the whole exome. Plos ONE 5,
e13630 (2010).
78. Wambach, J. A., Marshall, B. A., Koster, J. C.,
White, N. H. & Nichols, C. G. Successful
sulfonylurea treatment of an insulin-naive
neonate with diabetes mellitus due to a KCNJ11
mutation. Pediatr. Diabetes 11, 286–288 (2010).
79. Danne, T. et al. A comparison of postprandial and
preprandial administration of insulin aspart in
children and adolescents with type 1 diabetes.
Diabetes Care 26, 2359–2364 (2003).
80. Danne, T. et al. Parental preference of prandial
insulin aspart compared with preprandial human
insulin in a basal-bolus scheme with NPH insulin
in a 12-wk crossover study of preschool children
with type 1 diabetes. Pediatr. Diabetes 8,
278–285 (2007).
81. Bachran, R. et al. Basal rates and circadian
profiles in continuous subcutaneous insulin
infusion (CSII) differ for preschool children,
prepubertal children, adolescents and young
adults. Pediatr. Diabetes
82. Szypowska, A., Lipka, M., Błazik, M., Groele, L.
& Pańkowska, E. Insulin requirement in
preschoolers treated with insulin pumps at the
onset of type 1 diabetes mellitus. Acta Paediatr.
98, 527–530 (2009).
83. Alemzadeh, R., Berhe, T. & Wyatt, D. T. Flexible
insulin therapy with glargine insulin improved
glycemic control and reduced severe
hypoglycemia among preschool-aged children
with type 1 diabetes mellitus. Pediatrics 115,
1320–1324 (2005).
84. Tubiana-Rufi, N. Insulin pump therapy in neonatal
diabetes. Endocr. Dev. 12, 67–74 (2007).
85. Kapellen, T. M. et al. Changes in the use of
analogue insulins in 37,206 children and
adolescents with type 1 diabetes in 275 German
and Austrian centers during the last twelve
years. Exp. Clin. Endocrinol. Diabetes 117,
329–335 (2009).
86. Fox, L. A., Buckloh, L. M., Smith, S. D.,
Wysocki, T. & Mauras, N. A randomized
controlled trial of insulin pump therapy in young
children with type 1 diabetes. Diabetes Care 28,
1277–1281 (2005).
87. Mack-Fogg, J. E., Orlowski, C. C. & Jospe, N.
Continuous subcutaneous insulin infusion in
toddlers and children with type 1 diabetes
mellitus is safe and effective. Pediatr. Diabetes
6, 17–21 (2005).
88.Pańkowska, E., Błazik, M., Dziechciarz, P.,
Szypowska, A. & Szajewska, H. Continuous
subcutaneous insulin infusion vs. multiple daily
injections in children with type 1 diabetes:
a systematic review and meta-analysis of
randomized control trials. Pediatr. Diabetes 10,
52–58 (2009).
89. Berghaeuser, M. A. et al. Continuous
subcutaneous insulin infusion in toddlers
starting at diagnosis of type 1 diabetes mellitus.
A multicenter analysis of 104 patients from 63
centres in Germany and Austria. Pediatr.
Diabetes 9, 590–595 (2008).
90. Wilson, D. M. et al. A two-center randomized
controlled feasibility trial of insulin pump therapy
in young children with diabetes. Diabetes Care
28, 15–19 (2005).
91. Sulmont, V. et al. Metabolic control in children
with diabetes mellitus who are younger than
6 years at diagnosis: continuous subcutaneous
insulin infusion as a first line treatment?
J. Pediatr. 157, 103–107 (2010).
92. Müller, G. The molecular mechanism of
the insulin-mimetic/sensitizing activity of the
© 2012 Macmillan Publishers Limited. All rights reserved
antidiabetic sulfonylurea drug Amaryl. Mol. Med.
6, 907–933 (2000).
93. Hattersley, A. & Pearson, E. Transferring patients
with diabetes due to Kir6.2 mutation from
insulin to suphonylureas. Diabetes Genes
content/transferring-patients-diabetes-duekir62-mutation-insulin-sulphonylureas (2011).
94. Klupa, T. et al. Efficacy and safety of sulfonylurea
use in permanent neonatal diabetes due to
KCNJ11 gene mutations: 34-month median
follow-up. Diabetes Technol. Ther. 12, 387–391
95. Ziegler, R. et al. Frequency of SMBG correlates
with HbA1c and acute complications in children
and adolescents with type 1 diabetes. Pediatr.
Diabetes 12, 11–17 (2011).
96. Kordonouri, O. et al. Sensor-augmented pump
therapy from the diagnosis of childhood type 1
diabetes: results of the Paediatric Onset Study
(ONSET) after 12 months of treatment.
Diabetologia 53, 2487–2495 (2010).
97. Deiss, D., Kordonouri, O., Meyer, K. & Danne, T.
Long hypoglycaemic periods detected by
subcutaneous continuous glucose monitoring in
toddlers and pre-school children with diabetes
mellitus. Diabet. Med. 18, 337–338 (2001).
98. Slover, R. H. et al. Effectiveness of sensoraugmented pump therapy in children and
adolescents with type 1 diabetes in the STAR 3
study. Pediatr. Diabetes
99. Tamborlane, W. V. et al. Continuous glucose
monitoring and intensive treatment of type 1
diabetes. N. Engl. J. Med. 359, 1464–1476
100.Hovorka, R. et al. Overnight closed loop insulin
delivery (artificial pancreas) in adults with type 1
diabetes: crossover randomised controlled
studies. BMJ 342, d1855 (2011).
101.Elleri, D. et al. Automated overnight closed-loop
glucose control in young children with type 1
diabetes. Diabetes Technol. Ther. 13, 419–424
102.Keymeulen, B. et al. Four-year metabolic
outcome of a randomised controlled CD3antibody trial in recent-onset type 1 diabetic
patients depends on their age and baseline
residual beta cell mass. Diabetologia 53, 614–
623 (2010).
103.Ludvigsson, J. et al. GAD treatment and insulin
secretion in recent-onset type 1 diabetes.
N. Engl. J. Med. 359, 1909–1920 (2008).
104.Mastrandrea, L. et al. Etanercept treatment in
children with new-onset type 1 diabetes: pilot
randomized, placebo-controlled, double-blind
study. Diabetes Care 32, 1244–1249 (2009).
105.Wherrett, D. K. et al. Antigen-based therapy with
glutamic acid decarboxylase (GAD) vaccine in
patients with recent-onset type 1 diabetes:
a randomised double-blind trial. Lancet 378,
319–327 (2011).
106.Näntö-Salonen, K. et al. Nasal insulin to
prevent type 1 diabetes in children with HLA
genotypes and autoantibodies conferring
increased risk of disease: a double-blind,
randomised controlled trial. Lancet 372,
1746–1755 (2008).
107.Knip, M. et al. Dietary intervention in infancy and
later signs of beta-cell autoimmunity. N. Engl. J.
Med. 363, 1900–1908 (2010).
108.Couri, C. E. et al. C-peptide levels and insulin
independence following autologous
nonmyeloablative hematopoietic stem cell
transplantation in newly diagnosed type 1
diabetes mellitus. JAMA 301, 1573–1579 (2009).
109.Smart, C., Aslander-van Vliet, E. & Waldron, S.
Nutritional management in children and
adolescents with diabetes. Pediatr. Diabetes 10
(Suppl. 12), 100–117 (2009).
110.Sauer, C. W. & Kim, J. H. Human milk
macronutrient analysis using point‑of‑care nearinfrared spectrophotometry. J. Perinatol. 31,
339–343 (2011).
111.Detlofson, I., Kroon, M. & Aman, J. Oral bedtime
cornstarch supplementation reduces the risk for
nocturnal hypoglycaemia in young children with
type 1 diabetes. Acta Paediatr. 88, 595–597
112.Lange, K., Sassmann, H., von Schütz, W.,
Kordonouri, O. & Danne, T. Prerequisites for ageappropriate education in type 1 diabetes:
a model programme for paediatric diabetes
education in Germany. Pediatr. Diabetes
8 (Suppl. 6), 63–71 (2007).
113.Swift, P. G. Diabetes education in children and
adolescents. Pediatr. Diabetes 10 (Suppl. 12),
51–57 (2009).
114.McCrimmon, R. J., Gold, A. E., Deary, I. J.,
Kelnar, C. J. & Frier, B. M. Symptoms of
hypoglycemia in children with IDDM. Diabetes
Care 18, 858–861 (1995).
115.Hershey, T. et al. Frequency and timing of severe
hypoglycemia affects spatial memory in children
with type 1 diabetes. Diabetes Care 28,
2372–2377 (2005).
116.Wagner, V. M., Grabert, M. & Holl, R. W. Severe
hypoglycaemia, metabolic control and diabetes
management in children with type 1 diabetes in
the decade after the Diabetes Control and
Complications Trial—a large-scale multicentre
study. Eur. J. Pediatr. 164, 73–79 (2005).
117.Schoenle, E. J., Schoenle, D., Molinari, L. &
Largo, R. H. Impaired intellectual development in
children with Type I diabetes: association with
HbA(1c), age at diagnosis and sex. Diabetologia
45, 108–114 (2002).
118.Ferguson, S. C. et al. Influence of an early-onset
age of type 1 diabetes on cerebral structure and
cognitive function. Diabetes Care 28,
1431–1437 (2005).
119.Northam, E. A. et al. Neuropsychological profiles
of children with type 1 diabetes 6 years after
disease onset. Diabetes Care 24, 1541–1546
120.Brink, S. et al. Sick day management in children
and adolescents with diabetes. Pediatr. Diabetes
10 (Suppl. 12), 146–153 (2009).
121.Laffel, L. M. et al. Sick day management using
blood 3-hydroxybutyrate (3-OHB) compared with
urine ketone monitoring reduces hospital visits
in young people with T1DM: a randomized
clinical trial. Diabet. Med. 23, 278–284 (2006).
122.Hatton, D. L., Canam, C., Thorne, S. &
Hughes, A. M. Parents’ perceptions of caring for
an infant or toddler with diabetes. J. Adv. Nurs.
22, 569–577 (1995).
123.Karges, B. et al. Low discomfort and pain
associated with intensified insulin therapy in
children and adolescents. Diabetes Res. Clin.
Pract. 80, 96–101 (2008).
124.Haugstvedt, A., Wentzel-Larsen, T., Rokne, B. &
Graue, M. Perceived family burden and
emotional distress: similarities and differences
between mothers and fathers of children with
type 1 diabetes in a population-based study.
Pediatr. Diabetes 12, 107–114 (2011).
125.Patton, S. R., Dolan, L. M., Smith, L. B.,
Thomas, I. H. & Powers, S. W. Pediatric
parenting stress and its relation to depressive
symptoms and fear of hypoglycemia in parents
of young children with type 1 diabetes mellitus.
J. Clin. Psychol. Med. Settings
126.Forsander, G. A., Sundelin, J. & Persson, B.
Influence of the initial management regimen
NATURE REVIEWS | ENDOCRINOLOGY and family social situation on glycemic control
and medical care in children with type I diabetes
mellitus. Acta Paediatr. 89, 1462–1468 (2000).
127.Sullivan-Bolyai, S. et al. Helping other mothers
effectively work at raising young children with
type 1 diabetes. Diabetes Educ. 30, 476–484
128.Chisholm, V. et al. Predictors of treatment
adherence in young children with type 1
diabetes. J. Adv. Nurs. 57, 482–493 (2007).
129.Winkley, K., Ismail, K., Landau, S. & Eisler, I.
Psychological interventions to improve glycaemic
control in patients with type 1 diabetes:
systematic review and meta-analysis of
randomised controlled trials. BMJ 333, 65
130.Pihoker, C., Forsander, G., Wolfsdorf, J. &
Klingensmith, G. J. The delivery of ambulatory
diabetes care to children and adolescents with
diabetes. Pediatr. Diabetes 10 (Suppl. 12),
58–70 (2009).
131.Fröhlich-Reiterer, E. E. et al. Anthropometry,
metabolic control, and follow-up in children
and adolescents with type 1 diabetes mellitus
and biopsy-proven celiac disease. J. Pediatr.
158, 589–593 e2 (2011).
132.Warncke, K. et al. Polyendocrinopathy in children,
adolescents, and young adults with type 1
diabetes: a multicenter analysis of 28,671
patients from the German/Austrian DPV-Wiss
database. Diabetes Care 33, 2010–2012
133.Jansà, M. et al. Telecare in a structured
therapeutic education programme addressed
to patients with type 1 diabetes and poor
metabolic control. Diabetes Res. Clin. Pract. 74,
26–32 (2006).
134.Gerstl, E. M. et al. Metabolic control as reflected
by HbA1c in children, adolescents and young
adults with type-1 diabetes mellitus: combined
longitudinal analysis including 27,035 patients
from 207 centers in Germany and Austria during
the last decade. Eur. J. Pediatr. 167, 447–453
135.Margeirsdottir, H. D., Larsen, J. R.,
Kummernes, S. J., Brunborg, C. & DahlJorgensen, K. The establishment of a new
national network leads to quality improvement in
childhood diabetes: implementation of the ISPAD
Guidelines. Pediatr. Diabetes 11, 88–95 (2010).
136.Svensson, J., Johannesen, J., Mortensen, H. B. &
Nordly, S. Improved metabolic outcome in a
Danish diabetic paediatric population aged
0–18 yr: results from a nationwide continuous
Registration. Pediatr. Diabetes 10, 461–467
(2009). Beaufort, C. E. et al. Continuing stability of
center differences in pediatric diabetes care:
do advances in diabetes treatment improve
outcome? The Hvidoere Study Group on
Childhood Diabetes. Diabetes Care 30,
2245–2250 (2007).
138.Karges, B. et al. Long-acting insulin analogs and
the risk of diabetic ketoacidosis in children and
adolescents with type 1 diabetes: a prospective
study of 10,682 patients from 271 institutions.
Diabetes Care 33, 1031–1033 (2010).
The authors’ work was supported by the BMBF
Kompetenznetz Diabetes Mellitus (Competence
Network for Diabetes Mellitus) funded by the Federal
Ministry of Education and Research (FKZ 01GI0859).
Author contributions
B. Karges, A. Icks, T. Kapellen and R. W. Holl
researched the data for the article. All authors
contributed equally to all other aspects of the article.
VOLUME 8 | APRIL 2012 | 211
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