Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children

and adolescents

INTRODUCTION Type 1 diabetes mellitus (T1DM), one of the most common chronic
diseases in childhood, is caused by insulin deficiency following destruction of the insulin-
producing pancreatic beta cells. It most commonly presents in childhood, but one-fourth of
cases are diagnosed in adults. T1DM remains the most common form of diabetes in
childhood, accounting for approximately two-thirds of new diagnoses of diabetes in
patients 19 years of age in the United States, despite the increasing rate of type 2
diabetes [1-4].

The epidemiology, presentation, and diagnosis of T1DM in children and adolescents are
presented here. The pathogenesis of T1DM and the management and complications of
childhood T1DM are discussed separately.

The assessment and management of individuals presenting during infancy with

hyperglycemia also are discussed separately.

EPIDEMIOLOGY The incidence of childhood type 1 diabetes (T1DM) varies based

upon geography, age, gender, family history, and ethnicity.

Geographical variation The incidence of childhood T1DM varies worldwide [5,6]. In

Europe and China, the risk appears to rise as the geographical latitude (distance from the
equator) increases [7-9]. This North-South variation is not found in the United States, even
after adjusting for racial and ethnic variation [10]. When people relocate from a region of
low to high incidence, their risk of developing T1DM also increases, suggesting a
causative role for environmental factor(s). However, wide variations in incidence occur
between neighboring areas of similar latitude, suggesting the presence of other
contributing risk factors and demonstrating the complexity of the pathogenesis of T1DM.

The highest reported incidences of T1DM occur in Finland and Sardinia (37 to 65 per
100,000 children younger than the age of 15 years) [11]. Rates in these countries are
almost 400 times that of Venezuela and parts of China, which have the lowest incidence
(0.1 to 0.5 per 100,000 children) [5,8,12]. In the United States, the incidence of T1DM in
non-Hispanic white children and adolescents is 23.6 per 100,000 per year, and rates are
substantially lower in other racial or ethnic groups [13]. Some parts of Canada, such as
Newfoundland, have a higher incidence (36 per 100,000 per year) than the United States
[14]. The incidence in Quebec is lower, at 15 per 100,000 per year in children younger
than 15 years of age [15].

Age and gender The age of presentation of childhood onset T1DM has a bimodal
distribution, with one peak at four to six years of age and a second in early puberty (10 to
14 years of age) (figure 1) [16-18]. Overall, about 45 percent of children present before 10
years of age [19].

Although most autoimmune diseases are more common in females, there appears to be
no gender difference in the overall incidence of childhood T1DM [20]. However, in select
populations, T1DM occurs more frequently in males. As an example, older males of
European origin (13 years of age) are more likely to develop T1DM than females of
similar age and geographic location, with an approximate 3:2 male to female ratio [21,22].
The same 3:2 male to female ratio also was reported in children younger than six years of
age in an observational study from Massachusetts [23].

Time trends The incidence of childhood T1DM is rising worldwide, with reported
increases of 2 to 5 percent per year in Europe, the Middle East, and Australia [11,24-27]. In
the United States, the overall incidence of T1DM also appears to be rising in most age and
ethnic groups [20,28]. The reasons for the increasing incidence are unknown.

The rise appears to be primarily in younger children. A report using data from 17 European
countries revealed an annual rate increase of 5.4, 4.3, and 2.9 percent for the age groups
0 to 4, 5 to 9, and 10 to 14 years, respectively, over the 15-year period from 1989 to 2003;
the overall increase was 3.9 percent [26]. If these trends continue, the number of new
cases of T1DM in children younger than five years of age may double in some regions
between 2005 and 2020; furthermore, prevalent cases in children under 15 years will rise
by 70 percent [26]. Data reported from Philadelphia show that the incidence in children
less than five years of age increased by 70 percent between 1985 and 2004 [29]. The
trend towards younger age of onset is not seen in all populations. One study from Sweden
reported increases in age at diagnosis for children born in or after 2000, reversing the
previous trend [30]. Similarly, a study from New Zealand documented a trend toward older
age at diagnosis [31].

RISK FACTORS Both genetic and environmental factors contribute to the risk of
developing type 1 diabetes mellitus (T1DM).

Genetic susceptibility The lifetime risk of developing T1DM is significantly increased

in close relatives of a patient with T1DM [32,33]:

No family history 0.4 percent

Offspring of an affected mother 1 to 4 percent

Offspring of an affected father 3 to 8 percent

Offspring with both parents affected reported as high as 30 percent [34,35]

Non-twin sibling of affected patient 3 to 6 percent

Dizygotic twin 8 percent

Monozygotic twin 30 percent within 10 years of diagnosis of the first twin [36], and 65
percent concordance by age 60 years [37]

In the United States, there also are ethnic differences in incidence of T1DM. In a study that
sampled several large multiethnic populations in 2009, the highest prevalence was seen in
non-Hispanic white youth, followed by African American, Hispanic, Asian-Pacific Islanders,
and American Indians (2.55, 1.62, 1.29, 0.6, and 0.35 cases per 1,000 children 0 to 19
years old, respectively) (figure 2) [20]. Of note, Hispanic populations of Puerto Rican origin
have a markedly higher incidence rate than those of Mexican or South American descent
[38].

These observations of familial and ethnic risk factors are most likely the consequences of
gene polymorphisms in the major histocompatibility complex (MHC) or other genetic
susceptibility regions. Details regarding genetic susceptibility and the genes that increase
the risk of T1DM are presented elsewhere.

Other risk factors In genetically susceptible individuals, exposure to one or more

environmental agents appears to trigger an immune response that ultimately causes
destruction of the insulin-producing pancreatic beta cells. Identification of these factors
should lead to a better understanding of the pathogenesis of the disease and aid in
developing strategies to prevent T1DM.

Reports have linked each of the following factors to an increased risk of T1DM; however,
none of these associations have been verified and many have been contradicted by other
studies. They include:

Viral infections, particularly enterovirus infections

Immunizations

Diet, especially exposure to cow's milk at an early age

Higher socioeconomic status

Obesity [39-41]

Vitamin D deficiency

Perinatal factors such as maternal age, history of preeclampsia, and neonatal jaundice.
Low birth weight decreases the risk of developing T1DM
Seasonal variation has been suggested in some studies, with a higher reported incidence
of T1DM in colder as compared to warmer months, particularly in children [42-44].
However, another study did not find a seasonal variation in girls and reported a higher
incidence in the summer months for boys [45].

A more complete description of environmental factors and their potential link to T1DM is
discussed separately

CLINICAL PRESENTATION Childhood type 1 diabetes mellitus (T1DM) can present in

several different ways [46].

Classic new onset of chronic polydipsia, polyuria, and weight loss with hyperglycemia
and ketonemia (or ketonuria)

Diabetic ketoacidosis

Silent (asymptomatic) incidental discovery

Classic new onset Hyperglycemia without acidosis is the most common presentation
of childhood T1DM in most populations. Patients typically present with the following
symptoms:

Polyuria Polyuria occurs when the serum glucose concentration rises significantly
above 180 mg/dL (10 mmol/L), exceeding the renal threshold for glucose, which leads to
increased urinary glucose excretion. Glycosuria causes osmotic diuresis (ie, polyuria) and
hypovolemia. Polyuria may present as nocturia, bedwetting, or daytime incontinence in a
previously continent child. In children who are not toilet trained, parents may note an
increased frequency of wet diapers and/or diapers that are unusually heavy (wet).

Polydipsia Polydipsia is due to enhanced thirst because of increased serum osmolality

from hyperglycemia and hypovolemia. Despite the hypovolemia, patients may not have the
classic signs of dry mucus membranes or decreased skin turgor.

Weight loss Weight loss is a result of hypovolemia and increased catabolism. Insulin
deficiency in diabetic children impairs glucose utilization in skeletal muscle and increases
fat and muscle breakdown. Initially, appetite is increased, but over time, children are more
thirsty than hungry, and ketosis leads to nausea and anorexia, contributing to weight loss.

Patients with these symptoms usually present in the ambulatory setting appearing slightly
ill, with vague complaints, such as weight loss and lethargy [23]. In a study from Ireland,
the mean duration of symptoms before presentation was 10 days [47]. The classic
symptoms of polyuria and polydipsia are present in more than 90 percent of patients, but
these are not always the initial complaints and may become apparent only after obtaining
a careful history (eg, nocturia and bedwetting, increased frequency and/or unusually wet
diapers, and persistent thirst). Weight loss is a presenting symptom in about half of
children.

Other presentations include perineal candidiasis, which is a relatively common presenting

symptom in young children and in girls [23]. Visual disturbances are common because of
alterations in the osmotic milieu of the lens, and to a lesser extent the aqueous and
vitreous humors leading to changes in refractive index [48]. Children with longstanding
hyperglycemia may present with cataracts [49,50].

Diabetic ketoacidosis Diabetic ketoacidosis (hyperglycemia and ketoacidosis) is the

second most common form of presentation for T1DM in most populations. Symptoms are
similar but usually more severe than those of patients without acidosis. In addition to
polyuria, polydipsia, and weight loss, patients with ketoacidosis may present with a fruity-
smelling breath and neurologic findings including drowsiness and lethargy. DKA can be
misinterpreted as an acute vomiting illness because classic pediatric symptoms of
dehydration (decreased urination) are masked by the polyuria that is associated with
glycosuria.

The reported frequency of diabetic ketoacidosis (DKA) as the initial presentation for
childhood T1DM is approximately 30 percent, but varies from 15 to 67 percent [51-53].
Young children (<six years of age) or those from an adverse socioeconomic background
are more likely to have DKA as their initial presentation of T1DM. Among children younger
than age three years, more than half had DKA as their initial presentation of T1DM [52].

Children with DKA require hospitalization, rehydration, and insulin replacement therapy.

Silent presentation Some children will be diagnosed with T1DM before the onset of
clinical symptoms. This presentation is least common and typically occurs in children who
have another close family member with T1DM and are being closely monitored. The
diagnosis often is made by either a family member or clinician with a high index of
suspicion. Children with an affected close family member also may undergo pancreatic
autoantibody screening to assess risk for the disease [54], although this is not a clinical
care recommendation. The diagnosis is made based upon an elevated blood glucose
concentration using the criteria outlined below.

Special populations

Infants A variety of disorders can cause hyperglycemia during infancy. Although

autoimmune classic T1DM can occur in the first year of life, neonatal diabetes is
uncommonly if ever autoimmune in nature. Neonatal diabetes is a rare disorder
caused by one of several genetic defects in pancreatic development or beta cell function.
Young children Younger children are more vulnerable to dehydration compared with older
children because they are less able to compensate for pathologic processes by seeking
fluids and increasing fluid intake (to replace ongoing urinary losses). In addition, children
younger than six years of age are more likely to present with DKA, because health care
personnel and families less often suspect diabetes in this age group. This leads to a
prolonged duration of illness and more severe metabolic decompensation before
diagnosis.

Children in this age group also have polydipsia and polyuria, but these symptoms are
difficult to detect if the child is in diapers or is nonverbal and unable to communicate thirst.
Therefore, it is often difficult to recognize these symptoms of hyperglycemia in young
children, especially those younger than two years of age [23]. The history or presence of
prolonged or recurrent candidal infection (usually in the diaper area) is an important clue
that should raise suspicion about the possibility of diabetes mellitus in young children.
Candidal infection was present at diagnosis in a significant proportion of children younger
than six years with T1DM, and especially in those younger than two years of age [23].

These patients often have been seen by a clinician for nonspecific complaints before the
diagnosis [23]. In this vulnerable age group, a high index of suspicion is required for early
diagnosis. When a young child presents for evaluation of dehydration, abdominal pain, or
fatigue, the clinician should include diabetes in the differential diagnosis and consider
measuring serum glucose and testing for glucosuria.

DIAGNOSIS Type 1 diabetes mellitus (T1DM) is one of several different types of

diabetes mellitus. The initial step is to diagnose diabetes. The second step is to
differentiate T1DM from other causes of diabetes based upon the clinical presentation of
the patient and laboratory studies.

Diagnostic criteria for diabetes Diabetes mellitus is diagnosed based upon one of the
following four signs of abnormal glucose metabolism (table 1) [57,58]:

Fasting plasma glucose 126 mg/dL (7 mmol/L) on more than one occasion. Fasting is
defined as no caloric intake for at least eight hours.

Random venous plasma glucose 200 mg/dL (11.1 mmol/L) in a patient with classic
symptoms of hyperglycemia

Plasma glucose 200 mg/dL (11.1 mmol/L) measured two hours after a glucose load of
1.75 g/kg (maximum dose of 75 g) in an oral glucose tolerance test (OGTT). Most children
and adolescents are symptomatic and have plasma glucose concentrations well above
200 mg/dL (11.1 mmol/L); thus, OGTT is seldom necessary to diagnose T1DM.
Glycated hemoglobin (A1C) 6.5 percent (using an assay that is certified by the National
Glycohemoglobin Standardization Program). This criterion is more useful to diagnosis of
type 2 diabetes mellitus (T2DM) in adults, and should be confirmed by hyperglycemia.

Based upon the guidelines of the American Diabetes Association (ADA), these diagnostic
criteria resemble those used in adults with diabetes. Unless unequivocal symptomatic
hyperglycemia is present, the diagnosis should be confirmed by repeat testing.

A1C measures the percent of hemoglobin A bound to glucose via non-enzymatic glycation,
and indicates the average blood sugar levels for 10 to 12 weeks before the time of
measurement. A1C 6.5 percent is now an accepted criterion for diagnosis of diabetes in
adults [58]. However, the diagnostic utility of A1C for children is less well established than
for adults. A1C values 6.5 percent are diagnostic of diabetes in adults, but levels <6.5
percent do not exclude diabetes. Of note, in one study from Germany, all children with
symptomatic, new-onset T1DM had a glycated hemoglobin 6.35 percent, whereas those
with transient hyperglycemia had A1C values ranging from 4.5 to 6.1 percent [59].

Individuals with abnormal hemoglobins or rapid destruction of red blood cells may have a
measured A1C value that does not accurately reflect their average blood sugar values.
The accuracy of measurements in individuals with abnormal hemoglobins will improve with
use of improved techniques for assessing A1C and with standardization of A1C
measurements. For example, hemoglobin variants and derivatives interfere very minimally
with the commercially available boronate-affinity chromatography technique [60]. However,
rapid turnover of hemoglobin will still affect the reported A1C level.

Glycosuria is suggestive of diabetes, but not diagnostic. For example, patients with renal
glucosuria or Fanconi syndrome will present with glycosuria but have normal plasma
glucose concentration. Similarly, the presence of islet-specific autoantibodies supports the
diagnosis of T1DM (as discussed in the next section), but is not sufficient to make the
diagnosis.

Type 1 versus type 2 diabetes T1DM is characterized primarily by insulin deficiency,

whereas type 2 diabetes (T2DM) is characterized primarily by insulin resistance with
relative insulin deficiency. As the incidence of T2DM increases in children and adolescents,
it becomes increasingly important to distinguish type 1 from type 2 disease, because long-
term management differs.

No set of criteria or diagnostic test can consistently distinguish between T1DM and T2DM.
Therefore, differentiating between the two types is based upon a combination of the clinical
presentation and history, often supported by laboratory studies (table 2).

Clinical characteristics:
Body habitus Patients with T2DM are usually obese (body mass index [BMI]
95th percentile for age and gender). In contrast, children with T1DM are usually not obese
and often have a recent history of weight loss, although up to 25 percent are overweight
(BMI 85th to 95th percentile) [61].

Age Patients with T2DM generally present after the onset of puberty, whereas those
with T1DM often present at an earlier age. About 45 percent of children with T1DM present
before 10 years of age [19]. By contrast, almost all cases of T2DM present after 10 years
of age (figure 1).

Insulin resistance Patients with T2DM frequently have acanthosis nigricans (a sign of
insulin resistance), hypertension, dyslipidemia, and polycystic ovary syndrome (in girls).
These findings are less likely in children with T1DM. As an example, in studies in the
United States, 50 to 90 percent of youth diagnosed with T2DM have acanthosis nigricans
[2,62]. Among those clinically diagnosed with T1DM, up to 25 percent have biochemical
evidence of insulin resistance, and about 12 percent have acanthosis nigricans [62].

Family history Up to 10 percent of patients with T1DM have an affected close relative,
whereas 75 to 90 percent of those with T2DM have an affected close relative [2,63].

Laboratory testing The following laboratory tests are often helpful in differentiating
between T1DM and T2DM. We suggest including them in the evaluation:

Antibodies Although there is no specific test to distinguish between the two types of
diabetes, T1DM is suggested by the presence of circulating, islet-specific, pancreatic
autoantibodies against glutamic acid decarboxylase (GAD65), the 40K fragment of
tyrosine phosphatase (IA2), insulin, and/or zinc transporter 8 (ZnT8). However, the
absence of pancreatic autoantibodies does not rule out the possibility of T1DM. Up to 30
percent of individuals with the classical appearance and presentation of T2DM have
positive autoantibodies and may have a slowly progressive type of autoimmune diabetes
[64].

Insulin and C-peptide levels High fasting insulin and C-peptide levels suggest T2DM.
Levels are inappropriately low or in the normal range relative to the concomitant plasma
glucose concentration in T1DM. At presentation, insulin and C-peptide levels may be
suppressed by severe hyperglycemia and illness. It is usually best to assess these levels
after the newly diagnosed patient has recovered from acute illness.

Insulin deficiency in T1DM most commonly results from autoimmune destruction of

pancreatic beta cells and is referred to as type 1A diabetes (approximately 85 percent)
[62]. Patients with clinical features of T1DM but without detectable autoantibodies are
categorized as having type 1B diabetes (approximately 15 percent). In these patients,
there is no evidence of autoimmune beta-cell destruction and no other cause has been
identified.

Some patients may have mixed features, and are difficult to classify. As an example, in a
registry study in the United States, pediatric diabetes was classified based upon the
presence or absence of beta cell autoimmunity and the presence or absence of insulin
sensitivity [62]. More than 70 percent of patients fell into traditional categories of
autoimmune and insulin sensitive T1DM (55 percent) or nonautoimmune and insulin
resistant T2DM (16 percent). An additional 20 percent had both autoimmunity and insulin
resistance, a pattern typical for obese patients with T1DM. The remaining 10 percent of
patients were insulin sensitive in the absence of islet cell autoimmunity, most of whom
were clinically categorized as T1DM (ie, type 1B diabetes), and the remainder as T2DM
(suggesting that these patients need additional evaluation for the possibility of monogenic
diabetes, formerly referred to as maturity onset diabetes of the young [MODY]).

DIFFERENTIAL DIAGNOSIS

Other causes of hyperglycemia In the previously healthy child, diabetes mellitus is by

far the most common cause of clinically significant hyperglycemia. Other considerations
include:

Critically ill patients Patients with septic shock or other critical illnesses often have
abnormalities in glycemic control, leading to either hypoglycemia or hyperglycemia.

Medication Children receiving intravenous infusions containing glucose, or those who

receive acute sympathomimetic agents or high-dose glucocorticoids, may display
elevations in blood glucose that revert to normal after treatment is complete.

Neonatal hyperglycemia Causes of hyperglycemia in a neonate include excessive

glucose infusion, prematurity, stress, sepsis, drugs, and transient or permanent neonatal
diabetes mellitus.

Other causes of diabetes T1DM is distinguished from other diseases that cause
diabetes by patient characteristics, history, and laboratory studies. This approach is similar
to that used to differentiate type 1 from type 2 diabetes discussed above.

The following diseases that cause diabetes are discussed in greater detail separately.

Diseases of the exocrine system Cystic fibrosis, hereditary hemochromatosis, and

chronic pancreatitis.

Endocrine abnormalities in glucose regulation Cushing syndrome, growth-hormone

excess, glucagon-secreting tumors, catecholamine excess in pheochromocytoma. With
the exception of Cushing syndrome, these are all extremely rare. This possibility should be
evaluated in patients presenting with Cushingoid features (such as central obesity, facial
plethora, dorsocervical fat pad, and delayed linear growth). This is usually best
accomplished by measuring 24-hour urinary cortisol excretion or salivary cortisol at 11 PM
or midnight two or more times; additional testing may be required. It is important to
recognize that children with Cushing syndrome may not manifest the classic features seen
in adults. However, a deceleration of growth velocity despite increasing weight should
raise concern for Cushing syndrome in a growing child. It is very rare for a child with
Cushing syndrome to present with hyperglycemia, although relatively common in adults.

Drug-induced diabetes A number of drugs (eg, glucocorticoids, HIV protease

inhibitors, cyclosporine, L-asparaginase, and tacrolimus) and atypical antipsychotic agents
can impair glucose tolerance by inhibiting insulin secretion, increasing hepatic glucose
production, or causing insulin resistance (table 3).

Monogenic diabetes (formerly referred to as maturity onset diabetes of the young, or

MODY) Monogenic diabetes is a clinically heterogeneous disorder characterized by non-
insulin dependent diabetes presenting at a young age, with autosomal dominant
transmission and lack of autoantibodies. Many different genetic abnormalities have been
identified, each leading to a different type of disease. Monogenic diabetes should be
suspected in a patient presenting with non-insulin-dependent diabetes at a young age (<25
years), with autosomal dominant transmission across three generations, lack of islet
autoantibodies, and lack of acanthosis nigricans. The diagnosis of monogenic diabetes is
made by performing diagnostic genetic testing by direct sequencing of the gene.

Neonatal diabetes mellitus Neonatal diabetes is a rare cause of hyperglycemia in

infants. It can be transient or permanent, and usually is caused by mutations in one of
several genes that encode proteins that affect the function of the pancreatic beta-cell (eg,
proteins that are subunits of the ATP-sensitive potassium channel). Most of the infants are
small for gestational age, and they present with weight loss, volume depletion,
hyperglycemia, and glucosuria with or without ketonuria and ketoacidosis. The natural
history and management of diabetes in these infants depends on the genetic defect, as
discussed in a separate topic review.

TREATMENT

There are unique challenges in caring for children and adolescents with diabetes that
differentiate pediatric from adult care. These include the obvious differences in the size of
the patients, developmental issues such as the unpredictability of a toddler's dietary intake
and activity level and inability to communicate symptoms of hypoglycemia, and medical
issues such as the increased risk of hypoglycemia and diabetic ketoacidosis (DKA).
Because of these considerations, the management of a child with type 1 diabetes must
take into account the age and developmental maturity of the child.

Although most children with type 1 diabetes present with the classic signs and symptoms
of hyperglycemia without accompanying acidosis, approximately 30 percent of children in
the United States present with DKA [1,2]. The management of these patients is discussed
in detail separately.

The management of the child or adolescent with type 1 diabetes, who either did not
present with ketoacidosis or who has recovered from ketoacidosis, will be reviewed here.
The term parent will be used throughout the discussion, with recognition that the primary
caregiver may not be a parent.

Initial management The initial phase begins at the time of diagnosis. In these first few
days, the family begins to understand the disease process and is trained to successfully
measure blood glucose concentrations, administer insulin, recognize and treat
hypoglycemia, and measure blood or urine ketone concentration (table 1).

Basic understanding The diabetes team teaches the patient and family the cause and
treatment of type 1 diabetes, how to maintain a daily schedule and record of blood glucose
test results, insulin administration, and the timing and carbohydrate content of meals and
snacks.
Blood glucose testing Families must master blood glucose testing. A variety of easy-to-
use blood glucose meters are available for this purpose. The parents or caregivers are
instructed on the frequency and timing of blood glucose testing, depending upon the needs
of their child. (See 'Blood glucose monitoring' below.)
Insulin administration Training includes teaching the family about the different types of
prescribed insulin, how to measure and inject insulin, and how to rotate injection sites.
Family members and caretakers must learn about the duration and action of the various
types of insulin prescribed for their child. They must also understand how to adjust the
insulin dose based upon blood glucose concentrations and carbohydrate intake.
(See 'Insulin' below.)
In our practice, we encourage the parents to administer the first injection. Although this
requires additional assistance and fairly directive behavior on the part of the clinician, we
find that it facilitates the learning process. Because most parents are so frightened about
administering an injection to their child, their ability to learn is limited until they have
administered the first injection. We also find it useful to have the parents administer a
saline injection to themselves so that they realize the discomfort is minimal.
Hypoglycemia Families are taught to recognize the signs and symptoms of
hypoglycemia. Detection of hypoglycemia is particularly difficult in the nonverbal young
child and infant in whom the signs of hypoglycemia are nonspecific. Parents are trained to
check a blood glucose level and, if this is too low, to intervene with dietary
measures and/or glucagon. (See "Hypoglycemia in children and adolescents with type 1
diabetes mellitus" and 'Age-based care' below.)
Blood or urine ketones Families are taught to check urine for ketones or measure blood
beta-hydroxybutyrate concentration at times of illness and/or if two consecutive blood
glucose readings are greater than 250 mg/dL (13.9 mmol/L) [7]. This is especially
important in young children, insulin pump users, or those with a history of diabetic
ketoacidosis (DKA). (See 'Blood glucose monitoring' below.)

The initial educational and care phase may occur either in the inpatient or ambulatory
setting. Most institutions have moved from prolonged inpatient admissions for newly
diagnosed patients to either short hospitalizations or exclusively ambulatory management.
Patient outcome is similar with outpatient and inpatient management, regardless of the
length of inpatient hospitalization, and health care costs are much less with outpatient
treatment [8-11]. Accordingly, we initiate the care of most newly diagnosed children with
type 1 diabetes without ketoacidosis in the outpatient setting. A multidisciplinary team
provides close follow-up (daily phone contact and ambulatory visits as necessary),
comprehensive education, and an individualized management plan for the child and family.

Once the family and care providers are comfortable with the family's ability to manage the
child's diabetes at home, plans should be made to return the child to school or daycare
center, as appropriate. If insulin needs to be administered at the child's school or daycare
center, a responsible individual must be identified and trained in basic diabetes
management skills. In addition, appropriate individuals at the school or daycare center
must be provided with information regarding the detection and management of
hypoglycemia. (See "Special situations in children and adolescents with type 1 diabetes
mellitus", section on 'School and daycare'.)

Patients with diabetes should wear a medical emergency bracelet/necklace to enable

suitable intervention by emergency personnel should an emergency situation arise (ie,
hypoglycemia or DKA). MedicAlert provides an excellent resource (www.medicalert.org).

Ongoing management After the initial phase, the diabetes team continues to provide
care, teaching, and support to the child and family. Sessions with individual team members
(endocrinologist, nurse educator, dietitian, and a mental health professional) allow more in-
depth education and care directed toward the goal of maintaining excellent glucose
control. (See "Self-management education for the child with diabetes mellitus".)

During these sessions, the concepts that are required for glycemic control are taught and
reinforced. These include the interaction of insulin, diet, and exercise on blood glucose
concentrations. A management regimen specific for each patient is designed to achieve
the best possible glucose control. In addition, the clinician should explain that strict
glycemic control helps to prevent long-term sequelae of diabetes; this discussion should
be repeated and reinforced as often as necessary, particularly if glycemic control is
suboptimal.

Providing age-appropriate psychosocial support for the patient and the family by a
proficient mental health professional improves adherence to the management plan. In two
controlled trials, structured psychoeducational support significantly improved glycemic
control and reduced hospitalization rates in adolescents whose diabetes had previously
been poorly controlled [12,13].

As the child grows older, education and training are directed toward increased autonomy
and self-management for the patient. (See 'Age-based care' below.)

Printed literature and Web sites available for patient and family education are excellent
supplements to the teaching provided by the diabetes team (table 2).

AGE-BASED CARE The management plan of childhood-onset type 1 diabetes

depends on the child's age, cognitive ability, and emotional maturity, which affect his or her
ability to communicate symptoms and participate in self-management (table 3).

Because newer data point to an adverse effect of prolonged hyperglycemia on neurologic

development in younger children, recommended goals for glycemic control no longer vary
across the pediatric age groups. However, the goals should be individualized based on the
characteristics of the individual patient. (See 'Children and adolescents' below.)

The following discussion on age-based management is compatible with the American

Diabetes Association (ADA) guidelines for the care of children and adolescents with type 1
diabetes [4].

Infants Infants (younger than one year of age) with diabetes have the highest risk of
severe hypoglycemia [14,15]. Hypoglycemia is difficult to detect because infants are
unable to communicate their symptoms and clinical signs are nonspecific (eg, poor
feeding, lethargy, jitteriness, hypotonia).

Infants with severe hypoglycemia can present with seizures or coma, which may have
permanent neurologic sequelae. In addition, repeated prolonged episodes of
hypoglycemia as well as persistent hyperglycemia may have deleterious effects on brain
development and learning, especially in children younger than five years of age [16-19].
Clinical experience with modern management methods suggest that more stringent
glycated hemoglobin (A1C) targets improve glycemic control without significantly
increasing the risk for severe hypoglycemia [4,7]. As a result, targets for glycemic control
in infants and young children are now similar to those for older age groups, in which equal
value is placed on avoiding both hypo- and hyperglycemia. (See "Hypoglycemia in children
and adolescents with type 1 diabetes mellitus" and 'Glycemic control' below.)
The frequent feeding schedule of infancy makes it challenging to develop a management
plan that avoids episodes of hypoglycemia but provides sufficient glycemic control. In
addition, the stress of implementing the daily care plan can have adverse effects on
parents [4].

Toddlers The issues surrounding the care of toddlers (one to three years of age) are
similar to those in infants. The parents must learn to manage diabetes and be responsible
for the daily care of the patient and also learn to recognize episodes of hypoglycemia.
Avoiding hypoglycemia can be challenging because of the erratic food intake and activity
levels of toddlers. This problem can be addressed by frequent blood glucose monitoring
(or possibly the use of continuous glucose monitoring), and use of an insulin pump or other
flexible dosing systems. It also can be difficult to distinguish developmentally normal
episodes of oppositional behavior and temper tantrums from altered behavior caused by
hypoglycemia. The parents must learn to measure blood glucose before ignoring a temper
tantrum.

Preschool and early school-aged children For preschool and early school-aged
children (three to seven years of age), parents still provide most of the daily diabetes care.
However, some of these patients can begin to participate in their own care by testing their
blood glucose or preparing materials. Often, such mastery behaviors are short-lived, as
the children rapidly become bored and wish to forgo such responsibilities. The parents
must be counseled that this behavior is normal and age appropriate. Shared care with the
child is appropriate at this age only under direct parental supervision.

As these children enter daycare or school, childcare providers and school nurses must be
involved in their diabetes care. For parents, sharing care with others, including the patient,
may be difficult. Continued support by the care team is important to facilitate this transition.
In the United States, children younger than six years may be eligible to receive
supplemental Social Security income to help their parents with the economic impact of
diabetes management in the young child [20]. (See "Special situations in children and
adolescents with type 1 diabetes mellitus", section on 'School and daycare'.)

School-aged children For school-aged children (8 to 11 years of age), optimal care

consists of shared responsibility, so that the child begins to assume some of the daily
management of their diabetes but has close adult supervision and support. The child can
learn to administer the routine insulin injections, but still needs significant assistance and
supervision for management decisions that are not routine. All glucose testing and insulin
administration should be under adult supervision. Early independent self-management in
this age group with minimal or no adult supervision results in poorer glycemic control [21-
23].

The diagnosis of diabetes has a psychological impact on these children, which may be
manifested by depression and anxiety [24,25]. Children may also have difficulty with social
interactions because of their perception that they are different from their peers. The
parents and the diabetes team should encourage participation in school activities to
develop normal peer relationships and ensure regular school attendance [26]. Attendance
at diabetes camp may help children better adjust to their diagnosis [27,28]. Interactions at
camp can be useful in acquainting children with unfamiliar methods for glucose monitoring
and insulin administration and may engage patients with these technologies in a peer-
interactive rather than physician-driven environment.

Screening for behavioral disturbances and discussion of psychosocial issues should be

included in the routine medical care for a child with diabetes; at-risk children may
subsequently benefit from evaluation of parental mental health and family dynamics [4]. It
is important for caregivers to recognize developing cognitive deficits and learning
difficulties, and for appropriate care to be provided to children if these deficits develop [29].
This is particularly important because of the higher risk of cognitive deficits in children who
developed diabetes at a very young age, those with poor glycemic control, frequent
episodes of hypoglycemia, and longer duration of the disease. (See "Hypoglycemia in
children and adolescents with type 1 diabetes mellitus", section on 'Neurologic sequelae'.)

Adolescents Adolescence naturally is a time of increasing independence and self-

assertiveness, but also of risk-taking. Therefore, determining the appropriate extent of
adult involvement can be challenging [30]. Although adolescents can be responsible for
the daily management of their diabetes, minimal or no adult supervision results in poor
glycemic control [4]. While shared management between the adolescent and parents is
associated with better glycemic control [31], parent-child conflict over daily management
leads to poor control [32-34], and adolescent depression of even a mild degree can
interfere with family involvement and diabetes control [35].

Family-focused teamwork, which includes developing shared parent-child responsibility

and strategies to avoid conflict, improves the care of the older child with diabetes. This was
illustrated in a controlled trial of family-focused teamwork compared with standard
multidisciplinary diabetes care in children who ranged from 8 to 17 years of age [36].
Family-focused care, which included establishing a responsibility-sharing plan at the end
of each patient visit and active family discussion, increased family involvement, and
resulted in better glycemic control (adjusted A1C, 8.8 versus 9.3 percent). This approach
allows the care team to develop a shared responsibility plan that is appropriate for the
patient based upon his/her cognitive, physical, and psychosocial maturity.

Other issues for the adolescent patient with diabetes include [37]:

Driving Adolescent drivers with diabetes should be taught to test blood glucose levels
before driving. Data in adults demonstrate that a significant number of patients considered
it safe to drive when they were hypoglycemic [38]. It is essential for teenagers to
understand the risks of driving while hypoglycemic and to be urged to carry carbohydrate
snacks with them at all times. If hypoglycemic when they test their blood glucose before
driving, they should take a carbohydrate snack and confirm normalization of blood glucose
before driving.
Risky behavior Adolescence is also a time period that is characterized by
experimentation with risky behaviors, such as alcohol and drug use and unprotected
sexual intercourse.
Alcohol intake can be associated with severe hypoglycemia. Adolescents should be
aware of this risk, routinely assessed for alcohol use, and counseled, if appropriate.
Smoking is an important risk factor for long-term diabetic complications. Counseling about
smoking avoidance (or cessation, if appropriate) should be an important part of ongoing
care. (See "Management of smoking cessation in adolescents".)
Before initiating sexual activity, adolescent girls should be given preconception counseling
that includes the risks of diabetes complications to themselves and potentially the fetus.
Use of contraception should be reviewed and encouraged. (See "Pregestational diabetes:
Preconception counseling, evaluation, and management".)
Psychiatric issues Adolescent patients with diabetes have a threefold increased risk of
psychiatric disorders, primarily depression and eating disorders. Eating disorders may take
the form of intentional misuse of insulin for weight control, and symptoms of disordered
eating and the possibility of intentional insulin misuse should be specifically investigated
[39]. Children with diabetes should be screened annually for depression, especially during
adolescence [4]. (See "Complications and screening in children and adolescents with type
1 diabetes mellitus", section on 'Psychiatric disorders'.)

Transition into adult care As the adolescent approaches young adulthood, there
should be an orderly transition to independent self-management with support from the
family and diabetes team [4,37]. Each of the following issues should be monitored during
and after the transition to adult care:

Driving, alcohol, and smoking (see 'Adolescents' above)

Risk for eating disorders, including intentional insulin misuse
Contraception and education to minimize the maternal and fetal risks of pregnancy
Education about the adverse effects of alcohol on glycemic control, and of tobacco on the
cardiovascular complications of diabetes
Prevention and management of hypoglycemic episodes while driving
Possibility of discontinuation of insurance coverage, and education regarding insurance
options and maintenance of coverage
Education regarding expectation of greater autonomy in the adult diabetes clinic

Young adults tend to decrease the frequency of contact with their diabetes care provider
after transition to an adult program, and those with fragmented care have poorer glycemic
control and a higher rate of hospitalization [40]. Self-care behaviors tend to deteriorate
during this transitional time, and in many institutions transition practices are not optimal
[41,42]. Strategies to facilitate transition to adult health care include longer or more
frequent initial visits, use of a transition coordinator, or transition to a clinic designed for
young adults [37]. The National Diabetes Education Program has developed a transition
planning template to facilitate transition from pediatric to adult care; this includes a
checklist for the pediatric provider, a list of key health information to be transferred, and
patient information resources designed for this age group [43].

GLYCEMIC CONTROL Daily blood glucose levels are used to monitor glycemic control
and adjust management. The most widely used clinical test to evaluate long-term glycemic
control is blood glycated hemoglobin (also called A1C, hemoglobin A1C, glycohemoglobin,
or glycosylated hemoglobin). (See "Estimation of blood glucose control in diabetes
mellitus".)

Both in children and adults, the goal of management is to maintain glucose control as near
to normal as safely possible (ie, balance the risks of long-term complications of diabetes
and hypoglycemia). The targeted goal of this glycemic balance varies based upon the risk
of hypoglycemia, which is age dependent.

Adults In adults, a target A1C of <7 percent (53 mmol/mol) best balances the risks of
long-term sequelae and hypoglycemia. This was illustrated by the Diabetes Control and
Complications Trial (DCCT) [44]:

Long-term complications Strict glycemic control delayed the onset of microvascular

disease (retinopathy, nephropathy, and neuropathy), slowed progression of already-
present microvascular disease, and decreased the incidence of cardiovascular disease. As
A1C decreased, so did the risk of long-term sequelae, such as diabetic retinopathy (figure
1). Randomized trials in adolescents have shown a similar relationship between glycemic
control and long-term microvascular sequelae of diabetes. (See "Glycemic control and
vascular complications in type 1 diabetes mellitus".)
Hypoglycemia As A1C decreased, the incidence of severe hypoglycemic episodes
increased (figure 2).

Although there is a continued relative risk reduction of retinopathy and other complications
at A1C values below 7 percent, the absolute risk of developing these complications is low
if the A1C value is kept below this threshold (figure 1). Conversely, the absolute risk of
severe hypoglycemia increases progressively (figure 2). Therefore, an A1C goal of 7
percent has been recommended as a goal that balances the long- and short-term risks in
adults. (See "Estimation of blood glucose control in diabetes mellitus", section on 'Glycated
hemoglobin'.)

It is important to recognize that patients with erratic diabetes control and wide glycemic
excursions may achieve a similar A1C as patients with more stable glucose levels if the
mean blood glucose levels are similar.
Children and adolescents We suggest a target A1C of <7.5
percent (59 mmol/mol) for children and adolescents, consistent with guidelines from the
American Diabetes Association (ADA) and the International Society for Pediatric and
Adolescent Diabetes (ISPAD) [4,7]. To achieve a target A1C of <7.5 percent, target blood
glucose levels are approximately 90 to 130 mg/dL before meals, and 90 to 150 mg/dL at
bedtime and overnight. The ADA emphasizes that glycemic targets should be further
tailored to the individual patient [4]. More or less stringent goals may be appropriate for
individual patients, depending on their personal history of severe hyperglycemia and
severe hypoglycemia, hypoglycemia unawareness, known micro- and macrovascular
complications, and lifestyle or psychosocial considerations.

In the past, ADA set higher A1C targets for young children because of concerns that more
stringent targets might increase the risk for hypoglycemic episodes [5]. However, clinical
experience with modern management methods suggest that the target of <7.5 percent
does not significantly increase the risk for severe hypoglycemia. Moreover, increasing
evidence suggests that hyperglycemia is associated with micro- and macrovascular
complications, including in the central nervous system of the prepubertal child [4,45-47].

Glycemic control can be achieved in many pediatric patients. This was illustrated in a
single-center study of 455 pediatric patients (<18 years of age), among whom the mean
A1C level was 7.6 percent [48]. More than two-thirds of the children met the center's goal
of A1C <8 percent. Multiple linear regression analysis demonstrated that lower
socioeconomic status, older age, longer duration of diabetes, injection therapy (rather than
insulin pump therapy), and female gender were associated with poorer glycemic control.
However, other studies that included data from more diverse management settings
showed worse rates of glycemic control, particularly among adolescents: A1C levels were
>7.5 percent in more than 70 percent of adolescents, regardless of insulin regimen [49,50].
Similar findings were reported from a large cross-sectional registry study, in which children
less than six years old who used an insulin pump had an average A1C of 7.9 percent, and
those who did not use a pump had an average A1C of 8.5 percent [51]. Thus, achieving
ADA recommended goals is difficult for the majority of children.

BLOOD GLUCOSE MONITORING Optimal glycemic control is dependent upon

frequently monitoring blood glucose and appropriate adjustment of insulin dose. Ongoing
monitoring allows the child and family to become familiar with the patient's glycemic
response to different types and amount of foods, exercise, and stress. (See "Blood
glucose self-monitoring in management of adults with diabetes
mellitus" and 'Insulin' below.)

Frequent monitoring has been shown to improve glycemic control in children [4,52,53] and
decrease the frequency of severe hypoglycemic episodes [54]. Children and their parents
show poor ability to detect high or low blood glucose levels based on symptoms alone. In a
study that compared self-reporting of hypoglycemia with glucose meter results, children
(aged 6 to 11 years) and their parents failed to detect about half of the episodes of
clinically significant hypoglycemia (<55 mg/dL) [55]. Therefore, blood glucose monitoring is
essential to avoid severe hypoglycemia and to optimize blood glucose control. Generally,
the frequency of self-monitoring of blood glucose (SMBG) is highest in children under the
age of six years and decreases with increasing age [52]. Predictors of lower frequency of
SMBG include lower self-esteem, high stress life events, and inadequate parental support
[56]. Psychosocial support and parental supervision may help optimize the frequency of
SMBG in older children.

To prevent the development of diabetic ketoacidosis (DKA), patients must check for urine
or blood ketones when blood glucose is persistently 250 mg/dL (13.9 mmol/L), or during
acute episodes of increased stress, including intercurrent illnesses [7]. Patients who have
hyperglycemia and positive urine ketones or increased blood ketone concentrations should
be treated with additional insulin (with or without additional carbohydrates) and increased
fluid intake, combined with meticulous monitoring of blood glucose and ketone
concentrations. With these interventions, most cases of DKA can be avoided or aborted.
The education of patients and families should include information regarding the
parameters of when it is necessary to call the diabetes care team for assistance.
(See "Clinical features and diagnosis of diabetic ketoacidosis in children".)

Fingersticks Blood glucose should be tested at least four times a day (in the fasting
state: before meals and at bedtime); more frequent monitoring is often required, depending
on the environment and social situation [4,7]. This is especially true in very young children
who are at increased risk for severe hypoglycemia, and in patients who are treated with
intensive therapy who have multiple meals and snacks during the day and require blood
glucose checks prior to administration of a pre-meal bolus of insulin. To safeguard against
hypoglycemia, monitoring at anticipated peaks of insulin action and during periods of
increased physical activity may be necessary. (See 'Value of an intensive regimen' below.)

Blood glucose is typically monitored using a blood glucose meter, which requires a small
sample of blood (0.3 to 1 microliter) obtained by fingerstick. Many new lancet devices are
available, some of which are ultrafine gauge, and others of which contain multiple lancets
for ease and safety of handling. In general, using a lancet only once will minimize
discomfort, but children will sometimes use lancets more than once without much ill effect.
Some devices permit blood sampling from the forearm; this technique is less painful than
using the side of the finger, but provides a blood sample which is not as close to arterial
blood as that from the finger tip and may not identify hypoglycemia as quickly as a finger
tip sample.

Continuous glucose monitoring Subcutaneous glucose sensors that continuously

measure interstitial fluid glucose levels are now available and approved for use in children.
They are useful for optimizing glycemic control in motivated patients and also for
management of patients with a history of hypoglycemia unawareness [4]. The currently
available continuous glucose monitoring (CGM) systems are expensive and relatively
inaccurate in the lower (<70 mg/dL) glucose range, limiting their usefulness. They should
be used in conjunction with conventional monitoring (fingerstick), which is essential for
calibration and to ensure reliability [4]. The advantages and disadvantages of continuous
glucose monitoring systems, and the experience with these devices in adults are reviewed
separately. (See "Blood glucose self-monitoring in management of adults with diabetes
mellitus", section on 'Continuous glucose monitoring'.)

Several different types of CGM devices have been developed:

CGM without real-time feedback The first generation of CGM devices provided blood
glucose data only after downloading by the physician, and did not provide real-time
feedback to the patient. This type of device did not appear to improve glycemic control in
children, although there was some educational value in detecting patterns of blood glucose
fluctuations and episodes of hypoglycemia during periods of sleep [57]. This device is
sometimes used today to determine whether a patient wishes to be a candidate for a real-
time feedback device.
CGM with real-time feedback The newer generation of CGM devices report blood
glucose levels to the patient in real time. Short-term studies indicate clinical benefits of
these devices as compared with conventional methods of blood glucose monitoring when
used by motivated and well-informed patients. These devices do not directly control insulin
administration but provide glucose readings to permit finer control of insulin administration
by patients and their families.
These devices have moderate efficacy for patients who are willing to use them
consistently. This was shown in a randomized controlled study comparing continuous
glucose monitoring versus conventional home glucose monitoring, which reported a
significant decrease in glycated hemoglobin levels in adults using the CGM device [58].
This benefit was not seen in children and adolescents overall, but analysis of the subgroup
between 8 and 14 years old indicated that children who consistently used the continuous
glucose sensor were more likely to have A1C levels <7 percent, as compared with children
using conventional blood glucose monitoring. These benefits were not observed in
adolescents older than 14 years. There was no difference between groups in the number
of episodes of severe hypoglycemia in any age group. This type of CGM also improved
patient satisfaction because of increasing awareness of trends of rising or falling glucose
levels [59,60]. Several devices are approved by the US Food and Drug Administration
(FDA) and are commercially available.
Sensor-augmented insulin pump This refers to CGM used in conjunction with an insulin
pump (see 'Insulin pump' below); the patient or family manually adjusts the insulin dose
based on the CGM results. This approach generally leads to improved glycemic control but
requires a highly motivated user and good diabetes management skills, as illustrated by
the following studies (see "Management of blood glucose in adults with type 1 diabetes
mellitus", section on 'Sensor-augmented insulin pump'):
Sensor-augmented insulin pump therapy was compared with multiple daily injections
(MDI) in a randomized trial in 156 children and adolescents (STAR 3 study) [61,62]. After
one year of treatment, subjects using the sensor-augmented pump reduced their glycated
hemoglobin levels by 0.6 percentage points as compared with those using MDI, and 44
percent reached target glycated hemoglobin levels for their age, as compared with 20
percent in the group using MDI. Rates of severe hypoglycemia were similar between the
two groups (7 events among 78 subjects using the insulin pump, versus 4 events among
81 subjects using MDI, p=0.53). Similar findings were seen in adults enrolled in the same
study. However, a large number of children enrolled in these trials were unable or unwilling
to continue to use the sensors during the course of the trial [63-65]. An update from the
STAR 3 study reported that children compared with adolescents wore the CGM sensors
more often and were more likely to achieve age-specific A1C target values. This report
confirmed a reduction in A1C levels in the sensor group and also reported fewer
hyperglycemic excursions and lower glycemic variability in this group [62].
Sensor-augmented insulin pump therapy was compared with conventional SMBG and the
insulin pump in a randomized trial in 160 children and adolescents (ONSET study) [66]. No
differences in A1C levels were noted between the groups. However, A1C levels were lower
in children who used the sensor regularly versus those who used the sensor infrequently
or not at all. Additionally, the sensor group had lower glycemic variability and higher C-
peptide concentrations at the conclusion of the study. The sensor group had no episodes
of severe hypoglycemia compared with four such episodes in the conventional SMBG-
pump group.
Sensor-augmented insulin pump with threshold-suspend This is a partially closed loop
glucose monitoring and insulin infusion system that can respond to hypoglycemia by
stopping the insulin infusion; the device has been approved by the FDA [67]. This is a very
welcome addition to the armamentarium but is not a complete closed-loop system.
(See "Management of blood glucose in adults with type 1 diabetes mellitus", section on
'Sensor-augmented insulin pump'.)
Automated closed-loop insulin pump Studies are currently evaluating the safety and
efficacy of a fully automated closed loop system of insulin delivery based on continuous
glucose sensing, sometimes known as an "artificial pancreas." One small short-term study
reported near-normal glucose levels with the use of such a system [68], and another
reported reduction in nocturnal hypoglycemia [69]. A bihormonal version (using insulin
and glucagon) is also under development [70]. Trials of this type of system in adults and
children are described separately. (See "Management of blood glucose in adults with type
1 diabetes mellitus", section on 'Automated closed-loop insulin pump'.)

INSULIN Insulin therapy is the mainstay of treatment for type 1 diabetes mellitus. The
goal of insulin therapy is to replace the deficient hormone and to attain normoglycemia.
However, this goal remains elusive because of the difficulty in replicating the minute-to-
minute variations of physiologic insulin secretion and the difference in delivery of
exogenous insulin action compared with normal secretion of endogenous insulin directly
into the portal vein. The acute and chronic complications of diabetes are attributable to the
failure of exogenous insulin to completely mimic physiologic insulin secretion.
There are many different insulin preparations and delivery systems available. The selected
regimen is individualized for the child and family to fit their lifestyle and optimize
compliance while providing glycemic control. Input from the patient, if age appropriate, and
the family (eg, timing of meals and snacks, school/daycare, physical activity) is important
to ensure optimal glycemic control and minimize episodes of hypoglycemia. As a result,
the types of insulin and regimens used will vary among children and can change for an
individual child over time.

Preparations Insulin types can be classified by their onset and duration of action (table
4).

Rapid-acting (eg, lispro, aspart, glulisine) and/or short-acting insulins (eg, regular insulin)
are typically administered as a premeal bolus (typically 5 to 15 minutes before the meal for
the rapid-acting insulins, and 20 to 30 minutes before meals for the short-acting type)
based on (i) carbohydrate content of food and (ii) the blood glucose level. If necessary,
rapid-acting insulin can be administered after the meal in younger children in whom intake
is unpredictable. However, the goal should be to administer the insulin dose as soon as
the parent knows how many grams of carbohydrate the child will reliably eat, in order to
avoid carbohydrate-insulin mismatch and high followed by low blood glucose levels.
Rapid-acting insulins delivered by continuous subcutaneous infusion via an insulin pump
provide basal insulin levels. (See 'Insulin pump' below.)
Intermediate-acting Neutral Protamine Hagedorn (NPH) insulin is usually given two or
three times a day, but may be given in a targeted manner in combination with long-acting
insulins. Intermediate-acting insulin thus provides some coverage for meals (eg, NPH
insulin given before breakfast will cover lunch).
Long-acting insulin preparations (eg, insulin glargine and insulin detemir) are given once
or twice a day. In general, if a single injection is used, it should be given in the evening in
order to assure insulin availability during the night and suppress a counterregulatory
hormone response by morning. However, some small children who are at more risk of
hypoglycemia do better with administration in the morning hours.

The approximate time of onset, peak activity, and duration of action of the most commonly
used insulins are shown in the table (table 4). A more complete discussion on insulin
preparations is found separately. (See "Management of blood glucose in adults with type 1
diabetes mellitus", section on 'Choice of insulin regimen'.)

Insulin is administered by needle and syringe, pen, or pump. (See 'Insulin pump' below.)

Needle and syringe An advantage of needle and syringe is that NPH and short- or
rapid-acting insulins can be mixed in a single injection, thereby reducing the number of
injections. However, insulin glargine and detemir cannot be mixed with any other form of
insulin and must be administered separately. The smallest needle available is 31 gauge
and 6 mm (15/64") in length. Smaller needles are preferred for younger children. Syringes
are available in 30 (0.3 mL), 50 (0.5 mL), and 100 (1 mL) unit sizes. Thirty unit syringes
marked to administer half units are available.
Pens Pens are supplied pre-filled with insulin and may be either disposable or
reusable. The ease of use and portability of pens are appealing to many patients. The
smallest needle available is 32 gauge and 4 mm in length, and the smaller needles are
preferred for younger children. Although mixed insulin preparations are available in pens,
these are not tailored to the needs of children. Mixed insulin pens are usually reserved for
individuals who are limited in their ability to make dosing decisions and, as a result,
glycemia is not usually as strictly controlled. Pens that deliver aspart and lispro insulin are
available that offer the flexibility of half-unit delivery.

Value of an intensive regimen Insulin management can be categorized as "intensive"

or "conventional," depending on the frequency and type of insulin dosing. In general,
intensive regimens are recommended because they are more likely to meet glycated
hemoglobin (A1C) targets and have better clinical outcomes [4].

An intensive regimen provides insulin in a manner that more closely approaches

physiologic insulin secretion than does conventional therapy. It includes administration of
an insulin preparation that will maintain a basal insulin level and suppress lipolysis and
hepatic glucose production, with additional pre-meal and pre-snack boluses of rapid-acting
insulin to minimize postprandial elevation of blood glucose. These boluses are adjusted
according to the carbohydrate content of meals as well as the current blood glucose level.
This approach allows greater flexibility than the conventional regimen in terms of timing
and carbohydrate content of meals. Insulin regimens administered by an insulin pump are
also considered an intensive regimen. (See 'Insulin pump' below.)
Short-acting insulins are typically no longer included in the routine management of type 1
diabetes in the Unites States, but can be helpful under special circumstances such as
gastroparesis and intake of high fat meals, when mixed with rapid-acting insulin.
A conventional regimen was traditionally used for diabetes management, but this
approach is uncommon today because it is unlikely to achieve optimal glycemic control. It
included administration of an intermediate-acting insulin (NPH) at least twice a day (at
breakfast and a second dose either at dinner or bedtime), with a rapid-acting (ie, lispro,
aspart, or glulisine) or short-acting ("regular") insulin two or three times a day. The rapid- or
short-acting insulin would be given at breakfast and dinner, and sometimes at lunch or with
the afternoon snack depending on blood glucose concentrations. This regimen is fixed and
the patient and family must adjust their lifestyles so that meals and vigorous physical
activity occur on a relatively fixed daily schedule. Two-thirds of the total daily dose is
administered before breakfast (2/3 as NPH and 1/3 as rapid- or short-acting insulin) and
one-third before dinner and at bedtime (1/3 to 1/2 as rapid- or short-acting insulin before
dinner and 2/3 to 1/2 as NPH at bedtime). The dose of NPH can be split such that a
portion is delivered before dinner and the remainder at bedtime.
A modified-intensive regimen is sometimes used in children and offers the benefit of
fewer injections during school hours (useful when a school nurse is not available) and
flexibility around meals while at home. Such a regimen includes the administration of an
intermediate-acting insulin (NPH) with rapid-acting insulin (based on carbohydrate
counting) at breakfast, and insulin glargine or detemir with a dose of rapid-acting insulin
(based on carbohydrate counting) at dinner. This regimen avoids the need for a lunch-time
dose of rapid-acting insulin.

In adults, controlled studies such as the Diabetes Control and Complications Trial (DCCT)
have demonstrated that intensive insulin therapy achieved better glycemic control and
reduced the incidence of long-term sequelae, compared with conventional insulin therapy
(which utilized one or two fixed insulin injections, including mixtures of insulin) (figure
3 and figure 4).

In adolescents, controlled studies show similar improved glycemic control with intensive
therapy, as compared with conventional therapy [71,72]. As an example, among 195
adolescents (13 to 17 years of age) who participated in DCCT, intensive therapy improved
glycemic control and decreased the risk of retinopathy (RR 0.53, 95% CI 0.1 to 0.78) [72].
In addition, intensive therapy decreased the mean daily blood glucose level (177 31
versus 260 52 mg/dL) and decreased median A1C levels throughout the study.

Observational studies in children (age range from 1.9 to 19.6 years) have also reported
improved glycemic control with intensive therapy as compared with conventional insulin
regimens [73-76].

Types of intensive regimens An intensive regimen is delivered either by multiple daily

injections (MDI) or by continuous insulin infusion (pump). The choice of intensive regimen
is based upon patient, family, cost considerations, and clinician preferences.

Multiple daily injections The MDI regimen combines a baseline level of insulin using a
long-acting insulin analog (insulin glargine or detemir) with premeal/snack boluses of
rapid- or short-acting insulin. This approach results in more stable glycemic control and
fewer episodes of hypoglycemia than the conventional approach in children [71,73,74].
This was illustrated in a controlled cross-over trial of 28 adolescents with type 1 diabetes
that compared MDI using insulin glargine and lispro with conventional therapy using NPH
and regular insulin during two 16-week study periods [71], in which MDI compared with
conventional therapy resulted in lower mean fasting; pre- and post-breakfast, and pre- and
post-lunch blood glucose levels. In addition, the incidence of nocturnal hypoglycemia was
lower with MDI.

Pre-meal and pre-snack bolus doses of a rapid- or short-acting insulin are based upon
three factors:

Pre-meal blood glucose level

Estimated amount of carbohydrates to be consumed
Expected level of exercise after the meal
Exercise before the meal

Insulin glargine is the long-acting analog most commonly used in pediatric patients (table
4). It usually has a duration of action 24 to 26 hours, but the half-life is shorter in some
patients, requiring division of the daily dose into two injections per day.

Although the US Food and Drug Administration (FDA) has only approved insulin
glargine in children six years of age or older, the use of insulin glargine appears to be
beneficial in younger children as well. Observational studies in children younger than six
years of age have shown that the use of insulin glargine reduced the incidence of severe
hypoglycemic episodes [77-79] and improved glycemic control [78,79]. In a controlled
cross-over trial of 28 adolescents with type 1 diabetes, use of insulin glargine and lispro
resulted in a reduced incidence of nocturnal hypoglycemia compared with use of
conventional therapy with NPH and regular insulin [71]. These results are probably due to
the increased flexibility of this regimen in young children who have unpredictable patterns
of meal intake and variable levels of physical exercise.

MDI regimens using glargine in children should be carried out under the supervision of an
experienced pediatric diabetes team. Studies have explored the possibility of an
association between the use of glargine, which has a modified structure similar to insulin-
like growth factor 1 (IGF-1), and risk of malignancy. The results are not conclusive, and
most experts feel that this is not a concern [80,81].

Although many families choose an MDI regimen because of its increased flexibility
compared with a conventional regimen, MDI requires frequent blood glucose monitoring
and insulin injections. The patient and family also are required to count dietary
carbohydrates and accurately judge the effect of exercise on insulin requirements. Without
this active management by a well-trained patient and family, the benefits of this regimen
are not attained. Before initiation of MDI, the patient and family must understand and
accept the increased commitment and the need for increased frequency of blood
monitoring and insulin injections required by this therapeutic approach.

Insulin pump The insulin pump (continuous subcutaneous insulin infusion) is

increasingly used in the pediatric population. In 2006, there were more than 35,000
patients younger than the age of 21 years who received insulin therapy through a pump
system [82]. A position statement of the American Diabetes Association (ADA), European
Society for Pediatric Endocrinology, and others recommends that insulin pump therapy
should be considered for patients with one or more of the following characteristics [83]:

Recurrent severe hypoglycemia

Wide fluctuations in blood glucose levels (regardless of A1C)
Suboptimal diabetes control (A1C exceeds target range for age)
Microvascular complications and/or risk factors for macrovascular complications
Good metabolic control, but insulin regimen that compromises lifestyle
Other situations in which the insulin pump may be helpful include young children and
infants, adolescents with eating disorders, pregnant adolescents, ketosis-prone
individuals, and competitive athletes [83].

Insulin pumps deliver a basal rate (small aliquots every few minutes, evenly spaced over
an hour) of either rapid- or short-acting insulin subcutaneously. The rate of insulin
administration can be transiently increased to give mealtime or glucose correction boluses.
Most insulin pump therapy is now started with a rapid-acting insulin, rather than short-
acting insulin. Pre-meal/snack boluses are administered to minimize increases in
postprandial glucose concentrations. Insulin is delivered through a subcutaneously
inserted catheter that is replaced at two- to three-day intervals. Information on insulin
administration, frequency of catheter site changes, and frequency and timing of premeal
insulin boluses can be downloaded from a memory chip within the pump.

Currently, insulin pump therapy relies on frequent blood glucose monitoring with
appropriate readjustment of insulin infusion rates either by the patient or parent. The pump
also can be used in conjunction with a continuous glucose monitoring device; this
approach is known as sensor-augmented insulin pump therapy. Fully "closed loop"
systems are in development, in which blood glucose values are determined and
automatically used to reprogram the insulin pump. (See 'Continuous glucose
monitoring' above and "Management of blood glucose in adults with type 1 diabetes
mellitus", section on 'Automated closed-loop insulin pump'.)

Data from controlled studies in adults demonstrate the superiority of intensive therapy
compared with conventional therapy in achieving glycemic control and reducing the
incidence of long-term sequelae. In addition, one meta-analysis has reported that
continuous insulin infusion (pump therapy) appears to provide slightly better glycemic
control and decreased hypoglycemia than MDI. (See "Management of blood glucose in
adults with type 1 diabetes mellitus", section on 'Continuous subcutaneous insulin infusion
(insulin pump)'.)

Controlled trials of insulin pump therapy in children and adolescents generally suggest that
it is similar to or somewhat better than MDI in achieving glycemic control and avoiding
hypoglycemic episodes [82,84-89]. The following reports describe some of the beneficial
effects of insulin pump therapy:

A randomized controlled trial of 32 children demonstrated that insulin pump therapy

compared with MDI resulted in lower A1C levels (7.2 versus 8.1 percent) [90].
A meta-analysis of six randomized controlled trials revealed lower A1C levels and
reduction of daily insulin doses in children using the insulin pump as compared with those
using MDI [91].
A meta-analysis reported a reduction in severe hypoglycemia in patients using the insulin
pump compared with MDI [92].
Beneficial use of insulin pump therapy has been reported in children as young as two
years of age [75,84,93,94].
Insulin pump therapy is often preferred by children and their families. MDI regimens can
require as many as six to seven injections per day, which may be a barrier for some
patients and families. An insulin pump can be an attractive option for intensive therapy at
any age and appears to improve quality of life [84,94-96]. Of note, most families with
young children who participated in clinical studies decided to continue with pump therapy
even after the study was completed [85].

Many families choose the insulin pump because of its increased flexibility, particularly with
regards to meals and socialization [97], but similar to MDI therapy, continuous insulin
infusion therapy requires increased blood glucose monitoring, counting dietary
carbohydrates, judging the impact of exercise on insulin requirements, and making the
appropriate adjustments to insulin infusion rates. Without this increased commitment, the
benefits of this regimen are not attained. Before initiation of insulin pump therapy, the
patient and family must be informed and accept the increased work required by this
therapeutic approach. The beneficial effect of the insulin pump is maintained only if the
child and family continue to devote time to carbohydrate counting and determining
appropriate insulin boluses at mealtime.

Other considerations regarding the choice of regimen include the greater cost of the pump
and its supplies compared with those of syringes and needles used in MDI therapy, as well
as the complications of pump therapy, such as infusion pump failure, superficial infection,
and minor dermatologic changes such as nodules or scars at the catheter site [98,99].
Because rapid- or short-acting insulin is used alone in insulin pumps and patients have no
long-acting subcutaneous depot of insulin, pump failure can result in rapid onset of
diabetic ketoacidosis (DKA). This is another reason why frequent blood glucose checking
is mandated in children on insulin pump therapy [100].

Although multiple studies have demonstrated an improvement of diabetes control with the
insulin pump compared with MDI, decreased adherence to the pump protocol can occur
over time and is associated with deterioration in control. Parental involvement during this
time may help offset this risk in adolescents [101].

Dose Insulin requirement is based upon the body weight, age, and pubertal stage of the
child. In general, the newly diagnosed child requires an initial total daily insulin dose of 0.5
to 1.0 units/kg. Prepubertal children usually require lower doses, and the dose requirement
may be as low as 0.25 units/kg for a variable period following diagnosis. Higher doses are
needed in pubertal children, patients in ketoacidosis, or in patients receiving glucocorticoid
therapy.

In infants and toddlers who receive their insulin by syringe, the insulin dose may be so
small that dilution is required to allow for easier and more precise administration. The
smallest dose of insulin that can be accurately administered without dilution using a
syringe is 0.5 units. Many insulins can be diluted either at a specialized pharmacy or at
home with proper training. Specific diluent for many insulin preparations is available from
the insulin manufacturer. Some insulin pumps can deliver much smaller doses of insulin, of
the order of 0.025 units at a time, often obviating this problem.

Follow-up visits at least every three months are required to adjust for the increasing insulin
requirement with continued growth of the child and increasing insulin deficiency with
duration of diabetes. The family can be taught to make interim adjustments via telephone
consultation. As a child enters puberty, daily insulin requirements may increase to more
than 1 unit/kg because puberty increases insulin resistance [102].

Balance of insulins To use the different types of insulin in intensive therapy, the
various functions of exogenous insulin need to be considered.

Basal insulin In children, the basal insulin requirement (eg, insulin glargine or basal rate
of pump) usually is approximately 40 to 50 percent of the total daily dose.
Correction of elevated blood glucose An insulin correction factor can be used to select
an insulin dose to correct hyperglycemia before meals or between meals. For rapid-acting
insulin, divide 1500 by the total daily insulin dose. This calculation estimates the decrease
in blood glucose from one unit of a rapid-acting insulin. As an example, if the total daily
insulin dose is 30 units, then 1 unit of rapid-acting insulin will decrease the blood glucose
approximately by 50 mg/dL.
Utilization of ingested carbohydrate A rapid-acting insulin pre-meal or pre-snack is used
to provide the insulin requirements for the anticipated consumption of carbohydrates. The
amount of ingested carbohydrate covered by one unit of rapid-acting insulin is roughly
calculated based upon the total daily insulin dose and dividing this into 500. As an
example, if the total daily insulin dose is 50 units, then 1 unit of rapid-acting insulin will
cover 10 grams of carbohydrate. For short-acting (regular) insulin (rarely used in MDI or
pump regimens), divide 450 by the total daily insulin dose. However, there is a wide range
of insulin to carbohydrate ratios, with more insulin being required in older children and less
in younger children than indicated by these calculations.

On average, 1 unit of insulin is required to cover:

20 grams of carbohydrates in most young children (1 to 6 years of age)
10 to 12 grams of carbohydrates in older prepubertal children
8 to 10 grams in pubertal adolescents

Honeymoon phase A few weeks after the diagnosis and initiation of insulin therapy, a
period of decreasing exogenous insulin requirement occurs, commonly referred to as the
"honeymoon" or remission phase of diabetes. During this period, the remaining functional
beta cells secrete some endogenous insulin resulting in reduced exogenous requirement.
Close monitoring of blood glucose is mandatory as hypoglycemic episodes are likely if the
insulin dose is not appropriately adjusted. The duration of this phase is variable and may
last several months to several years. Rising blood glucose levels, A1C, and increasing
exogenous insulin need indicates the end of this phase.

Converting from MDI to insulin pump therapy When converting a patient from MDI
or conventional therapy to insulin pump, the initial dose is dependent on diabetes control
and total daily insulin dose. If control has been excellent, the initial daily insulin pump dose
is 10 to 20 percent less than the previous dose. If control has been poor, the same total
previous daily dose should be used. One study suggests patients using detemir insulin
may require greater dose reductions (26 to 33 percent) when switching from MDI to the
insulin pump [103]. More sophisticated approaches to control of postprandial
hyperglycemia include administration of bolus insulin as a dual wave and as a square
wave, prolonging its action [91,104]. For dual wave administration, the mealtime insulin
dose is divided into a bolus followed by a continuous infusion over two hours; this is useful
for meals with varied glycemic content, and especially high fat. For square wave
administration (also known as extended bolus), the dose of insulin is given as a continuous
infusion over two hours; this is useful for snacking over an extended period of time, as
might occur in social settings. (See 'Insulin pump' above.)

OTHER MANAGEMENT ISSUES Other issues that need to be addressed in the

management of children and adolescents with type 1 diabetes include nutrition, exercise,
and psychosocial factors that impact on glycemic control.

Nutrition Prescriptive nutritional therapy depends in large part on the choice of insulin
regimen. Ideally, meal planning should provide a consistent carbohydrate intake. This is
especially true for children on a conventional fixed insulin regimen who require a nutritional
prescription. Meal planning must be individualized to accommodate the child's food
preference and cultural eating patterns and schedules. In young children, mealtime
behaviors and eating habits may complicate bolus insulin therapy because of failure to
completely finish food and picky eating habits [106].

Many patients have experienced weight loss when diabetes is first diagnosed. The lost
weight is generally regained during the first few weeks of therapy due to insulin, hydration,
and adequate energy intake. During this time of increased consumption, children often
require large amounts of insulin to control their blood glucose levels. After the weight loss
is corrected, ongoing assessment of growth (eg, weight, height, body mass index [BMI]) is
necessary to monitor adequacy of dietary intake and glycemic control [107].

Excellent glycemic control is necessary for normal growth and development [108]. Excess
insulin administration, or failure to reduce insulin dose post puberty or after initial regain of
weight, may lead to excessive weight gain as the child attempts to treat hypoglycemia by
overeating. If the child becomes overweight, caloric intake or insulin administration may
need to be reduced [4].
Consultation with a registered dietitian with experience in pediatric nutrition and diabetes is
an important component of diabetes care [4]. The dietitian provides instruction regarding
the effect of food on blood glucose concentration, a diet that ensures adequate nutritional
intake, and information regarding carbohydrate counting. Mastery of carbohydrate
counting and understanding the glycemic effects of different kinds of carbohydrates is
especially important in patients on an intensive regimen, who need to adjust pre-meal
boluses insulin based upon the anticipated glycemic effect of consumed carbohydrates.
The glycemic effect also depends on the balance among carbohydrates, fats, and proteins
in a given meal. (See 'Balance of insulins' above.)

Nutrition management including consistency of carbohydrate intake, carbohydrate

counting, and glycemic content and index is discussed in greater detail separately.
(See "Nutritional considerations in type 1 diabetes mellitus".)

Exercise Regular exercise has important health and social benefits for children and
adolescents with type 1 diabetes mellitus and should be encouraged. Exercise also
presents several important challenges, which require careful management. In patients with
diabetes, the intensity and duration of exercise affects the physiologic response and risk
for hypoglycemia. Hypoglycemia can occur during or immediately after exercise, or be
delayed by several hours. The physiologic response to exercise also depends upon the
plasma insulin concentration at the time of exercise. Exercise also can trigger
hyperglycemia under certain circumstances. (See "Management of exercise for children
and adolescents with type 1 diabetes mellitus", section on 'Clinical consequences'.)

Children who participate in sport activities require increased monitoring of blood glucose
(before, after, and at regular intervals during prolonged strenuous activity) and appropriate
adjustment of insulin dosing. School personnel and coaches need to recognize symptoms
of hypoglycemia and know how to treat hypoglycemia. At the beginning of a new sports
season, frequent blood glucose monitoring during the 12 hours after physical activity
should be performed to guide insulin dose adjustment as insulin requirements will
decrease during this period. Afternoon or evening exercise may cause hypoglycemia later
that night. Therefore, it is prudent for patients to check blood glucose during the overnight
period after strenuous exercise. (See "Management of exercise for children and
adolescents with type 1 diabetes mellitus".)

Psychosocial issues We suggest routinely assessing for depression, anxiety, school

absences, family conflict, and other mental health challenges during most routine visits for
diabetes care. This is especially important for children 10 years and older and for those
who are not adhering to the diabetes management regimen. Patients with significant
depression or other concerns should be referred for evaluation by a mental health
specialist. (See 'Referrals' below.)
Diabetes has a psychological impact on the patient and family, as do other chronic
diseases. Depression and anxiety are common in older children, and adolescents with
diabetes and their parents [24,25,109,110]; adolescents are at risk for an eating disorder.
In older children and adolescents, family conflict arises over the level of adult involvement
in the care of the patient during a normal developmental period of increasing
independence and self-assertiveness. These psychological issues lead to poorer glycemic
control and an increased risk of hospitalization and episodes of diabetic ketoacidosis
(DKA) [111-113]. (See 'Adolescents' above and "Complications and screening in children
and adolescents with type 1 diabetes mellitus", section on 'Psychiatric disorders'.)

In addition, socioeconomic factors such as single-parent families, poor socioeconomic

status, and chronic physical or mental health problems in a parent or other close family
member are associated with poorer diabetes control and increased hospitalizations
[4,49,111,114-116]. As an example, one study from New Zealand reported that Maori or
Pacific ethnicity and social deprivation are independent predictors of poor metabolic
control in type 1 diabetes [117].

Comprehensive management of diabetes that addresses these psychosocial issues can

improve glycemic control and reduce hospitalization even in the high-risk adolescent. In
two controlled studies, structured psychoeducational support significantly improved
glycemic control and reduced hospital admission rates in previously poorly controlled
adolescents [12,13]. Additionally, psychological screening of newly diagnosed patients with
type 1 diabetes may help identify families at risk for poor adherence and poor diabetes
control [118]. (See "Complications and screening in children and adolescents with type 1
diabetes mellitus", section on 'Psychiatric disorders'.)

Factors associated with better health-related quality of life in children and adolescents with
diabetes include later age at onset, fewer hyperglycemic episodes, lower glycated
hemoglobin (A1C), older age, and the male gender [119].

Parental and caregiver involvement Several studies have examined the role of the
family's attitudes and support systems in determining the quality of diabetes management:

Stressors and support systems for parents Parental fatigue ("burn-out") can
increase the risk for poor control, and predictors of burn-out in a parent include low
self-esteem, inadequate social support, high need for control, lack of leisure time,
financial concerns, and the perception that the child's disease affects everyday life
[120]. Another study reported that involvement of the father in diabetes care was
important for diabetes management in adolescents [121].

Parenting style One study reported that diabetes control in children is optimized by
an authoritative parenting style, in which the parents set clear and consistent
expectations, but are also responsive to the child's opinions and needs [121].
 Similarly, adolescents who perceive greater sharing of responsibility for diabetes care
with their caregivers are more likely to engage in better management of diabetes
[122]. One study reported an improvement in A1C levels and an improvement in
quality of life responses in adolescents with type 1 diabetes who chose to participate
in physician moderated chat sessions [123].

Immunizations Patients with diabetes should be given the following immunizations:

All standard childhood immunizations, on a standard schedule. (See "Standard

immunizations for children and adolescents", section on 'Overview'.)

Annual influenza vaccine (also recommended for all individuals six months of age
and older). Children with diabetes should receive the inactivated (injectable) vaccine
rather than the live attenuated (intranasal) form of the vaccine. (See "Seasonal
influenza in children: Prevention with vaccines", section on 'Target
groups' and "Seasonal influenza in children: Prevention with vaccines", section on
'Choice of vaccine'.)

Pneumococcal vaccine. Children with diabetes should receive the pneumococcal

conjugate vaccine, which is recommended for all children. They should also be given
the pneumococcal polysaccharide vaccine because they are considered to be at high
risk for invasive pneumococcal disease. (See "Pneumococcal (Streptococcus
pneumoniae) conjugate vaccines in children" and "Pneumococcal (Streptococcus
pneumoniae) polysaccharide vaccines in children", section on 'Indications'.)

There is no evidence for an association between immunizations and the development of

type 1 diabetes. (See "Autism and chronic disease: No evidence for vaccines as a
contributing factor", section on 'Type 1 diabetes mellitus'.)

FOLLOW-UP The frequency of follow-up visits is tailored to the needs of the child and
family. Visits are more frequent during the initial educational phase, when the patient and
family require intensive training in self-care management, and during periods when
adjustment of glycemic control and insulin dose are problematic. More frequent visits are
also necessary when major changes in insulin regimen are made (eg, commencing insulin
pump therapy).

Once the family is well trained and a management plan is established and stable, we
recommend follow-up at least every three months to review glycemic control and adjust
management as needed [4]. However, families must be trained to perform interim
adjustments and to contact the diabetes team for assistance in adjustment of insulin
dosing between visits.
Routine monitoring Routine follow-up should be performed at least four times a year
and includes the following (table 5A) [4]:

Physical examination

Height and weight Monitor for normal growth, with vigilance for weight gain that is
either insufficient or excessive.

Blood pressure Screen for hypertension.

Pubertal assessment Identify the patient's stage of puberty to anticipate changes

in insulin requirements; insulin resistance and insulin requirements increase in early
puberty.

Thyroid Check for thyroid enlargement to screen for autoimmune hypothyroidism,

a condition that is associated with type 1 diabetes. (See "Associated autoimmune
diseases in children and adolescents with type 1 diabetes mellitus", section on
'Autoimmune thyroiditis'.)

Skin Examine the child's usual insulin injection sites for evidences of
lipohypertrophy or atrophy that can alter insulin absorption rates. Also examine the
sites used for blood glucose monitoring to make sure there is no skin irritation.

Eyes A general eye examination is an appropriate part of the routine evaluation.

However, a funduscopic examination without dilation of the pupils is of little value as a
screen for retinopathy because diabetic retinopathy usually starts at the periphery of
the retina. Therefore, all patients should have regularly scheduled dilated funduscopic
examinations, as discussed below. (See 'Referrals' below.)

Extremities A foot examination should be performed annually in children 10 years

of age. As the disease duration increases, extremity examination for evidence of
limited joint mobility (sclerodactyly, joint or finger stiffness) or peripheral neuropathy
(feet). (See "Musculoskeletal complications in diabetes mellitus" and "Clinical
manifestations and diagnosis of diabetic polyneuropathy".)

Laboratory evaluation Laboratory evaluation includes evaluation of glycemic control

and screening for long-term sequelae (table 5A):

A1C, to evaluate glycemic control Perform every three months.

Urine albumin-to-creatinine ratio in a spot specimen, to screen for nephropathy

Perform annually beginning when the child is 10 years old (or at onset of puberty if
earlier), and has had diabetes for five years. A normal albumin/creatinine result is
<30 mg/g (<3.4 mg/mmol).

Celiac disease screening Perform a celiac-specific antibody test (eg, tissue

transglutaminase, tTG), at diagnosis [4]. We suggest repeating the screen
approximately every two to three years thereafter, or if suggestive symptoms develop
(eg, gastrointestinal symptoms or unexplained hypoglycemia). The optimal frequency
of testing thereafter has not been established, but the majority of cases of celiac
disease are diagnosed within the first five years after the diabetes is diagnosed [124].

Lipid profile, to screen for dyslipidemia (as recommended in the ADA guidelines
(table 5B)) Initiate screening at age 10 years (or onset of puberty begins if earlier).
Perform earlier for children with risk factors for cardiovascular disease, including
obesity or a family history of early cardiovascular disease.

If results are normal (low-density lipoprotein [LDL] <100 mg/dL), repeat the
screen every five years.

If results are abnormal, screen annually.

If the initial screen is normal but the child's diabetes is in poor control (eg, A1C
>9 percent), we suggest screening at least every two years because children
who are in poor glycemic control may manifest new lipid abnormalities.

Thyroid stimulating hormone (TSH), to screen for autoimmune hypothyroidism

Perform every one or two years, or if features of hypothyroidism, or if an enlarged
thyroid are evident.