Chapter 35: Diabetes Mellitus

Epidemiology & Description

A. Type 1 Diabetes

Type 1 diabetes (T1D) is the most common type of diabetes mellitus in people younger than 20 years, but it can develop at any age and most cases are diagnosed after age 20. The classical presentation includes increased thirst (polydipsia), increased urination (polyuria), and weight loss; however, the patient may be overweight or even obese. T1D is further divided into T1a (autoimmune) (~ 95% of the cases) and T1b (idiopathic) diabetes. T1b is more common in individuals of African or Asian ancestry. In the United States, T1D affects an estimated 1.5 million people, including more than 200,000 patients younger than 20 (~ 25,000 diagnosed annually).

T1D incidence is the highest in children of European ancestry, followed by African Americans and Hispanics; rates are low in Asians and Native Americans. About 6% of siblings or offspring of persons with T1D also develop diabetes (compared with prevalence in the general population of 0.2%–0.3%). However, fewer than 10% of children newly diagnosed with T1D have a parent or sibling with the disease.

B. Type 2 Diabetes

Type 2 diabetes (T2D) is a heterogeneous phenotype diagnosed most often in persons older than 40 who are usually obese and initially not insulin dependent. T2D is rare before age 10; however, puberty is a time of heightened risk for development of T2D in susceptible individuals. Due to the epidemic of childhood obesity, T2D has increased in frequency in older children. T2D is more common in youth of ethnic and racial minorities, particularly the native American population. Other risk factors include female sex, poor diet and sleep, and low socioeconomic status. The vast majority of the 30 million patients with diabetes in the United States have T2D, but less than 20,000 patients are younger than 20 (~ 5000 diagnosed annually).

C. Monogenic Forms of Diabetes

Monogenic forms of diabetes can be diagnosed at any age. They account for less than 1% of childhood diabetes, but form the majority of cases diagnosed before the ninth month of life. Neonatal diabetes is transient in about one-half of the cases; if persistent, it presents a significant clinical challenge and requires subspecialty care. Some infants respond better to sulfonylurea than insulin. Maturity-onset diabetes of the young (MODY) presents as a nonketotic and usually non–insulin-dependent diabetes in the absence of obesity or islet autoantibodies. A strong family history of early-onset diabetes is common. The most frequent forms are due to mutations in glucokinase or hepatic nuclear factor 1 or 2 genes. Glucokinase mutations rarely require therapy; other forms respond to oral hypoglycemic agents or insulin. Commercial and research-oriented genotyping services are available to aid correct diagnosis.

D. Cystic Fibrosis-Related Diabetes

Cystic fibrosis-related diabetes (CFRD) occurs in about 20% of adolescents with cystic fibrosis (CF) and is the most common comorbidity in CF (for more information, see Chapter 19). The primary defect is insulin insufficiency, exacerbated by insulin resistance especially in times of illness or with glucocorticoid therapy. The presence of CFRD is associated with worse nutritional status, more severe lung disease, and greater mortality. Patients with CF should be routinely screened beginning by age 10, and treatment has been shown to improve outcomes.

Pathogenesis

A. Type 1 Diabetes

T1D is caused by a combination of genetic factors and unknown environmental factors. The resulting autoimmune destruction of the insulin-producing β cells of the pancreatic islets is marked by the presence of autoantibodies to islet cell autoantigens (insulin, GAD65, IA-2, and ZnT8) that can be measured in the blood. The persistence of two or more islet autoantibodies is highly predictive of development of symptomatic diabetes. Thus, in 2015 a new staging definition of T1D was adopted with multiple islet autoimmunity being defined as stage 1 T1D (Table 35–1). Ongoing β-cell destruction occurs over months or years, leading first to asymptomatic dysglycemia (stage 2) and later to symptomatic T1D (stage 3) when most of the pancreatic β cells have been destroyed. Insulin production, measured by fasting or stimulated C-peptide levels, is usually low at diagnosis but may increase after initiation of insulin therapy (“honeymoon period”) and persist for weeks or months until eventual total or near-complete loss of β-cell function.

More than 90% of children with T1D carry at least one of the two high-risk HLA haplotypes—DR4/DQ8 or DR3/DQ2—and 40% of US children diagnosed before age of 10 years have both (one from each parent), compared with only 2.5% of the general population. Over 50 non-HLA genetic variants have also been implicated.

B. Type 2 Diabetes

T2D has a strong genetic component, although the inherited defects of insulin secretion vary in different families. There is evidence to suggest that T2D progresses differently in youth compared to adults with more rapid decline in β-cell function and greater risk for early development of complications. Obesity, particularly central, and lack of exercise do contribute but are rarely sufficient alone to cause diabetes in youth. T2D and associated insulin resistance adversely affect long-term cardiovascular health.

Prevention

A. Type 1 Diabetes

Since the 1950s, the incidence of T1D has increased worldwide, doubling every 20 years. Despite much research on early childhood infections and diet, the environmental factor(s) responsible for this epidemic are poorly defined.

Islet autoantibodies do not mediate β-cell destruction but offer a useful screening tool as they are usually present for years prior to diagnosis. It has been shown that intensive follow-up of individuals with multiple islet autoantibodies (stage 1 T1D) reduces the severity of the presentation. Antibody screening is not yet standard of care but is available in the research setting for children with a first- or second-degree relative with T1D (www.trialnet.org) or in general population children living in Colorado (www.askhealth.org) or Bavaria, Germany (www.typ1diabetes-frueherkennung.de).

As β-cell damage is mediated by T lymphocytes, immunosuppression at different checkpoints of the autoimmune process can slow down β-cell loss. Immunomodulation, including induction of tolerance to islet autoantigens, with or without immunosuppression, is an area of intensive research. Various immunotherapies have shown promising effects in prolonging β-cell function (“honeymoon”) in newly diagnosed individuals (stage 3 T1D). Recent stage II trials of teplizumab, an Fc receptor–nonbinding anti-CD3 monoclonal antibody, demonstrated for the first time delayed progression from stage 2 to 3 T1D. Identification of individuals with early-stage T1D is likely to play an important role in efforts to modify disease trajectory in the future.

B. Type 2 Diabetes

The Diabetes Prevention Program study done in adults with impaired glucose tolerance (IGT) found that 30 minutes of exercise per day (5 days/wk) and a low-fat diet reduced the risk of diabetes by 58%. In adults, taking metformin also reduced the risk of T2D by 31%. There is less data in youth; however, an intensive 12-month intensive behavior modification intervention resulted in reduced lipids, body mass index (BMI), and insulin resistance in obese youth without diabetes and improved glycemic profile in youth with prediabetes.

Clinical Findings

A. Symptoms and Signs

A combination of polyuria, polydipsia, and weight loss in a child is unique to diabetes. Unfortunately, these symptoms are often missed by parents and primary care providers. The frequency of diabetic ketoacidosis (DKA) in US children with newly diagnosed T1D has not decreased in the past 20 years and is approximately 40%, a sign of poor provider and community awareness. More than one-half of DKA patients were seen by a provider in the days preceding diagnosis, and obvious symptoms and signs were missed. The correct diagnosis could be improved with better history-taking and point-of-care blood or urine analysis. Initial diagnosis can be easily confirmed by blood glucose and ketone measurements using widely available and inexpensive meters.

The clinical presentation of DKA includes abdominal pain, nausea, and vomiting that can mimic the flu, gastroenteritis or an acute abdomen. Patients are mildly to moderately dehydrated (5%–10%), may have Kussmaul respiration, and become progressively somnolent and obtunded. While the majority of diagnoses occur in older children, the distribution has shifted to include younger ages; infants, toddlers, and preschool age children. They often have symptoms of minor infection or gastrointestinal upset. A heavy diaper in a dehydrated child without diarrhea should always raise alarm. A blood or urine glucose test could be lifesaving.

B. Laboratory Findings

Laboratory findings diagnostic of diabetes are shown in Table 35–2.

It should be noted that while hemoglobin A_1C (HbA_1C) can be used for diagnosis of diabetes, most clinical laboratories do not perform HbA_1C assays that meet diagnostic criteria (ie, NGSP certified and standardized to the Diabetes Control and Complications Trial reference assay). For this reason, HbA_1C measurements are prone to error and must be interpreted with caution, especially in the absence of other signs or symptoms of diabetes. Additionally, the HbA_1C is less sensitive than blood glucose-based criteria and may underestimate dysglycemia in young children whose progression to T1D can be especially rapid. Children with impaired fasting glucose (IFG) or IGT and no islet autoantibodies are at high risk of T2D and require careful follow-up and lifestyle modification with weight loss, if obese.

Blood glucose higher than 200 mg/dL in a child is always abnormal and must be promptly and meticulously followed in consultation with a pediatric endocrinology service. If there are significant ketones in urine or blood, treatment is urgent. Conversely, if the presentation is mild and an outpatient diabetes education service is available, hospitalization is often not necessary.

Differential Diagnosis

A combination of polyuria, polydipsia, and weight loss in a child is unique to diabetes. Of note, not all hyperglycemia in children is diabetes; transient, “stress-” or steroid-induced hyperglycemia can occur with illness or trauma. In an asymptomatic, well child, the diagnosis must not be based on a single plasma glucose test or a borderline result obtained using a glucose meter.

The differentiation between type of diabetes can have important implications for management and education. Testing children for islet autoantibodies can be helpful to establish ongoing islet autoimmunity (T1D). The absence of the three most available autoantibodies (to insulin, GAD, and IA-2) provides 80% negative predictive value, and other causes of diabetes should be assessed. Monogenic diabetes should be considered in a child with an autosomal dominant family history of diabetes, presentation before 12 months of age, mild fasting hyperglycemia, a prolonged period of persistent insulin production (“honeymoon”) over 1 year, or associated conditions such as syndromic features, deafness or optic atrophy. All children diagnosed with diabetes in the first 6 months of life should have genetic screening for neonatal diabetes.

If HbA_1C is normal, home monitoring of blood glucose for several days, including fasting and 2-hour postprandial measurement, can be helpful to establish the glycemic profile. In children progressing to overt diabetes, hyperglycemia after meals is usually the initial abnormality, while fasting hyperglycemia develops much later.

In the era of increasing prevalence of childhood obesity, it is nonetheless important to note that T1D is still much more common in children overall, particularly those who are younger than 10 or prepubertal, regardless of weight status. Factors lending credence to a diagnosis of T2D include a strong family history, ethnic/racial minority status, central obesity, and pubertal status. Acanthosis nigricans, a thickening and darkening of the skin over the posterior neck, armpits, or elbows, is a sign of insulin resistance and may increase suspicion for T2D. It should be noted, however, that it is present in many obese children and is not specific for the diagnosis of T2D.

While DKA is more common at presentation of T1D, approximately 6% of children with T2D present in DKA.

Treatment

Treatment of both T1D and T2D should take a holistic approach to the child in the context of family and greater environment. There are many common themes to management of diabetes in the pediatric patient, regardless of pathogenesis. Effective diabetes management requires access to a multidisciplinary diabetes team including a physician, diabetes nurse educator, registered dietician, and psychologist or social worker.

A. General Principles for Diabetes Management

1. Treatment goals

The HbA_1C level reflects the average blood glucose levels over the previous 3 months. The overarching goals of therapy in diabetes include prevention of acute and long-term complications by reducing chronic hyperglycemia while maximizing the quality of life. In T1D, these goals must be tempered by preventing frequent or prolonged hypoglycemia and associated morbidities. Each child should have targets individually determined to aim for the lowest HbA_1C that can be sustained without severe hypoglycemia or frequent moderate hypoglycemia (see Quality Assessment & Outcomes Metrics). In T2D, addressing obesity and associated comorbidities, when present, is also a major focus in maximizing health outcomes (see Chapters 4 and 11).

2. Patient and family education

All caregivers need to learn about diabetes, how to give insulin via injections or insulin pump, perform home blood glucose monitoring, and handle acute complications. While teenagers can be taught to perform many of the tasks of diabetes management, they do better when supportive, not overbearing, parents continue to be involved in management of their disease. The use of educational books (see below) can be very helpful to the family.

3. Psychological care

The diagnosis of diabetes changes lives of the affected families and brings on relentless challenges. It is impossible to take a “vacation” from diabetes without some unpleasant consequences. The stress imposed on the family around the time of initial diagnosis may lead to feelings of shock, denial, sadness, anger, fear, and guilt. Meeting with a counselor to express these feelings at the time of diagnosis helps with long-term adaptation. Persistent adjustment problems may indicate underlying dysfunction of the family or psychopathology of the child or caregiver. Young people with T1D are more frequently diagnosed with and treated for psychiatric disorders, disordered eating, neurocognitive learning problems, and poor coping skills than the general population. In T2D, socioeconomic status and obesity are both risk factors for the disease as well as for psychological stress, depression, and other mental illness.

Routine assessment should be made of developmental adjustment to and understanding of diabetes management, including diabetes-related knowledge, insulin adjustment skills, goal setting, problem-solving abilities, regimen adherence, and self-care autonomy and competence. This is especially important during late childhood and prior to adolescence. General and diabetes-related family functioning such as communication, parental involvement and support, and roles and responsibilities for self-care behaviors need to be assessed. Teaching parents effective behavior management skills, especially at diagnosis and prior to adolescence, emphasizes involvement and support, effective problem-solving, self-management skills, and realistic expectations. Adolescents should be encouraged to assume increased responsibility for diabetes management, but with continued, mutually agreed parental involvement and support. The transition to adult diabetes care should be negotiated and planned between adolescents, their parents, and the diabetes team well in advance of the actual transfer.

4. Diet and exercise

A thorough dietary history should be obtained including the family’s dietary habits and traditions, the child’s typical meal times, and patterns of food intake. At least 60 minutes of daily aerobic exercise is important for children with diabetes. Exercise fosters a sense of well-being; helps increase insulin sensitivity (a drop in glycemia in response to insulin); and helps maintain proper weight, blood pressure, and high-density lipoprotein (HDL)-cholesterol levels.

B. Treatment of Type 1 Diabetes

1. Home blood glucose monitoring

All families must be able to monitor blood glucose levels at least four times daily; however, 7–10 checks per day are typically needed for optimal diabetes management. Higher frequency of self-monitoring of blood glucose and/or use of continuous glucose monitoring (CGM) have been associated with improved HbA_1C.

CGM is now routinely available and can significantly improve diabetes management if used most of the time. Subcutaneous glucose levels are obtained every 1–5 minutes from a sensor placed under the skin. The sensor must be replaced every 6–10 days. A transmitter sends glucose levels from the sensor to a receiver that can be inside an insulin pump, smartphone, or separate receiver device. Low and high blood glucose alarms can be set. As with insulin pump therapy (see below), intensive education and follow-up are required, usually at a specialty diabetes center. The user is trained on how to keep the real-time displayed blood glucose “between the lines,” that is, in the target range.

The Food and Drug Administration (FDA) has now approved insulin dosing based on the Dexcom G5 and G6 CGM glucose values, which reduces the need for fingersticks, particularly in the school setting. As subcutaneous glucose levels can lag behind blood glucose levels in times of rapid change, finger stick blood glucose is still recommended for treatment and monitoring of recovery from hypoglycemic or significant hyperglycemic events.

In some systems CGM data may be used to automatically change insulin pump delivery rate (see section “Artificial Pancreas” Systems).

Regular evaluation of blood glucose results or CGM data by the family helps to identify patterns of changing insulin needs, especially when combined with logs of insulin dosage and significant events (eg, illness, parties, exercise, menses, and episodes of hypoglycemia or ketonuria/ketosis). If more than 30% of the values are above the desired range for age or more than 15% below the desired range, the insulin dosage needs to be adjusted.

Some families are able to make these changes independently, whereas others need help from the health care provider to optimize insulin dose between visits. Children with diabetes should be evaluated by a diabetes provider every 3 months to check compliance, adjust insulin dose according to growth, measure HbA_1C, and review blood glucose patterns, as well as for routine review of systems, physical examination, and laboratory tests.

2. Nutritional management

Nutritional management in children with T1D does not require a restrictive diet, just a healthy dietary regimen from which both children and their families can benefit. Insulin pump and multiple daily injection (MDI) therapy utilize carbohydrate counting in which the grams of carbohydrate to be eaten are counted and a matching dose of insulin is administered. This plan allows for the most freedom and flexibility in food choices, but it requires expert education and commitment and may not be suitable for many families or situations, such as for school lunches and teenagers. As an alternative to precise carb counting, “exchanges” may be taught to estimate 10- or 15-g servings of carbohydrate.

3. Insulin

Insulin has three key functions: (1) it allows glucose to pass into the cell for oxidative utilization; (2) it decreases the physiologic production of glucose, particularly in the liver; and (3) it turns off lipolysis and ketone production.

A. INSULIN TREATMENT OF NEW-ONSET TYPE 1 DIABETES

In children who present without DKA and who have adequate oral intake, the initial insulin dose can be administered subcutaneously. Typically, 0.2–0.3 U/kg of long-acting insulin analog—glargine (Lantus or Basaglar), detemir (Levemir), or degludec (Tresiba)—can be administered subcutaneously to provide the “basal” level of insulin. Additionally, a small amount of short-acting insulin (regular) or, preferentially, rapid-acting analog: lispro (Humalog), aspart (NovoLog), or glulisine (Apidra) can be used for correction and mealtime dosing. This usually suffices for the initial 12–24 hours preceding systematic diabetes education.

The dose is adjusted with each injection during the first week. The rule of thumb is to start insulin at the low end of the estimated daily requirement and titrate it up based on frequent blood-glucose monitoring or CGM glucose levels. The initial daily dose of insulin is higher in the presence of ketosis, infection, obesity, or steroid treatment. It also varies with age, pubertal status and severity of onset. A total subcutaneous daily dose of 0.3–0.7 U/kg/day may suffice in prepubertal children, while pubertal or overweight children and those with initial HbA_1C greater than 12% commonly require 1.0–1.5 U/kg/day of insulin during the initial week of treatment. Children younger than 12 years cannot reliably administer insulin without adult supervision because they may lack fine motor control and/or may not understand the importance of accurate dosage.

The insulin dose peaks about 1 week after diagnosis and decreases slightly with the waning of glucotoxicity and voracious appetite. Approximately 3–6 weeks after diagnosis, most school children and adolescents experience a partial remission or “honeymoon period.” Temporary decrease in the insulin dose during this period is necessary to avoid severe hypoglycemia. The remission tends to last longer in older children but is rarely complete and never permanent. Other types of diabetes should be considered in patients with unusually low insulin requirements.

B. LONG-TERM INSULIN DOSAGE

Children usually receive a rapid-acting insulin to cover food intake or correct high blood glucose and a long-acting insulin to suppress endogenous hepatic glucose production. This is achieved by combining insulins with the desired properties. Understanding the onset, peak, and duration of insulin activity is essential (Table 35–3).

Nearly all children diagnosed with T1D at our center receive insulin from a pump or through basal-bolus MDI. This usually consists of three to four injections (boluses) of rapid-acting analog before meals and one to two injections of long-acting analog insulin. The dose of premeal rapid-acting insulin is calculated based on anticipated carbohydrate content of the meal and additional insulin to correct for high blood glucose, if needed. Sliding scales for dosing of rapid-acting insulin (based only on current blood glucose level) are helpful initially, while families learn carbohydrate counting. This shortcut assumes that the content of carbohydrates, for example in dinner, does not vary from day to day; therefore, this may lead to significant under- and overdosing.

Children younger than 4 years usually need 0.5–2 units of rapid-acting insulin to cover carbohydrate intake. Children aged 4–10 years may require up to 4 units of rapid-acting insulin to cover breakfast and dinner, whereas 4–10 units of rapid-acting insulin are used in older children. These estimates do not include correction for high blood glucose.

Families gradually learn to make small weekly adjustments in insulin dosage based on home blood glucose testing or CGM values. Rapid-acting analog insulin is given 10–20 minutes before eating to account for delay in insulin action. If slower human regular insulin is used, the injections should be given 30–60 minutes before meals—rarely a practical option. In young children who eat unpredictably, it may be necessary to wait until after the meal to decide on the appropriate dose of rapid-acting insulin, which is a compromise between avoiding hypoglycemia and tolerating hyperglycemia after meals.

A long-acting analog insulin glargine (Lantus or Basaglar) or detemir (Levemir) is given once or twice a day to maintain basal insulin levels between meals. Degludec (Tresiba) is administered once daily, whenever convenient. Daily adjustments in long-acting insulin dose usually are not needed. However, decreases should be made for heavy activity (eg, sports, hikes) or overnight events.

In the past, most children would receive two injections per day of rapid-acting insulin and an intermediate-acting insulin (NPH), often mixed just before injection. About two-thirds of the total dosage would be given before breakfast and the remainder before dinner. This regimen has been shown to be inferior in achieving recommended HbA_1C levels and avoiding hypoglycemia, compared with the basal-bolus regimen described above. When changing a patient from NPH insulin to an analog, initially only 50% of the daily units of long-acting insulin is recommended.

C. INSULIN PUMP TREATMENT

Continuous subcutaneous insulin infusion (insulin pump) therapy is currently the best way to restore the body’s physiologic insulin profile. The standard insulin pump delivers a variable programmed basal rate that corresponds to the diurnal variation in insulin needs. Prepubertal children require higher basal rate in the early part of night, while postpubertal patients who experience the “dawn phenomenon” require higher rates in the morning. Lower rates are set for periods of vigorous activity. The user initiates bolus doses before meals and to correct hyperglycemia. Most pumps can receive wireless transmission of test results from glucose meters, but the patient or caregiver must still manually enter the amount of carbohydrate being consumed. The pump calculates the amount of insulin needed for a meal or correction based on previously entered parameters that include insulin-to-carbohydrate ratios, insulin sensitivity (or correction) factor, glycemic target, and duration of insulin action (set at 2–3 hours to protect from accumulating too much insulin). The user may override the suggestion or press a button to initiate the bolus.

Most clinical trials have demonstrated better HbA_1C and less severe hypoglycemia with pump therapy, compared to MDI. Pump therapy can improve the quality of life in children who have trouble with or fear of injections or who desire greater flexibility in their lifestyle, for example with sleeping in, sports, or irregular eating. Insulin pumps can be particularly helpful in young children or infants who have multiple meals and snacks and require multiple small doses of rapid-acting insulin. The newer generation of insulin pumps can deliver as little as 0.025 U/h, but higher rates using diluted insulin may be needed for uninterrupted flow.

Compliance problems include infrequent blood glucose testing, not changing pump infusion sets on a timely basis, not reacting to elevated blood glucose, incorrect carbohydrate counting, or missing mealtime boluses altogether. Side effects of insulin pump treatment include failures of insulin delivery because of a displaced or obstructed infusion set. Insulin pump treatment is significantly more expensive than regimens based on injections. For some patients, pumps may be too difficult to operate; some cannot comply with the multiple testing and carbohydrate counting requirements, or the pump is unacceptable because of body image issues or extreme physical activity (swimming, contact sports).

D. “ARTIFICIAL PANCREAS” SYSTEMS

The newest generation of insulin pumps receive CGM sensor input that leads to automatic changes in insulin infusion. The simplest system available features sensor-initiated automatic suspension of insulin delivery at a predetermined low-glucose level and automatic resumption of the delivery after glucose levels rise. Other systems react to predicted, rather than current, low or high blood glucose levels. The first hybrid closed-loop system, the Medtronic 670G, became available in 2017. The Tandem Control-IQ system was approved in 2020, and there are more systems in active development. The hybrid closed loop replaces a programmed basal rate with variable basal dosing determined automatically in response to CGM input. All current “artificial pancreas” systems still require the wearer to give boluses before meals based on carbohydrate consumption.

4. Exercise

Hypoglycemia during exercise or in the 2–12 hours after exercise can be prevented by (1) careful monitoring of blood glucose before, during, and after exercise; (2) reducing the dosage of the insulin active at the time of (or after) the exercise, including reducing or temporarily stopping the basal rate on an insulin pump; and (3) providing extra snacks. Fifteen grams of glucose usually covers about 30 minutes of exercise. The use of drinks containing 5%–10% dextrose, such as Gatorade, during the period of exercise is often beneficial. Insulin dose for meals as well as the basal insulin pump rate should be reduced before, during, and sometimes after the exercise; the longer and more vigorous the activity, the greater the reduction in insulin dose.

5. Sick day management

Families must be educated to check blood or urine ketone levels during any illness, when a fasting blood/CGM glucose level is above 240 mg/dL (13.3 mmol/L), or a randomly measured glucose level is above 300 mg/dL (16.6 mmol/L). The health care provider should be called in the presence of moderate or significant ketonuria or ketonemia (blood β-hydroxybutyrate > 1.0 mmol/L, by Precision Xtra meter). Usually 10%–20% of the total daily insulin dosage is given subcutaneously as rapid-acting analog or regular insulin every 2–3 hours until blood glucose normalizes. This prevents progression to ketoacidosis and allows most patients to receive treatment at home. Water is the oral fluid of choice if blood/CGM glucose is more than 250 mg/dL; at lower levels of glycemia, one should switch to Gatorade/Powerade or other glucose-containing beverages.

C. Treatment of Type 2 Diabetes

Treatment of T2D in children varies with the severity of the disease.

1. Lifestyle management

If the HbA_1C is still near normal, family-centered modification of lifestyle is the first line of therapy. Lifestyle interventions have mixed results in the pediatric population, compared to adults, possibly reflecting the complex family and environmental context for T2D in youth. Interventions should emphasize eating a balanced diet, achieving and maintaining a healthy weight and regular exercise. Dietary intervention should be culturally appropriate and recognize limitations in family resources.

2. Medications

Pharmacologic therapy has been historically limited to two approved medications: metformin and insulin; however, in 2019, for the first time in almost 20 years, an additional medication, liraglutide (Victoza), was approved for youth with T2D age 10 and older.

With HbA_1C less than 8.5% and no symptoms or ketosis, metformin is usually started at a dose of 500 mg daily with dose increased weekly to a maximum dose of 1000 mg twice daily. If the presentation is more severe, with ketosis, HbA_1C 8.5% or greater, random blood glucose levels 250 mg/dL or greater, or uncertainty regarding the distinction between T1D and T2D, initial treatment should include insulin. An initial basal insulin dose of 0.25–0.5 U/kg is typically effective. Metformin can be initiated after ketosis has resolved. An attempt to wean insulin can be started after 2–6 weeks, once fasting and postprandial glucose levels have reached normal or near-normal levels. If target HbA_1C of less than 7% (47.5 mmol/mol) is not achieved within 4 months on metformin alone, basal insulin should be considered up to 1.5 U/kg/day. If target is not reached on combination metformin and basal insulin, prandial insulin should be started (MDI or insulin pump).

If glycemic targets are not met with metformin (with or without basal insulin), liraglutide should be considered in those 10 years of age or greater. Personal or family history or medullary thyroid carcinoma or multiple endocrine neoplasia type 2 are contraindications. Liraglutide is given by once-daily injection and results in higher levels of glucagon-like peptide-1 (GLP-1) that increases insulin production, reduces glucagon levels, delays gastric emptying, and decreases appetite. When combined with either metformin alone or metformin and insulin, liraglutide reduced HbA_1C by 0.64%. Similar to adults, youth experienced gastrointestinal side effects (nausea, vomiting and diarrhea); this can be minimized with low initial dose and gradual increase. Of note, youth on liraglutide improved weight loss relative to placebo at 1 year of treatment.

Clinical trials are underway examining the safety and efficacy of additional pharmacologic therapies.

3. Home glucose monitoring

Home blood glucose monitoring is typically less frequent in youth who are treated with metformin or lifestyle alone (eg, first morning and 2-hour postprandial test on 3 days per week); however, those taking insulin may require more frequent testing depending on the dose and type of insulin used.

Recommendations for the medical care of children and adolescents with diabetes and assessment of outcomes are summarized yearly in the American Diabetes Association’s position statement, Standards of Medical Care in Diabetes, as well as the International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines (available online references in the following text).

In the seminal DCCT trial, HbA_1C values of 7%, compared to 9%, resulted in greater than 50% reductions in the eye, kidney, cardiovascular, and neurologic complications of T1D. Unfortunately less than 30% of the US children and youth with T1D have HbA_1C of less than 7.5%. At present, the ADA and ISPAD recommend individualized goals for children and adolescents with diabetes. All children should have a target HbA_1C of less than 7.5%. In patients with access to comprehensive diabetes care with analog insulins, insulin pump technology and the ability closely monitor glucose via frequent fingersticks or use of CGM, ISPAD recommends a target HbA_1C of less than 7.0%. A goal of HbA_1C less than 7.5% may be more appropriate for those with resource-limited environments, a history of severe hypoglycemia, an inability to articulate symptoms of hypoglycemia (eg, young children), or hypoglycemia unawareness. A more stringent target of less than 6.5% (48 mmol/mol) may be appropriate in selected patients, particularly those with residual β-cell function, if this can be achieved without significant hypoglycemia. CGM time in range (time with sensor values between 70 and 180 mg/dL [3.9–10.0 mmol/L]) is becoming a useful measure of diabetes control in those using these devices. Recommended goals for blood glucose and CGM values to reach HbA_1C targets are shown in Table 35–4.

Complications

A. Diabetic Ketoacidosis (DKA)

Ketoacidosis (venous blood pH < 7.30 or bicarbonate < 15 mEq/L) is unfortunately still a frequent acute complication in patients with newly diagnosed T1D.

In established T1D, DKA may occur in those who miss insulin injections, do not check blood or urine ketone levels, or fail to seek help when ketones are elevated. Repeated episodes of DKA signify that counseling may be indicated, and that a responsible adult must take over the diabetes management. If, for any reason, this is not possible, a change in the child’s living situation may be necessary.

Treatment of DKA is based on four physiologic principles: (1) restoration of fluid volume; (2) intravenous insulin to inhibit lipolysis and return to glucose utilization; (3) replacement of electrolytes; and (4) correction of acidosis. Mild DKA is defined as a venous blood pH of 7.2–7.3; moderate DKA, a pH of 7.10–7.19; and severe DKA, a pH below 7.10. Patients with severe DKA should be hospitalized in a pediatric intensive care unit, if available. Laboratory tests at the start of treatment should include venous blood pH, glucose, and an electrolyte panel. More severe cases may benefit from determination of blood osmolality, calcium, phosphorus, and urea nitrogen levels. Severe and moderate episodes of DKA generally require hourly determinations of serum glucose, electrolytes, and venous pH levels, whereas these parameters can be measured every 2 hours if the pH level is 7.20–7.30.

1. Restoration of fluid volume

Dehydration is judged by estimated loss of body weight, dryness of oral mucous membranes, low blood pressure, and tachycardia. Initial treatment is with normal saline (0.9%), 10–20 mL/kg during the first hour (can be repeated in severely dehydrated patients during the second hour). The total volume of fluid in the first 4 hours of treatment should not exceed 20–40 mL/kg because of the danger of cerebral edema. After initial expansion, 0.45%–0.9% saline is given at 1.5 times maintenance to replace losses over 24–36 hours. When blood glucose level falls below 250 mg/dL (13.9 mmol/L), 5% dextrose is added to the intravenous fluids. If blood glucose level falls below 120 mg/dL (6.6 mmol/L), 10% dextrose can be added.

2. Inhibition of lipolysis and return to glucose utilization

Insulin turns off fat breakdown and ketone formation. After initial fluid bolus, regular insulin is given as a continuous drip at a rate of 0.05–0.1 U/kg/h to achieve drop in blood glucose of approximately 100 mg/dL/h. An IV insulin bolus is not recommended as it may increase the risk of brain edema. Insulin should be delayed pending potassium replacement if the patient is hypokalemic (see below). If necessary to address rapid fall in glucose or hypokalemia, the insulin dosage can be reduced, but it should not be discontinued before the venous blood pH reaches 7.30. Intravenous insulin should be continued for at least 30 minutes after the initial subcutaneous injection of both a long- and short-acting insulin to prevent rebound ketosis.

3. Replacement of electrolytes

In patients with DKA, both sodium and potassium are depleted. Serum sodium concentrations may be corrected for hyperglycemia. Sodium is usually replaced adequately by the use of 0.45%–0.9% saline in the rehydration fluids.

Although total body potassium is often depleted, serum potassium levels may be elevated initially because of inability of potassium to stay in the cell in the presence of acidosis. Potassium should not be added to IV fluids until the serum potassium level is known to be less than 5.0 mEq/L and urine output is confirmed. It is then usually given in replacement fluid at a concentration of 40 mEq/L, with half of the potassium (20 mEq/L) either as potassium acetate or potassium chloride and the other half as potassium phosphate (20 mEq/L). Hypocalcemia can occur if all of the potassium is given as the phosphate salt; hypophosphatemia may occur if none of the potassium is the phosphate salt.

If initial potassium is low, potassium replacement should be started at the time of initial fluid bolus and before initiation of insulin. Failure to adequately replace potassium before starting insulin can lead to life-threatening cardiac complications.

4. Correction of acidosis

Acidosis corrects spontaneously as the fluid volume is restored and insulin facilitates aerobic glycolysis and inhibits ketogenesis. Bicarbonate is generally not recommended as it may increase risk of cerebral edema.

5. Management of cerebral edema

Some degree of cerebral edema has been shown by computed tomography scan to occur commonly in DKA. Associated clinical symptoms are rare, unpredictable, and may be associated with demise. Cerebral edema may be related to the degree of dehydration, cerebral hypoperfusion, acidosis, and hyperventilation at the time of presentation. In general, it is recommended that no more than 40 mL/kg of fluids be given in the first 4 hours of treatment and that subsequent fluid replacement does not exceed 1.5 times maintenance. Cerebral edema is more common when the serum sodium is noted to be falling rather than rising. Early neurologic signs may include headache, excessive drowsiness, and dilated pupils. Prompt initiation of therapy should include elevation of the head of the bed, mannitol (1 g/kg over 30 minutes), and fluid restriction. Hypertonic saline (3%) at 2.5–5 mL/kg over 10–15 minutes may be used as an alternative to mannitol or in addition to mannitol if there has been no response to initial bolus. If the cerebral edema is not recognized and treated early, over 50% of patients will die or have permanent brain damage.

B. Hyperosmolar Hyperglycemic State

Hyperosmolar hyperglycemic state (HHS) is rare but a severe metabolic decompensation in an individual with some level of insulin production. It is associated with hyperglycemia (plasma glucose > 600 mg/dL/ 33.3 mmol/L) and hyperosmolarity above 320 mOsm/kg. There is typically little to no ketosis (negative or “trace” urine dipstick) or acidosis (bicarbonate > 15 mEq/L, venous pH > 7.25). HHS can often go unrecognized until a profound level of dehydration occurs, up to twice the fluid loss seen in DKA. Presentation frequently includes profound mental status changes, ranging from combativeness to coma. Complications of HHS most often relate to thromboembolic events. Rhabdomyolysis may also occur, with associated muscle swelling, kidney failure, and electrolyte disturbances including hypokalemia and hypocalcemia with cardiac arrhythmia or arrest leading to compartment syndrome. There are several reports of a malignant hyperthermia-like syndrome of unclear cause, and treatment with dantrolene should be initiated early in children with fever associated with a rise in creatine kinase. While HHS would be suspected to have a risk of cerebral edema similar to DKA, this complication has been reported exceedingly rarely. Similar to reports in adults, HHS in the pediatric population is more common in obese, male African Americans. The adult literature describes HHS as a complication of T2D; however, in the pediatric population, it has been reported in individuals with both T1D and T2D.

Children with HHS should be managed in an intensive care unit with cardiac monitoring and hourly evaluation of serum glucose, vital signs, and hydration status as well as close monitoring of electrolytes, kidney function, osmolality, and creatine kinase (to evaluate for evolving rhabdomyolysis). Cornerstones of care include restoration of fluid volume, avoidance of overly rapid decline in blood glucose, and replacement of electrolytes.

C. Hypoglycemia

Hypoglycemia (or “insulin reaction”) is the most common acute complication of T1D and is defined as a blood glucose level below 60 mg/dL (3.3 mmol/L). For preschool children, values below 70 mg/dL (3.9 mmol/L) should be cause for concern. The common symptoms of hypoglycemia are hunger, weakness, shakiness, sweating, drowsiness (at an unusual time), headache, and behavioral changes. If low blood glucose is not treated immediately with simple sugar, hypoglycemia may result in loss of consciousness and seizures; brain damage or death can occur with prolonged hypoglycemia. Severe hypoglycemic episodes (loss of consciousness or seizure) occur at a rate of about 3–7 events per 100 patient-years.

Children learn to recognize hypoglycemia at different ages but can often report “feeling funny” as young as age 4–5 years. School personnel, sports coaches, and babysitters must be trained to recognize and treat hypoglycemia. Consistency in daily routine, correct insulin dosage, regular blood glucose monitoring, controlled snacking, compliance of patients and parents, and good education are all important in preventing severe hypoglycemia. In addition, insulin should not be injected prior to getting into a hot tub, bath, or shower as the heat may cause more rapid insulin uptake. The use of insulin analogs as well as technologies including insulin pumps, CGM and “artificial pancreas” systems that use CGM input to control insulin output (see Treatment section) have all helped to reduce the occurrence of hypoglycemia.

The treatment of mild hypoglycemia involves giving 4 oz of juice; a sugar-containing soda drink, or milk; and waiting 10–15 minutes. If the blood glucose level is still below 60 mg/dL (3.3 mmol/L), the liquids are repeated. If the glucose level is above 60 mg/dL, solid foods are given. Moderate hypoglycemia, in which the person is conscious but incoherent, can be treated by squeezing one-half tube of concentrated glucose (eg, Insta-Glucose or cake frosting) between the gums and lips and stroking the throat to encourage swallowing.

Families are advised to have glucagon in the home and in their travel pack to treat severe hypoglycemia by giving subcutaneous or intramuscular injections of 0.3 mL (30 units in an insulin syringe) for children younger than 5 years; 0.5 mL (50 units) to those older than 5 years; and 1 mL (100 units) to those heavier than 100 lb. Smaller doses of glucagon (2 units + number of units equal to the age of the child, eg, 2 + 10 = 12 units in a 10-year-old) up to a maximum of 15 units can be used to prevent severe hypoglycemia during nondiabetic illness (gastroenteritis, respiratory infections). Nasal glucagon, when available, is as effective as injected glucagon for resolution of hypoglycemia.

Some patients fail to recognize the symptoms of low blood glucose (hypoglycemic unawareness), often after a history of at least 10 years of diabetes or frequent hypoglycemic events. For these individuals, use of CGM with hypoglycemia alarms or artificial pancreas technologies should be considered.

D. Long-Term Complications

Table 35–5 summarizes routine tests helpful in assessing for and preventing long-term complications.

1. Hypertension

Elevated blood pressure is prevalent among children with diabetes and strongly predicts micro- and macrovascular complications. Blood pressure should be evaluated at each clinic visit. If hypertension or high-normal blood pressure is confirmed, nondiabetic causes should first be excluded (see Chapter 20). High-normal blood pressure may be first addressed with dietary modification and exercise aimed at weight control, if appropriate, for 3–6 months before consideration of pharmacologic intervention. For confirmed hypertension, angiotensin-converting enzyme inhibitors are the first-line agents; if not tolerated well, angiotensin II receptor blockers can be used. Goal of therapy is blood pressure consistently below the 90th percentile for age, sex, and height. (The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents https://www.nhlbi.nih.gov/files/docs/resources/heart/hbp_ped.pdf.)

2. Lipid abnormalities

Lipid profiles are generally favorable in children with T1D, but dyslipidemia is more common in children with T2D. Good glycemic control should be established in newly diagnosed patients prior to screening, but screening should not be delayed more than 1 year after diagnosis. Abnormal results from a random lipid panel should be confirmed with a fasting lipid panel. Initial therapy includes optimizing glycemic control, increasing physical activity, and decreasing the amount of saturated fat in the diet using a step 2 American Heart Association diet. If lifestyle changes and improved diabetes management fail after 6 months, statin therapy should be considered. Criteria for considering stating therapy in T1D are age more than 10 years with low-density lipoprotein (LDL) levels greater than 160 mg/dL (4.1 mmol/L) or those with LDL greater than 130 mg/dL (3.4 mmol/L) and one or more cardiovascular disease risk factors. Criterion for statin therapy in youth with T2D is persistent LDL greater than 130 mg/dL (3.4 mmol/L). The treatment goals are LDL less than 100 mg/dL (2.6 mmol/L). Statins are teratogenic; therefore, prevention of unplanned pregnancies is critically important in postpubertal girls.

For youth with T2D and hypertriglyceridemia (fasting triglycerides > 400 mg/dL [5.6 mmol/L] or nonfasting > 1000 mg/dL [11.3 mmol/L]), beyond lifestyle modifications and promotion of weight loss, some studies have shown efficacy of omega-3 fatty acid supplementation at a dose of 2–4 g per day.

3. Nephropathy

Rapid decline of the glomerular filtration rate (GFR) is the first clinical manifestation of diabetic kidney disease and may be reversible with diligent glycemic and blood pressure control. Microalbuminuria is an established risk factor, defined as urinary albumin excretion rate between 20 and 200 mcg/min or urinary albumin/creatinine ratio 2.5–25 mg/mmol in males and 3.5–25 mg/mmol in females or 30–300 mg/g (spot urine). The diagnosis of microalbuminuria requires documentation of two out of three abnormal samples over a period of 3–6 months. Once persistent microalbuminuria is confirmed, nondiabetic causes of renal disease should be excluded. Following this evaluation, treatment with an ACE inhibitor should be started, even if the blood pressure is normal. Patients should be counseled about the importance of glycemic and blood pressure control and smoking cessation, if applicable. Patients with T2D should have microalbuminuria assessed soon after diagnosis and then annually.

4. Retinopathy

While rare in children, proliferative retinopathy does occur in adolescents with long duration and poor control of diabetes. Laser treatment to coagulate proliferating capillaries prevents bleeding and leakage of blood into the vitreous fluid or behind the retina. This treatment preserves useful vision.

5. Neuropathy

Annual comprehensive foot examination should include inspection; palpation of dorsalis pedis and posterior tibial pulses; evaluation of patellar and Achilles reflexes; and determination of proprioception, vibration, and monofilament sensation.

Table 35–5 summarizes recommended screening for autoimmune diseases in T1D.

While Hashimoto thyroiditis is the most common autoimmune thyroid disorder in children with T1D, Graves disease can also occur. Thyroid peroxidase autoantibody (TPO) is usually the first test to become abnormal in the autoimmune thyroiditis affecting up to 20% of individuals with T1D. If TPO is positive, screening with TSH is recommended every 6–12 months (for management of thyroid disease, see Chapter 34).

Transglutaminase autoantibodies offer a sensitive and specific screening test for celiac disease affecting up to 10% of children with T1D with the highest risk in those diagnosed with T1D before age 5. Risk of celiac disease is most strongly associated with the HLA-DR3-DQ2 haplotype. Signs and symptoms suggestive of celiac include poor growth or poor weight gain, abdominal pain, signs of malabsorption, frequent unexplained hypoglycemia, or deteriorating glycemic control. About one-half of celiac disease cases develop several years after diagnosis of T1D. Most of the biopsy-confirmed children are “asymptomatic,” but report improved health status upon initiation of gluten-free diet. Untreated celiac disease may lead to severe hypoglycemia, increased bone turnover, and decreased bone mineralization, among many other long-term complications (see Chapter 21).

The 21-hydroxylase autoantibody, a marker of increased risk of Addison disease, is present in approximately 1% of patients with T1D, although Addison disease develops (usually slowly) in only about one-third of these antibody-positive individuals (see Chapter 34 for further information). Other less common autoimmune disorders include rheumatoid arthritis, lupus, psoriasis, scleroderma, vitiligo, dermatomyositis, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, and myasthenia gravis.

At the time of diagnosis of T2D, comorbidities such as hypertension, dyslipidemia, nephropathy, and retinopathy may already be present and therefore should be evaluated within initial visits followed by ongoing screening (see Table 35–5). As T2D in youth frequently occurs in the setting of obesity, associated comorbidities should be assessed including hepatic steatosis, sleep apnea, and orthopedic complications (see Chapters 4 and 11 for discussion). In female adolescents with T2D, assessment for polycystic ovary syndrome (PCOS) should also be considered (see Chapter 4).

Prognosis

The long-term prognosis of children diagnosed with T1D has improved significantly over the past 20 years, primarily due to better control of blood glucose and blood pressure. While life expectancy is now only slightly shorter in these patients compared to the general population, the risk of cardiovascular disease in later adulthood is still 4–10 times higher, especially in women with diabetes. Observation of teenagers and young adults who had been diagnosed with diabetes during childhood or adolescence showed that youth with T2D had a significantly higher prevalence of complications compared to those with T1D.

Modern diabetes care generally leads to excellent health outcomes. Tremendous progress in biotechnology—insulin analogs, insulin pumps, continuous glucose sensing, as well as the artificial pancreas—has reduced risk acute and long-term complications. However, comprehensive and continuing education of patients and their families remains the foundation of a healthy and quality life with diabetes.