Diabetes Mellitus in Children and Adolescents

Diabetic ketoacidosis is common among patients with known type 1 diabetes; 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.

Mental health issues are very common among children with diabetes and their families. Up to half of children develop depression, anxiety, or other psychologic problems. Eating disorders are a serious problem in adolescents, who sometimes also skip insulin doses in an effort to control weight. Psychologic 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 in type 1 diabetes; prolonged poor glycemic control is the greatest long-term risk factor for the development of vascular complications. Microvascular complications include diabetic nephropathy, retinopathy, and neuropathy. Microvascular complications are more common among children with type 2 diabetes than type 1 diabetes and in type 2 diabetes may be present at diagnosis or earlier in the disease course. Although neuropathy is more common among children who have had diabetes for a long duration (≥ 5 years) and poor control (glycosylated hemoglobin [HbA1c] > 10%), it can happen in young children who have had diabetes for a short duration and good control. Macrovascular complications include coronary artery disease, peripheral vascular disease, and stroke.

Diagnosis of diabetes 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. Measurements are 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 hours.

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 diabetes.

The HbA1c criterion is typically more useful for diagnosing type 2 diabetes, and hyperglycemia should be confirmed. Although the HbA1c screening test is commonly used for the diagnosis of type 2 diabetes in children, the results of the test should be used with caution. Data promoting HbA1c as a screening test are derived from adults, and several studies have questioned its validity because of its poor sensitivity for identifying children with dysglycemia (prediabetes or diabetes mellitus). In children with hemoglobinopathies (eg, sickle cell disease), alternative measurements (eg, fructosamine) should be considered.

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 tests, and calcium, magnesium, phosphorus, and hematocrit levels.

Additional tests should be done to confirm the type of diabetes, including

• C-peptide and insulin (if not yet treated with insulin) levels

• HbA1c levels (if not already done)

• Tests for autoantibodies against pancreatic islet cell proteins

Autoantibodies include glutamic acid decarboxylase, insulin, insulinoma-associated protein, and zinc transporter ZnT8. More than 90% of patients with newly diagnosed type 1 diabetes have ≥ 1 of these autoantibodies, whereas the absence of antibodies strongly suggests type 2 diabetes. However, about 10 to 20% of children with the type 2 diabetes phenotype have autoantibodies and are reclassified as type 1 diabetes, 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 and type 2 diabetes. The diagnosis should be considered in children with a strong family history of diabetes but who lack typical features of type 2 diabetes; that is, they have only mild fasting (100 to 150 mg/dL [5.55 to 8.32 mmol/L]) or postprandial hyperglycemia, are young and not obese, 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 diabetes can progress with age.

Patients with type 1 diabetes should be tested for other autoimmune disorders by measuring celiac disease antibodies and thyroid-stimulating hormone, thyroxine, and thyroid antibodies. Testing for thyroid disease and celiac disease should occur every 1 to 2 years thereafter. Other autoimmune disorders, such as primary adrenal insufficiency (Addison disease), rheumatologic disease (eg, rheumatoid arthritis, systemic lupus erythematosus, psoriasis), other gastrointestinal disorders (eg, inflammatory bowel disease, autoimmune hepatitis), and skin disease (eg, vitiligo), may also occur in children with type 1 diabetes but do not require routine screening.

Patients with type 2 diabetes should have liver tests, fasting lipid profile, and urine microalbumin:creatinine ratio done at the time of diagnosis because such children (unlike those with type 1 diabetes, 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:

• Obesity: Test for nonalcoholic steatohepatitis

• Daytime somnolence or snoring: Test for obstructive sleep apnea

• Hirsutism, acne, or menstrual irregularities: Test for polycystic ovary syndrome

Asymptomatic children ≤ 18 years of age 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 years or at onset of puberty, if puberty occurred at a younger age, and should be repeated every 3 years.

Children at risk include those who are overweight (body mass index > 85th percentile for age and sex, or weight for height > 85th percentile) and who have any 2 of the following:

• Family history of type 2 diabetes in 1st- or 2nd-degree relative

• Native American, Black, Hispanic, Asian American, and Pacific Islander heritage

• Signs of insulin resistance or conditions associated with insulin resistance (eg, acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight)

• Maternal history of diabetes or gestational diabetes

Lifestyle modifications that benefit all patients include

• Eating regularly and in consistent amounts

• Limiting intake of refined carbohydrates and saturated fats

• Increasing physical activity

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 diabetes, 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, activity level, pubertal status, and length of time from initial diagnosis. Technologic advances have allowed for greater precision and customization of insulin doses. A good rule of thumb for age is

• Birth to 5 years: 1 unit insulin per 30 g carbohydrate

• 6 to 12 years: 1 unit insulin per 15 g carbohydrate

• Adolescence: 1 unit insulin per 5 to 10 g carbohydrate

In type 2 diabetes, 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 years is 1000 calories + (100 × child's age in years). 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

Plasma glucose targets ( see Table: Glucose and HbA1c Target Levels in Children and Adolescents with Type 1 Diabetes) are established to balance the need to normalize glucose levels with the risk of hypoglycemia. Patients beyond the honeymoon phase (ie, patients who no longer have residual beta-cell function) 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.

HbA1c target levels for type 1 diabetes in children and adolescents have been lowered over time in an effort to reduce complications—lower HbA1c levels during adolescence and young adulthood are associated with a lower risk of vascular complications. An HbA1c target level of < 7% (< 53 mmol/mol) is appropriate for most children, but many children and adolescents do not meet this target.

An increased frequency of self-monitoring of blood glucose levels (up to 6 to 10 times per day) or use of a continuous glucose monitoring (CGM) system can improve 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). When used properly, intermittently scanned CGM in conjunction with insulin therapy can be used to replace self-monitoring of blood glucose.

HbA1c levels correlate well to the percentage of time that blood glucose levels remain in the normal range, termed the percentage time-in-range. Time-in-range is commonly used as a therapeutic goal to assess the efficacy of the insulin regimen in combination with HbA1c level. A 10% change in time-in-range corresponds to about a 0.8 percentage point change in HbA1c. For example, a time-in-range of 80% corresponds to an HbA1c level of 5.9% (41 mmol/mol), 70% corresponds to 6.7% (50 mmol/mol), 60% corresponds to 7.5% (58 mmol/mol), and 40% time-in-range corresponds to an HbA1c level of 9% (75 mmol/mol) (1).

In addition to time-in-range, CGM provides information related to average sensor glucose, time-above-range (> 180 mg/dL [> 10 mmol/L]) and time-below-range (< 70 mg/dL [< 3.9 mmol/L]), glycemic variability, glucose management indicator, and information related to adherence (eg, active CGM time, days worn).

CGM metrics derived from use over the most recent 14 days are recommended to be used in conjunction with HbA1c level. CGM data can be reported in a standardized format. The ambulatory glucose profile (AGP) is a standardized report of the mean glucose, time-in-range, and time-below-range. When using the AGP to monitor glycemia, a goal of time-in-range of > 70% with a time-below-range of < 4% may be used as a glycemic control goal along with the goal of an HbA1c target of < 7% (< 53 mmol/mol). Another report is the glucose management indicator, which provides an estimated HbA1c from mean CGM glucose levels, preferably from ≥ 14 days of data.

HbA1c target levels for type 2 diabetes

is the cornerstone of management of type 1 diabetes. 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 insulin requirements because of residual beta-cell function (honeymoon phase). This honeymoon phase can last from a few months up to 2 years, 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.

include

• Multiple daily injections (MDI) regimen using basal-bolus regimen

• Fixed forms of MDI regimen or premixed insulin regimen (less common)

A basal-bolus regimen is typically the preferred MDI regimen. 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-a-day injection (sometimes every 12 hours for younger children) of a long-acting insulininsulin.

In insulin (CSII) through a catheter placed under the skin. Mealtime and correction boluses also are delivered via the insulin pump. 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.

Insulin

More fixed formsinsulin 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. However, this regimen provides less flexibility, requires a set daily schedule for meals and snack times, and has been largely supplanted by the analog insulins glargine and detemir because of the lower risk of hypoglycemia.

use preparations of 70/30 (70% insulininsulin) or 75/25 (75% insulininsulin 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.

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,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 hours 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 hours, or if the clinical status worsens (eg, respiratory distress, continued vomiting, change in mental status).

As in type 1 diabetes, lifestyle modifications, with improved nutrition and increased physical activity, are important.

is started in children who present with more severe diabetes (HbA1c > 9% [> 75 mmol/mol] or with DKA); glargine, detemir, or premixed insulinInsulin requirements may decline rapidly during the initial weeks of treatment as endogenous insulin secretion increases; insulin often can be stopped several weeks after regaining acceptable metabolic control.

is an insulin sensitizer and is the only oral antihyperglycemic drug approved for patients < 18 years of age. Other oral drugs used in adultsinsulininsulin

Liraglutide is started at 0.6 mg subcutaneously once a day and may be increased weekly by 0.6 mg until control is adequate up to 1.8 mg once a day. Extended-release exenatide dose is 2 mg subcutaneously once/week, which may improve patient adherence. Both drugs promote weight loss, likely through the effect of delayed gastric emptying and appetite reduction. The most common adverse effects of GLP-1 agonists are gastrointestinal, especially nausea and vomiting. Liraglutide and exenatide can be used if metformin is not tolerated or added on if HbA1c target levels are not achieved with metformin alone within 3 months. Liraglutide and exenatide can be used in place of or in combination with insulin as part of intensive treatment of type 2 diabetes.

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 hepatic nuclear factor 4-alpha and hepatic nuclear factor 1-alpha types are sensitive to sulfonylureas, but some ultimately require insulin

Routine monitoring involves

• Multiple daily glucose checks by fingerstick or continuous glucose monitoring

• HbA1c measurements every 3 months

In type 1 diabetes, blood glucose levels should be monitored 6 to 10 times per day by using a glucose meter or a continuous glucose monitoring (CGM) system to optimize control. Traditionally, 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 hours, 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).

Patients with type 2 diabetes

In type 2 diabetes, blood glucose levels should be measured regularly but typically less often than in type 1 diabetes. The frequency of self-monitoring of blood glucose 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 months in type 1 diabetes and in type 2 diabetes if insulin is being used or metabolic control is suboptimal. Otherwise, in type 2 diabetes, levels can be measured twice a year, although every 3 months is optimal.

Continuous glucose monitoring (CGM) systems are a common method (> 60% of children use one) of monitoring blood glucose levels and can replace routine self-monitoring of blood glucose for some patients. They are a more sophisticated and effective approach to monitoring that uses a subcutaneous sensor to measure interstitial fluid glucose levels every 1 to 5 minutes and then translate the measurements into blood glucose values, thus more closely detecting glucose fluctuations that can then be acted upon in real time. CGM systems transmit results wirelessly to a monitoring and display device that may be built into an insulin pump or may 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 diabetes more safely reach glycemic goals.

Two types of CGM systems are currently available: real-time CGM and intermittently scanned CGM. Real-time CGM can be used in children ≥ 2 years of age. The system automatically transmits a continuous stream of glucose data to the user in real time, provides alerts and active alarms, and also transmits glucose data to a receiver, smartwatch, or smartphone. Real-time CGM should be used as close to daily as possible for maximal benefit. Intermittently scanned CGM can be used in children ≥ 4 years of age. It provides the same type of glucose data as real-time CGM but requires the user to purposely scan the sensor to obtain information and does not have alerts and alarms. Intermittently scanned CGM should be used frequently, a minimum of once every 8 hours. Children using CGM devices need to be able to measure blood glucose by fingerstick to calibrate their monitor and/or to verify readings if they are discordant from symptoms.

Compared to intermittent monitoring, CGM systems can help lower HbA1c levels, increase the percentage of time-in-range, and lower the risk of hypoglycemia.

Although CGM devices can be used with any regimen, they are typically worn by insulininsulin doses based on CGM results. Other CGM systems are integrated with a pump and can also suspend the basal rate for up to 2 hours when glucose levels drop below a set threshold. This integration can reduce the number of hypoglycemic events, even when compared to sensor-augmented pump therapy.

Closed-loop insulin pumps can be used in children ≥ 2 years of age. These hybrid closed-loop systems automate blood glucose management through sophisticated computer algorithms that are on a smartphone or similar device and link a CGM sensor to an insulin pump to determine blood glucose levels and control insulin delivery. Delivery is controlled by suspending, increasing, or decreasing basal insulin in response to CGM values. Current hybrid closed-loop systems are not truly automated because they require users to administer a bolus for meals and snacks. These systems help more tightly control insulin dosing and limit hyperglycemic and hypoglycemic episodes. A fully automated closed-loop system, sometimes known as a bihormonal (insulin

Patients are screened regularly for complications depending on the type of diabetes ( see Table: Screening Children for Complications of Diabetes and Associated Disorders). If complications are detected, subsequent testing is done more frequently.

elevated blood pressure 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 angiotensin-converting enzyme inhibitor. For children with dyslipidemia, if low-density lipoprotein (LDL) cholesterol remains > 160 mg/dL (4.14 mmol/L) or > 130 mg/dL (3.37 mmol/L) and one or more cardiovascular risk factors remain despite lifestyle interventions, statins should be considered in children > 10 years, although long-term safety is not established.

1. 1. Beck RW, Bergenstal RM, Cheng P, et al: The relationships between time in range, hyperglycemia metrics, and HbA1c. Diabetes Technol Ther 13(4):614–626, 2019. doi: 10.1177/1932296818822496