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Diabetes in Children and Adolescents
Diabetes mellitus involves absence of insulin secretion (type 1) or peripheral insulin resistance (type 2), causing hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia, polyphagia, polyuria, and weight loss. Diagnosis is by measuring plasma glucose levels. Treatment depends on type but includes drugs that reduce blood glucose levels, diet, and exercise.
(See also Diabetes Mellitus in adults.)
The types of diabetes mellitus (DM) in children are similar to those in adults, but psychosocial problems are different and can complicate treatment.
Type 1 DM is the most common type in children, accounting for two thirds of new cases in children of all ethnic groups. It is one of the most common chronic childhood diseases, occurring in 1 in 350 children by age 18; the incidence has recently been increasing, particularly in children < 5 yr. Although type 1 can occur at any age, it typically manifests between age 4 yr and 6 yr and between 10 yr and 14 yr.
Type 2 DM, once rare in children, has been increasing in frequency in parallel with the increase in childhood obesity (see obesity in children and see Obesity in Adolescents). It typically manifests after puberty, with the highest rate between age 15 yr and 19 yr.
Monogenic forms of diabetes, previously termed maturity-onset diabetes of youth (MODY), are not considered type 1 or type 2 (although they are sometimes mistaken for them) and are uncommon (1 to 4% of cases).
Prediabetes is impaired glucose regulation resulting in intermediate glucose levels that are too high to be normal but do not meet criteria for diabetes. In obese adolescents, prediabetes may be transient (with reversion to normal in 2 yr in 60%) or progress to diabetes, especially in adolescents who persistently gain weight. Prediabetes is associated with the metabolic syndrome (impaired glucose regulation, dyslipidemia, hypertension, obesity).
There appears to be a familial component to all types of DM in children, although the incidence and mechanism vary.
In type 1 DM, the pancreas produces no insulin because of autoimmune destruction of pancreatic beta-cells, possibly triggered by an environmental exposure in genetically susceptible people. Close relatives are at increased risk of DM, with overall incidence 10 to 13% (30 to 50% in monozygotic twins). Children with type 1 DM are at higher risk of other autoimmune disorders, particularly thyroid disease and celiac disease. Inherited susceptibility to type 1 DM is determined by multiple genes (> 60 risk loci have been identified). Susceptibility genes are more common among some populations and explain the higher prevalence of type 1 DM in certain ethnic groups (eg, Scandinavians, Sardinians).
In type 2 DM, the pancreas produces insulin, but there are varying degrees of insulin resistance and insulin secretion is inadequate to meet the increased demand caused by insulin resistance (ie, there is relativeinsulin deficiency). Onset often coincides with the peak of physiologic pubertal insulin resistance, which may lead to symptoms of hyperglycemia in previously compensated adolescents. The cause is not autoimmune destruction of beta-cells but rather a complex interaction between many genes and environmental factors, which differ among different populations and patients. Risk factors include
Monogenic forms of diabetes are caused by genetic defects that are inherited in an autosomal dominant pattern, so patients typically have one or more affected family members. There is no insulin resistance or autoimmune destruction of beta-cells. Onset is usually before age 25 yr.
In type 1 DM, lack of insulin causes hyperglycemia and impaired glucose utilization in skeletal muscle. Muscle and fat are then broken down to provide energy. Fat breakdown produces ketones, which cause acidemia and sometimes a significant, life-threatening acidosis (diabetic ketoacidosis [DKA]).
In type 2 DM, there is usually enough insulin function to prevent DKA at diagnosis, but children can sometimes present with DKA (up to 25%) or, less commonly, hyperglycemic hyperosmolar state (HHS), in which severe hyperosmolar dehydration occurs. HHS most often occurs during a period of stress or infection, with nonadherence to treatment regimens, or when glucose metabolism is further impaired by drugs (eg, corticosteroids). Other metabolic derangements associated with insulin resistance include
Atherosclerosis begins in childhood and adolescence and markedly increases risk of cardiovascular disease.
In monogenic forms of DM, the underlying defect depends on the type. The most common types are caused by defects in transcription factors that regulate pancreatic beta-cell function (eg, hepatic nuclear factor 4-alpha [HNF-4-α] and hepatic nuclear factor 1-alpha [HNF-1-α]). In these types, insulin secretion is impaired but not absent, there is no insulin resistance, and hyperglycemia worsens with age. Another type of monogenic DM is caused by a defect in the glucose sensor, glucokinase. With glucokinase defects, insulin secretion is normal but glucose levels are regulated at a higher set point, causing fasting hyperglycemia that worsens minimally with age.
In type 1 DM, initial manifestations vary from asymptomatic hyperglycemia to life-threatening DKA. However, most commonly, children have symptomatic hyperglycemia without acidosis, with several days to weeks of urinary frequency, polydipsia, and polyuria. Polyuria may manifest as nocturia, bed-wetting, or daytime incontinence; in children who are not toilet-trained, parents may note an increased frequency of wet or heavy diapers. About half of children have weight loss as a result of increased catabolism and also have impaired growth. Fatigue, weakness, candidal rashes, blurry vision (due to the hyperosmolar state of the lens and vitreous humor), and/or nausea and vomiting (due to ketonemia) may also be present initially.
In type 2 DM, children are often asymptomatic and their condition may be detected only on routine testing. However, some children present with symptomatic hyperglycemia, HHS, or, despite the common misconception, DKA.
Diabetic ketoacidosis is common among patients with known type 1 DM; it develops in about 1 to 10% of patients each year, usually because they have not taken their insulin. Other risk factors for DKA include prior episodes of DKA, difficult social circumstances, depression or other psychiatric disturbances, intercurrent illness, and use of an insulin pump (because of a kinked or dislodged catheter, poor insulin absorption due to infusion site inflammation, or pump malfunction). Clinicians can help minimize the effects of risk factors by providing education, counseling, and support.
Psychosocial problems are very common among children with diabetes and their families. Up to half of children develop depression, anxiety, or other psychologic problems (see Overview of Mental Disorders in Children and Adolescents). Eating disorders are a serious problem in adolescents, who sometimes also skip insulin doses in an effort to control weight. Psychosocial problems can also result in poor glycemic control by affecting children's ability to adhere to their dietary and/or drug regimens. Social workers and mental health professionals (as part of a multidisciplinary team) can help identify and alleviate psychosocial causes of poor glycemic control.
Vascular complications rarely are clinically evident in childhood. However, early pathologic changes and functional abnormalities may be present a few years after disease onset. Microvascular complications include diabetic nephropathy, retinopathy, and neuropathy. Macrovascular complications include coronary artery disease, peripheral vascular disease, and stroke. Although neuropathy is more common among children who have had diabetes for a long duration (≥ 5 yr) and poor control (glycosylated Hb [HbA1c] > 10%), it can happen in young children who have had diabetes for a short duration and good control.
(For recommendations about diagnosis, see also the American Diabetes Association's standards in medical care in diabetes and the International Society for Pediatric and Adolescent Diabetes' (ISPAD) guidelines for type 2 diabetes in children and adolescents.)
Diagnosis of DM and prediabetes is similar to that in adults, typically using fasting or random plasma glucose levels and/or HbA1c levels, and depends on the presence or absence of symptoms (see Table: Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation). Diabetes may be diagnosed with the presence of classic symptoms of diabetes and blood glucose measurements (random plasma glucose ≥ 200 mg/dL ( ≥ 11.1 mmol/L) or fasting plasma glucose ≥ 126 mg/dL (≥ 7.0 mmol/L); fasting is defined as no caloric intake for 8 h).
An oral glucose tolerance test is not required and should not be done if diabetes can be diagnosed by other criteria. When needed, the test should be done using 1.75 g/kg (maximum 75 g) glucose dissolved in water. The test may be helpful in children without symptoms or with mild or atypical symptoms and may be helpful in suspected cases of type 2 or monogenic DM. The HbA1c criterion is typically more useful to diagnose type 2 DM, and hyperglycemia should be confirmed.
Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation
For patients suspected of having diabetes but who do not appear ill, initial testing should include a basic metabolic panel, including electrolytes and glucose, and urinalysis. For ill patients, testing also includes a venous or arterial blood gas, liver function tests, and calcium, magnesium, phosphorus, and Hct levels.
Additional tests should be done to confirm the type of diabetes, including
Autoantibodies include glutamic acid decarboxylase, insulin, insulinoma-associated protein, and zinc transporter ZnT8. More than 90% of patients with newly diagnosed type 1 DM have ≥ 1 of these autoantibodies, whereas the absence of antibodies strongly suggests type 2 DM. However, about 10 to 20% of children with the type 2 DM phenotype have autoantibodies and are reclassified as type 1 DM, because such children are more likely to require insulin therapy and are at greater risk of developing other autoimmune disorders.
Monogenic diabetes is important to recognize because treatment differs from type 1 DM and type 2 DM. The diagnosis should be considered in children with a strong family history of diabetes but who lack typical features of type 2 DM; that is, they have only mild fasting (100 to 150 mg/dL) or postprandial hyperglycemia, are young and nonobese, and have no autoantibodies or signs of insulin resistance (eg, acanthosis nigricans). Genetic testing is available to confirm monogenic diabetes. This testing is important because some types of monogenic DM can progress with age.
Patients with type 1 DM should be tested for other autoimmune disorders by measuring celiac disease antibodies (see Celiac Disease : Diagnosis), thyroid-stimulating hormone, thyroxine, and thyroid antibodies (see Overview of Thyroid Function : Laboratory Testing of Thyroid Function).
Patients with type 2 DM should have liver function tests, fasting lipid profile, and urine microalbumin:creatinine ratio done at the time of diagnosis because such children (unlike those with type 1 DM, in whom complications develop over many years) often have comorbidities, such as fatty liver, hyperlipidemia, and hypertension, at diagnosis. Children with clinical findings suggestive of complications should also be tested:
Asymptomatic children (≤ 18 yr) who are at risk should be screened for type 2 diabetes or prediabetes by measuring HbA1c. This test should first be done at age 10 yr or at onset of puberty, if puberty occurred at a younger age, and should be repeated every 3 yr.
Children at risk include those who are overweight (BMI > 85th percentile for age and sex, weight for height > 85th percentile, or weight > 120% of ideal body weight) and who have any 2 of the following:
Family history of type 2 DM in 1st- or 2nd-degree relative
Native American, black, Hispanic, Asian American and Pacific Islander heritage
Maternal gestational diabetes or maternal history of diabetes
Intensive education and treatment in childhood and adolescence may help achieve treatment goals, which are to normalize blood glucose levels while minimizing the number of hypoglycemic episodes and to prevent or delay the onset and progression of complications. (For recommendations about treatment, see also the American Diabetes Association's standards in medical care in diabetes and the International Society for Pediatric and Adolescent Diabetes' (ISPAD) guidelines for type 2 diabetes in children and adolescents.)
Lifestyle modifications that benefit all patients include
In general, the term diet should be avoided in favor of meal plan or healthy food choices. The main focus is on encouraging heart-healthy diets low in cholesterol and saturated fats.
In type 1 DM, the popularity of basal–bolus regimens and the use of carbohydrate counting (parents estimate the amount of carbohydrate in an upcoming meal and use that amount to calculate the preprandial insulin dose) has changed meal plan strategies. In this flexible approach, food intake is not rigidly specified. Instead, meal plans are based on the child's usual eating patterns rather than on a theoretically optimal diet to which the child is unlikely to adhere, and insulin dose is matched to actual carbohydrate intake. The insulin:carbohydrate ratio is individualized but varies with age. A good rule of thumb for age is
In type 2 DM, patients should be encouraged to lose weight and thus increase insulin sensitivity. A good rule of thumb to determine the amount of calories needed by a child age 3 to 13 yr is 1000 calories + (100 × child's age in yr). Simple steps to improve the diet and manage caloric intake include
Eliminating sugar-containing drinks and foods made of refined, simple sugars (eg, processed candies and high fructose corn syrups)
Discouraging skipping meals
Avoiding grazing on food throughout the day
Controlling portion size
Limiting high-fat, high-calorie foods in the home
Increasing fiber intake by eating more fruits and vegetables
Insulin is the cornerstone of management of type 1 DM. Available insulin formulations are similar to those used in adults (see Table: Onset, Peak, and Duration of Action of Human Insulin Preparations*). Insulin should be given before a meal, except in young children whose consumption at any given meal is difficult to predict. Dosing requirements vary by age, activity level, pubertal status, and length of time from initial diagnosis. Within a few weeks of initial diagnosis, many patients have a temporary decrease in their insulinrequirements because of residual beta-cell function (honeymoon phase). This honeymoon phase can last from a few months up to 2 yr, after which insulin requirements typically range from 0.7 to 1 unit/kg/day. During puberty, patients require higher doses (up to 1.5 units/kg/day) to counteract insulin resistance caused by increased pubertal hormone levels.
Types of insulin regimens include
A basal-bolus regimen is typically preferred. In this regimen, children are given a daily baseline dose of insulin that is then supplemented by doses of short-acting insulin before each meal based on anticipated carbohydrate intake and on measured glucose levels. The basal dose can be given as a once/day injection (sometimes q 12 h for younger children) of a long-acting insulin (glargine or detemir) or as a continuous infusion of rapid-acting insulin (usually aspart or lispro) using an insulin pump, which delivers insulin continuously through a catheter placed under the skin. The supplemental boluses are given as separate injections of rapid-acting insulin or by using the insulin pump. Glargine or detemir injections are typically given at dinner or bedtime and must not be mixed with short-acting insulin. The basal dose helps keep blood glucose levels in range between meals and at night. Using an insulin pump to deliver the basal dose allows for maximal flexibility; the pump can be programmed to give different rates at different times throughout the day and night. A basal–bolus regimen may not be an option if adequate supervision is not available, particularly if an adult is not available to give daytime injections at school or daycare.
An MDI regimen can be used if a basal–bolus regimen is not an option (eg, because the family needs a simpler regimen, the child or parents have a needle phobia, lunchtime injections cannot be given at school or daycare). In this regimen, children usually receive neutral protamine Hagedorn (NPH) insulin before eating breakfast and dinner and at bedtime and receive rapid-acting insulin before eating breakfast and dinner. Because NPH and rapid-acting insulin can be mixed, this regimen provides fewer injections than the basal–bolus regimen and may be preferred by younger children. However, this regimen provides less flexibility and requires a set daily schedule for meals and snack times.
Premixed insulin regimens use preparations of 70/30 (70% insulin aspart protamine/30% regular insulin) or 75/25 (75% insulin lispro protamine/25% insulin lispro). Premixed regimens are not a good choice but are simpler and may improve adherence because they require fewer injections. Children are given set doses twice daily, with two thirds of the total daily dose given at breakfast and one third at dinner. However, premixed regimens provide much less flexibility with respect to timing and amount of meals and are less precise than other regimens because of the fixed ratios.
Clinicians should use the most intensive management program children and their family can adhere to in order to maximize glycemic control and thus reduce the risk of long-term vascular complications.
Plasma glucose targets (see Table: Glucose and HbA1c Target Levels) are established to balance the need to normalize glucose levels with the risk of hypoglycemia. Patients beyond the honeymoon phase should try to have ≥ 50% of blood glucose levels in the normal range (70 to 180 mg/dL [3.9 to 10 mmol/L]) and < 10% below range.
HbA1ctargets were previously higher for younger children (< 8.5%) but recently, a target of < 7.5% was recommended for all patients < 18 yr to reduce risk of harm from prolonged hyperglycemia in childhood. However, many children and adolescents do not meet this target. An increased frequency of self-monitoring of blood glucose levels is associated with improved HbA1c levels because patients are better able to adjust insulin for meals, have an improved ability to correct hyperglycemic values, and are potentially able to detect hypoglycemia earlier, which prevents overcorrection (ie, excessive carbohydrate intake as treatment for hypoglycemia, resulting in hyperglycemia).
Treatment goals should be individualized based on patient age, diabetes duration, comorbid conditions, and psychosocial circumstances. The risk of hypoglycemia in children who have hypoglycemia unawareness or lack the maturity to recognize the symptoms of hypoglycemia can limit aggressive attempts to achieve treatment goals.
Glucose and HbA1c Target Levels
Hypoglycemia is a critical but common complication in children treated with an intensive insulin regimen. Most children have several mild hypoglycemic events per week and self-treat with 15 g of fast-acting carbohydrates (eg, 4 oz of juice, glucose tablets, hard candies, graham crackers, or glucose gel).
Severe hypoglycemia, defined as an episode requiring the assistance of another person to give carbohydrates or glucagon, occurs in about 30% of children each year, and most will have had such an episode by age 18. Oral carbohydrates may be tried, but glucagon 1 mg IM is usually used if neuroglycopenic symptoms (eg, behavioral changes, confusion, difficulty thinking) prevent eating or drinking. If untreated, severe hypoglycemia can cause seizures or even coma or death. Real-time continuous glucose monitoring devices can help children with hypoglycemia unawareness because they sound an alarm when glucose is below a specified range or when glucose declines at a rapid rate (see Monitoring glucose and HbA1c levels).
Ketonuria/ketonemia is most often caused by intercurrent illness but also can result from not taking enough insulin or from missing doses and can be a warning of impending DKA. Because early detection of ketones is crucial to prevent progression to DKA and minimize need for emergency department or hospital admission, children and families should be taught to check for ketones in the urine or capillary blood using ketone test strips. Blood ketone testing may be preferred in younger children, those with recurrent DKA, and insulin pump users or if a urine sample is difficult to obtain. Ketone testing should be done whenever the child become ill (regardless of the blood sugar level) or when the blood sugar is high (typically > 240 mg/dL [13.3 mmol/L]). The presence of moderate or large urine ketone levels or blood ketone levels > 1.5 mmol/L can suggest DKA, especially if children also have abdominal pain, vomiting, drowsiness, or rapid breathing. Small urine ketone levels or blood ketone levels 0.6 to 1.5 mmol/L also must be addressed.
When ketones are present, children are given additional short-acting insulin, typically 10 to 20% of the total daily dose, every 2 to 3 h until ketones are cleared. Also, additional fluid should be given to prevent dehydration. This program of measuring ketones and giving additional fluid and insulin during illness and/or hyperglycemia is called sick-day management. Parents should be instructed to call their health care provider or go to the emergency department if ketones increase or do not clear after 4 to 6 h, or if the clinical status worsens (eg, respiratory distress, continued vomiting, change in mental status).
As in type 1 DM, lifestyle modifications, with improved nutrition and increased physical activity, are important.
Insulin is started in children who present with more severe DM (HbA1c > 9% or with DKA); glargine, detemir, or premixed insulin can be used. If acidosis is not present, metformin is usually started at the same time. Insulin requirements may decline rapidly during the initial weeks of treatment as endogenous insulinsecretion increases; insulin often can be stopped several weeks after regaining acceptable metabolic control.
Metformin is an insulin sensitizer and is the only oral antihyperglycemic drug approved for patients < 18 yr. Other oral drugs used in adults may benefit some adolescents, but they are more expensive, and there is limited evidence for their use in youth. Metformin should be started at a low dose and taken with food to prevent nausea and abdominal pain. A typical starting dose is 500 mg once/day for 1 wk, which is increased weekly by 500 mg for 3 to 6 wk until reaching the maximal target dose of 1000 mg po bid. The goal of treatment is HbA1c < 6.5%. If this cannot be achieved with metformin alone, insulin should be started. Unfortunately, about half of adolescents with type 2 DM ultimately fail metformin monotherapy and require insulin.
Management of monogenic diabetes is individualized and depends on subtype. The glucokinase subtype generally does not require treatment because children are not at risk of long-term complications. Most patients with HNF-4-α and HNF-1-α types are sensitive to sulfonylureas, but some ultimately require insulin. Other oral hypoglycemics such as metformin are typically not effective.
Routine monitoring involves
In type 1 DM, blood glucose levels should be measured using a fingerstick sample before all meals and before a bedtime snack. Levels also should be checked during the night (around 2 to 3 am) if nocturnal hypoglycemia is a concern (eg, because of hypoglycemia or vigorous exercise during the day, or when an insulin dose is increased). Because exercise can lower glucose levels for up to 24 h, levels should be checked more frequently on days when children exercise or are more active. To prevent hypoglycemia, children may increase carbohydrate intake or lower insulin dosing when they anticipate increased activity. Sick-day management should be used with hyperglycemia or illness.
Parents should keep detailed daily records of all factors that can affect glycemic control, including blood glucose levels; timing and amount of insulin doses, carbohydrate intake, and physical activity; and any other relevant factors (eg, illness, late snack, missed insulin dose).
Continuous glucose monitoring (CGM) systems use a subcutaneous sensor to measure interstitial fluid glucose levels every 1 to 5 min. CGM systems are calibrated with fingerstick blood glucose levels and transmit results wirelessly to a monitoring and display device that may be built into an insulin pump or be a stand-alone device. By identifying times of consistent hyperglycemia and times of increased risk of hypoglycemia, CGM systems can help patients with type 1 DM more safely reach glycemic goals. All devices allow targets to be set; alarms will alert the user if glucose levels are above or below the target, and some CGMs integrated with a pump can also suspend the basal rate for up to 2 h when glucose level drops below a set threshold. Although CGM devices can be used with any regimen, they are typically worn by insulin pump users.
The so-called artificial pancreas (a closed-loop insulin delivery system) for patients ≥ 14 yr has been approved by the FDA. These systems automate blood glucose management through sophisticated computer algorithms that are on a smartphone or similar device. Artificial pancreas systems link to a CGM sensor and insulin pump to determine blood glucose levels and control insulin delivery. These systems help to more tightly control insulin dosing and limit hyperglycemic and hypoglycemic episodes.
In type 2 DM, blood glucose levels should be measured regularly but typically less often than in type 1 DM. The frequency of self-monitoring of blood glucose (SMBG) should be individualized based on the patient's fasting and postprandial glucose levels, the degree of glycemic control deemed achievable, and the available resources. The frequency of monitoring should increase if glycemic control targets are not being met, during illness, or when symptoms of hypoglycemia or hyperglycemia are felt. Once targets are achieved, home testing is limited to a few fasting and postprandial blood glucose measurements per week.
HbA1c levels should be measured every 3 mo in type 1 DM and in type 2 DM if insulin is being used or metabolic control is suboptimal. Otherwise, in type 2 DM, levels can be measured twice a year, although every 3 mo is optimal.
Patients are screened regularly for complications depending on the type of diabetes (see Table: Screening for Complications of Diabetes). If complications are detected, subsequent testing is done more frequently.
Screening for Complications of Diabetes
Complications detected on examination or screening are treated first with lifestyle interventions: increased exercise, dietary changes (particularly limiting saturated fat intake), and cessation of smoking (if applicable). Children with microalbuminuria (albumin/creatinine ratio 30 to 300 mg/g) on repeat samples or with persistently elevated BP readings (> 90th to 95th percentiles for age or > 130/80 mm Hg for adolescents) who do not respond to lifestyle interventions typically require antihypertensive therapy, most commonly using an ACE inhibitor. For children with dyslipidemia, if LDL cholesterol remains > 160 mg/dL (or > 130 mg/dL plus one or more cardiovascular risk factors) despite lifestyle interventions, statins should be considered in children > 10 yr, although long-term safety is not established.
Type 1 DM is caused by an autoimmune attack on pancreatic beta-cells, causing complete lack of insulin; it accounts for two thirds of new cases in children and can occur at any age.
Type 2 DM is caused by insulin resistance and relative insulin deficiency due to a complex interaction among many genetic and environmental factors (particularly obesity); it is increasing in frequency in children and occurs after puberty.
Most children have symptomatic hyperglycemia without acidosis, with several days to weeks of urinary frequency, polydipsia, and polyuria; children with type 1 DM and rarely type 2 DM may present with DKA.
Screen asymptomatic, at-risk children for type 2 DM or prediabetes.
All children with type 1 DM require insulin treatment; intensive glycemic control helps prevent long-term complications but increases risk of hypoglycemic episodes.
Children with type 2 DM are initially treated with metformin and/or insulin; although most children requiring insulin at diagnosis can be successfully transitioned to metformin monotherapy, about half eventually require insulin treatment.
Psychosocial problems can lead to poor glycemic control through lack of adherence to dietary and drug regimens.
Insulin doses are adjusted based on frequent glucose monitoring and anticipated carbohydrate intake and activity levels.
Children are at risk of microvascular and macrovascular complications of DM, which must be sought by regular screening tests.
Type 2 Diabetes in the Child and Adolescent (ISPAD Clinical Practice Consensus Guidelines)