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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

Introduction
The diagnosis of diabetes mellitus in an infant aged lifelong medical therapy. TNDM is more frequent than
≤2 years constitutes a diagnostic and therapeutic chal- PNDM (57% versus 43%).3 Multiple genetic abnormali-
lenge to patients, their families, caregivers and profes- ties have been identified as causes of NDM (Figure 1),
sional diabetes health-care teams. Although clinically some of which also affect the function of the exocrine
distinct from diabetes mellitus with an onset during pancreas and other organ systems (Table 2).
childhood, the complexity of this disorder in infancy
has frequently not received adequate emphasis. Infants Transient neonatal diabetes mellitus
aged ≤2 years represent approximately 4–5% of all pedi- TNDM is caused by overexpression of an imprinted gene Division of
atric diabetes patients (Table 1).1,2 Identification of the region in chromosome 6q24 in about 70% of cases.4,5 Endocrinology and
Diabetes, RWTH
underlying defect facilitates adequate medical treat- Activating mutations of one of the two subunits of the Aachen University,
ment and family counseling. In this Review, we will pancreatic β‑cell ATP-sensitive inward rectifier potassium Pauwelsstraße 30,
dis­cuss the clinical management of diabetes mellitus in (KATP) channel, Kir6.2 (encoded by KCNJ11) and sulfonyl- D‑52074 Aachen,
Germany (B. Karges).
infants, including diagnostic and therapeutic approaches, urea receptor 1 (SUR1; encoded by ABCC8),6,7 are found Department of General
ongoing diabetes care and quality control. in approximately 25% of patients, whereas pre-proinsulin Pediatrics and
Neonatology, University
(INS) gene mutations are even rarer.3,8,9 Further causes Children’s Hospital
Forms of diabetes mellitus in infancy of TNDM are mutations in the zinc finger transcription (T. Meissner),
Several specific etiologies of diabetes mellitus have to factor ZFP57, which result in hypo­methylation of multiple Department of Public
Health and German
be considered in infants, including monogenic perma- imprinted loci.10 Diabetes Center
nent or transient forms of neonatal diabetes mellitus In addition to diabetes mellitus, individuals with (A. Icks), Heinrich Heine
University of
(NDM), developmental disorders of the pancreas and TNDM can exhibit neurological symptoms and congeni- Düsseldorf,
auto­immune diabetes mellitus, that is, type 1 diabetes tal heart disease (Table 2). TNDM is often accompanied Moorenstraße 5,
D‑40225 Düsseldorf,
mellitus (T1DM). by severe intrauterine growth retardation that requires
Germany. Department
hospitalization, which leads to an early diagnosis of dia- of Pediatrics, University
Neonatal diabetes mellitus betes mellitus. Patients with 6q24 anomalies have lower of Leipzig, Liebigstraße
20a, D‑04103 Leipzig,
Two types of NDM exist, which exhibit a different clini- birth weight and are, therefore, usually diagnosed at an Germany (T. Kapellen).
cal course. Patients with transient NDM (TNDM) show earlier age than individuals with KCNJ11 or ABCC8 muta- Institute of
Epidemiology and
spontaneous remission at least before 18 months of age, tions.7 After clinical remission, diabetes mellitus recurs in Medical Biometry,
whereas those with permanent NDM (PNDM) require adolescence or early adulthood in approximately 50% of University of Ulm,
patients with TNDM.4,9,11 Albert-Einstein-Allee 41,
D‑89081 Ulm, Germany
Competing interests
(R. W. Holl).
T. Kapellen declares an association with the following
Permanent neonatal diabetes mellitus
companies: Medtronic, Roche. See the article online for Correspondence to:
details of the relationships. The other authors declare no PNDM is most often caused by activating mutations of B. Karges
competing interests. KCNJ11 or ABCC8,6,12–15 which lead to channel overactivity bkarges@ukaachen.de

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Key points improvement.3,19,21 A milder variant without epilepsy and

less severe developmental delay, intermediate DEND
■■ Diabetes mellitus in infants and children differs in etiology, clinical presentation
and therapeutic options; heterogeneous etiologies of diabetes mellitus in infancy
(iDEND), is more frequent than DEND.22 Other mono-
include genetic abnormalities, developmental defects and autoimmune disease genic causes of PNDM include INS mutations8,12,23–25 and
■■ Monogenic forms of neonatal diabetes mellitus almost always occur in the first
homozygous GCK mutations.12,26,27
6 months of life and very rarely after 12 months; onset of diabetes mellitus in Wollcott–Rallison syndrome is a common cause of
infants aged >6 months is mostly due to type 1 diabetes mellitus (T1DM) PNDM in consanguineous families and is associated with
■■ Infants with T1DM exhibit rapid disease onset, poor residual β‑cell function skeletal abnormalities and liver dysfunction.28 Further
and a low rate of transient recovery clinical findings include cardiac and renal abnormalities,
■■ Insulin is preferentially provided by continuous subcutaneous infusion mental retardation, epilepsy and neutropenia, with poor
prognosis and often early death.28,29 The syndrome results
■■ Treatment with sulfonylurea is possible in most patients with mutations in the
genes that encode the ATP-sensitive inward rectifier potassium (KATP) channel from mutations in EIF2AK3, which encodes eukaryotic
translation initiation factor 2α kinase 3. Mutations in the
■■ Special needs of infants with diabetes mellitus include comprehensive
education of caregivers and provision of ongoing diabetes care
gene FOXP3, which encodes a fork-winged helix family
of transcription factors, cause the IPEX (immune dys-
regulation, polyendocrinopathy enteropathy, X‑linked)
Table 1 | Comparison of infant-onset and childhood-onset diabetes mellitus* syndrome.30 This disorder is often fatal, but a milder
pheno­t ype with PNDM and hypothyroidism, auto­
Characteristics Infant-onset Childhood-onset diabetes
diabetes mellitus mellitus immune enteropathy or nephritic syndrome has been
reported and accounts for about 4% of male cases of
Age (years) ≤2 years >2–11 years >11–18 years
PNDM.31 Intractable diarrhea and NDM are also found
n 1,047 12,450 8,042
in indivi­duals with biallelic NEUROD1 or NEUROG3
Male sex (%) 55.40 50.07 59.12 mutations, which cause a lack of enteroendocrine
Duration of symptoms before 1.45 2.06 2.72 cells.32–34 Other causes of PNDM associated with complex
diagnosis (weeks) clinical phenotypes include mutations that affect the zinc
Diabetic ketoacidosis at 39.82 18.40 19.83 finger protein GLIS3 (encoded by GLIS3),35,36 transcrip-
diagnosis, pH <7.3 (%) tion factor PAX6 (encoded by PAX6),37,38 a thiamine
Severe diabetic ketoacidosis at 15.09 5.09 4.44 transporter (encoded by SLC19A2)39,40 and the glucose
diagnosis, pH <7.1 (%) transporter GLUT-2 (encoded by SLC2A2)41–43 (Table 2).
Blood glucose at diagnosis 28.23 24.54 23.75
(mmol/l) Developmental disorders of the pancreas
HbA1c at diagnosis (%) 9.82 10.79 11.74 PNDM due to pancreatic hypoplasia can be caused by
Duration of diabetes 0.50 0.73 0.65 different genetic defects of transcription factors involved
remission (years)‡ in pancreas development. In this case, different clini-
β-cell autoantibody positive (%)§ 87.82 86.74 87.53 cal pheno­types have been described in relation to the
Celiac disease antibody 18.00 16.76 13.80
mutated gene and the functional consequences of the
positive (%)|| mutation. The effects can be limited to the pancreas, but
Celiac disease (%)¶ 5.94 3.67 2.05
can also affect other organs (Table 2). The pancreatic and
duo­denal homeobox 1 transcription factor PDX1 (previ-
*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 ously known as IPF1) is expressed in all pan­creatic epi-
positive autoantibody against ICA, GAD2, insulin or ICA512. ||At least one positive autoantibody against
endomysium or tissue transglutaminase. ¶Clinical diagnosis of celiac disease.
thelial precursor cells. As a result, homozygous PDX1
mutations result in pancreatic agenesis associated with
exocrine deficiency.44,45 PTF1A is another transcrip-
with impaired insulin secretion (Figure 2).16,17 Activated tion factor involved in early pancreas develop­ment and
KATP channels cause diabetes mellitus, whereas loss-of- cerebellar neurogenesis. Hypoplasia of the pancreas
function mutations lead to congenital hyper­insulinism.18 and cerebellum result from PTF1A mutations, which
An overlap exists between activating KCNJ11 and ABCC8 cause a reduction in transactivation of PDX1 protein
mutations that cause TNDM and those that result in expres­sion.46 Other transcription factors such as RFX6
PNDM.3 It has been hypothesized that ‘more active’ are involved in the more distal process of endocrine
PNDM mutations completely suppress insulin release and speci­f ication. Hypoplasia of the pancreas and gall­
induce β‑cell apoptosis, whereas ‘less active’ TNDM muta- bladder, intestinal atresia and intract­able diarrhea are
tions allow some insulin release and postnatal increase in features of RFX6 mutations.47 However, in several cases
β‑cell mass sufficient for diabetes remission.3 The most of PNDM, extended molecular genetic analyses could
important clinical feature of indivi­duals with activating not identify the underlying cause of pancreas hypoplasia
KATP channel mutations is their responsiveness to oral or agenesis.48,49
sulfonylurea therapy, which allows for discontinuation
of insulin therapy.6,19,20 DEND (develop­mental delay, epi- Type 1 diabetes mellitus
lepsy, neonatal diabetes) syndrome occurs in some cases, T1DM is a chronic T‑cell-mediated disease that leads to
as these genes are also expressed in the brain. Patients with destruction of the β cells within the pancreas. Infiltration
DEND respond to sulfonylurea therapy with neuro­logical of pancreatic islets by lymphocytes causes a variable rate

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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 suscep-
tibility 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 genome-
wide 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 clini-
cal onset of T1DM, a partial transient recovery (honey-
moon 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 environ-
mental factors predisposing to β‑cell auto­immunity in the
context of a leaky intestinal mucosal barrier and altered
intestinal immune responsiveness.2,61
Epidemiology
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 develop-
ment of β‑cell auto­immunity, effective before birth or in
early postnatal life.
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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 hyper-
glycemia 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 morbid-
ity 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
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Table 2 | Genetic causes of neonatal diabetes mellitus

Gene Inheritance Diabetes phenotype Associated clinical features
Chromosome Imprinting disorder, paternal Diagnosed week 1–4 IUGR, macroglossia, umbilical hernia, cardiac
6q24 uniparental disomy, duplication Diabetic ketoacidosis rare abnormalities, dysmorphy, bone dysplasia and
or methylation defect TNDM delayed maturation
ZFP57 Autosomal recessive; Diagnosed week 1–4 Similar to 6q24, developmental delay,
imprinting disorder, mosaicism Diabetic ketoacidosis rare hypotonia, hypoplasia of corpus callosum,
of hypomethylation TNDM impaired vision and hearing
KCNJ11 Autosomal dominant Diagnosed month 1–2 DEND or iDEND syndrome
TNDM, PNDM
ABCC8 Autosomal dominant, Diagnosed week 4–16 DEND or iDEND syndrome
autosomal recessive TNDM, PNDM IUGR rare
INS Autosomal dominant, TNDM, PNDM IUGR
autosomal recessive Onset month 6–12 rare
GCK Autosomal recessive PNDM IUGR
EIF2AK3 Autosomal recessive PNDM Wollcott–Rallison syndrome
FOXP3 X-linked recessive, PNDM IPEX syndrome, enteropathy, eczema, thyroiditis,
male limited infections
NEUROD1 Autosomal recessive PNDM Intractable diarrhea
NEUROG3 Autosomal recessive PNDM IUGR, diarrhea
GLIS3 Autosomal recessive PNDM Hypothyroidism, cholestasis, glaucoma,
polycystic kidneys, recurrent infections, deafness
PAX6 Autosomal recessive PNDM Eye and brain anomalies
SLC19A1 Autosomal recessive PNDM or late-onset Megaloblastic anemia, deafness, heart defects,
visual impairment
SLC2A2 Autosomal recessive Neonatal onset rare Fanconi–Bickel syndrome, renal dysfunction,
hypergalactosemia
PDX1 Autosomal recessive PNDM Exocrine pancreas deficiency
PTF1A Autosomal recessive PNDM Hypoplasia of cerebellum
RFX6 Autosomal recessive PNDM 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 pre-
dominantly caused by insulin deficiency in infants.
Criteria for the diagnosis of diabetes mellitus in child-
hood 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 diagnos-
tic 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 gradu-
ally 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
are proposed to elucidate the underlying defect (Box 1).
Careful investigation of associated clinical findings
and target-oriented genetic analysis are helpful to clas-
sify 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, fol-
lowed 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

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susceptibility and a strong humoral auto­immunity against a Glucose

islet cells and antigens, with poorly preserved residual GLUT2
β‑cell function and a lower rate of partial remission,
compared with patients aged >2 years.1,2 These observa- β cell

tions might explain why metabolic control during the Glucose

first 6 months after diagnosis is poorer in infants than in Glucokinase
older children.1 Glucose-6-phosphate Glycolysis

Nucleus PDX1,
Treatment and management with ER PTF1A,
Citric
Insulin treatment is acutely required in most infants with GLIS3, PAX6,
acid
RFX6,
newly diagnosed diabetes mellitus to treat or prevent NEUROD1, cycle
NEUROG3
ketoacidosis and dehydration and to allow weight gain.
Rarely, spontaneous normalization of blood glucose in ATP/ADP
Insulin
asymptomatic ketone-negative neonates with TNDM can processing Insulin-containing
granula Closure
occur that justifies withholding insulin therapy. In familial K+
Ca2+
PNDM due to activating KATP channel mutations, sulfonyl­
KATP
urea therapy has been successfully initiated in an insulin- VDCC channel SUR1
naive neonate.78 The majority of children diagnosed with Kir6.2
diabetes mellitus during infancy will have T1DM, requir- Insulin
secretion Depolarization K+
ing permanent insulin substitution, which presents a par- Ca2+
ticular challenge in these very young children with respect b Glucose
to precise and flexible dosage.
GLUT2

Insulin injection and subcutaneous infusion β cell

Insulin replacement therapy in infants is provided by
Glucose
multiple daily insulin injections (MDI) or continuous Glucokinase
subcutaneous insulin infusion (CSII). To accommodate Glucose-6-phosphate Glycolysis
meal-dependent insulin requirements, regular insulin
and the rapid-acting insulin analogues aspart, glulisine Nucleus PDX1,
with ER PTF1A,
or lispro are available. Mealtime insulin dose is calcu- GLIS3, PAX6, Citric
RFX6, acid
lated based on carbohydrate intake. Rapid-acting insulin NEUROD1, cycle
analogues for meals are more convenient for parents of NEUROG3
young children, as they allow prandial injections of short- ATP/ADP
acting insulin instead of preprandial regular insulin in Proinsulin Insulin-containing
the context of unpredictable food intake.79,80 Basal insulin processing, granula No
ER toxicity
K+ closure
is substituted in infants by intermediate-acting NPH Ca2+
(neutral protamine Hagedorn) insulin, or by the basal KATP
VDCC channel SUR1
insulin analogues detemir or glargine—although these
Kir6.2
two agents are not formally approved for infants—and Decreased
Hyperglycemia
mainly by CSII using rapid-acting insulin analogues insulin Hyperpolarization K+
secretion Ca2+
(Figure 3). In infants, basal insulin accounts for 10–30%
of total daily insulin with CSII81,82 and for 30–50% with Figure 2 | Pathogenesis of decreased insulin secretion in neonatal diabetes
MDI.83 The very low insulin demand is difficult to obtain mellitus. a | Mechanisms of normal insulin secretion. Glucose is transported into
by (diluted) NPH or regular insulin injections, bearing the β cell by GLUT-2. Glucokinase phosphorylates glucose to glucose‑6-phosphate
in mind the risk of hypoglycemia.48 At low doses, NPH as the rate-limiting enzyme in glucose metabolism. Glycolysis increases the ATP/
insulin has a shorter action profile than at high doses, ADP ratio, sensed by the KATP channels. Increase of the ATP/ADP ratio leads to
requiring more frequent injections. KATP channel closure, followed by membrane depolarization resulting in opening of
In neonates with total parenteral nutrition or con- VDCC. Influx of calcium triggers exocytosis of insulin. Within the nucleus, different
transcription factors regulating insulin synthesis are shown. b | Localization of
tinuous enteral feeding, only basal insulin substitution
genetic defects within the β cell and their effect on impaired insulin release.
with CSII is sufficient.84 When breast or bottle feeding Defective GLUT-2 results in decreased glucose influx into the β cell. Glucokinase
is started, basal insulin typically accounts for about 30% deficiency leads to impaired glucose phosphorylation, which reduces the
and mealtime insulin for 70% of daily insulin doses. The generation of ATP. Activating mutations of the genes encoding the two subunits
total daily insulin requirement can vary from 0.29 U/kg SUR1 and Kir6.2 of the pancreatic KATP channel result in channel opening.
to 1.4 U/kg per day.84 In the case of very low insulin Increased potassium outflow leads to hyperpolarization and stabilization of the
requirements (≤0.02 U/h or bolus ≤0.2 U), CSII of diluted membrane potential, thus blocking insulin exocytosis. Mutations in the INS gene
insulin (5 or 10 U/ml) is the treatment of choice, as this cause abnormal proinsulin processing within the endoplasmic reticulum, leading
to β‑cell toxicity. Mutations in genes encoding transcription factors PDX1, PTF1A,
approach reduces the risk of hypoglycemia. 48,84 CSII
RFX6, GLIS3, PAX6, NEUROD1 and NEUROG3 cause abnormal development of
administered by insulin pumps provides close to physio­ pancreas or endocrine cells. Abbreviations: ER, endoplasmic reticulum; GLUT-2,
logic insulin de­livery due to its variable low-dose basal solute carrier family 2 facilitated glucose transporter member 2; KATP, ATP-
insulin administra­tion and mealtime insulin bolus, which sensitive inward rectifier potassium; VDCC, voltage-dependent calcium channels.

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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 –
90 –
80 –
70 –
Proportion of patients (%)
60 –
50 –
40 –
30 –
20 –
10 –
0–
≤2 >2–11 >11–18
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 calcula-
tion 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 random-
ized controlled trials of insulin pump therapy in young
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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 chil-
dren 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
Sulfonylurea
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 pore-
forming Kir6.2 subunits or regulatory SUR1 subunits of
Insulin pump (CSII) the KATP channel induces hyperglycemia due to impaired
4+ injections insulin secretion (Figures 4a,b). Binding of sulfonylurea
3 injections to SUR1 induces ATP-independent channel closure in
1–2 injections response to high glucose, resulting in insulin secretion
(Figure 4c). Sulfonylurea compounds also alleviate extra-
pancreatic 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 chromo-
some 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 immedi-
ate 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 subcu-
taneous 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 retrospec-
tively. 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

Differences between sensor and blood glucose are caused
by the distinct compartments used for glucose measure-
ment, 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 inter-
ventions have been performed to preserve β‑cell func-
tion after disease manifestation or in individuals at
increased diabetes risk. T‑cell directed CD3 antibodies,
TNF-blocking etanercept or GAD vaccination demon-
strated 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 auto-
immunity 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 nutri-
tional 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
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© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
a Normal b Overactive c Sulfonyurea restores
function
Glucose Glucose Glucose
ATP ATP ATP
Sulfonylurea
SUR1 SUR1
Kir6.2 Kir6.2
K+ K+ K+
Normal Decreased Normalized
insulin secretion insulin secretion insulin secretion
Euglycemia
Figure 4 | Molecular mechanism of Hyperglycemia Euglycemia
sulfonylurea therapy in neonatal diabetes
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 cal-
culate 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 injec-
tions, food availability, glucose monitoring and other
treatment aspects. Limited verbal communication
skills, variable appetite with unforeseeable eating, fluc-
tuating 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, includ-
ing age-appropriate, demand-oriented and individual-
ized practical information and skills training for parents
of affected children have been effective in improving
metabolic control.112,113 Apart from teaching diabetes
REVIEWS
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 diffi-
cult 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 defi-
cits 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 dia-
betic 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 treat-
ment 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 around-
the-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 read-
ings 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 treat-
ment 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  www.nature.com/nrendo
© 2012 Macmillan Publishers Limited. All rights reserved
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 dia­betes-
specific 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 includ-
ing 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, dieti-
cian, 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, hos-
pitalization, 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.
 REVIEWS

Conclusions diabetes management. Future research will focus on facili-

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 remis-
sion. 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
tation 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
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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.

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Acknowledgments
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.