Chapter 35: Diabetes Mellitus

Type 1 Diabetes

Type 1 diabetes (T1D) is the most common type of diabetes mellitus in people younger than 20 years, but can develop at any age and most cases are diagnosed after age 20. The classical presentation includes increased thirst (polydipsia), ­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. T1a diabetes is marked by the presence of autoantibodies to islet cell autoantigens (insulin, GAD65, IA-2, and ZnT8) and high-risk HLA (human leucocyte antigen) haplotypes (DR4-DQ8, and DR3-DQ2). Insulin production, measured by fasting or stimulated C-peptide levels, is usually low. In the United States, T1D affects an estimated 1.5 million people, including more than 200,000 patients younger than age 20 (~25,000 diagnosed annually).

Type 2 Diabetes

Type 2 diabetes (T2D) is a heterogeneous phenotype diagnosed most often in persons older than age 40 who are usually obese and initially not insulin-dependent. T2D is rare before age 10, but has increased in frequency in older children as a consequence of the epidemic of obesity. The vast majority of the 29 million patients with diabetes in the United States have T2D, but less than 20,000 patients are younger than age 20 (~5000 diagnosed annually).

Monogenic Forms of Diabetes

Monogenic forms of diabetes can be diagnosed 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. All children diagnosed with diabetes in the first 6 months of life should have genetic screening for neonatal diabetes. Neonatal diabetes is transient in about 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.

Cystic Fibrosis-Related Diabetes

Cystic fibrosis-related diabetes (CFRD) occurs in about 20% of adolescents with cystic fibrosis and is the most common comorbidity in cystic fibrosis. 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 cystic fibrosis should be routinely screened starting by age 10, and treatment has been shown to improve outcomes.

A. Type 1 Diabetes

Type 1 diabetes (T1D) results from autoimmune destruction of the insulin-producing β cells of the pancreatic islets. This destruction occurs over months or years and symptoms do not appear until most of the pancreatic islets have been destroyed.

The incidence is the highest in children of European ancestry, followed by African Americans and Hispanics; the 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. 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 a more rapid decline in β-cell function and a 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 is more common in youth of ethnic and racial minorities. Puberty is a time of high risk for development of T2D in susceptible individuals. Other risk factors include female sex, poor diet and sleep, and low socioeconomic status. This combination of psychosocial and cultural factors can impact the effectiveness of lifestyle interventions, a key component of T2D management. T2D and associated insulin resistance adversely affect cardiovascular health.

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. There is no effective prevention as of 2018; however, screening of high-risk groups for islet autoantibodies and intensive follow-up reduces the severity of the presentation. Islet autoantibodies do not mediate β-cell destruction, but offer a useful screening tool as they are usually present for years prior to diagnosis. Free antibody screening is now available for children with a first- or second-degree a relative with T1D (TrialNet: 1-800-425-8361). The β-cell damage is mediated by T lymphocytes. Immunosuppression at different checkpoints of the autoimmune process can slow down the damage, but has no durable effect when stopped. Immunomodulation, including induction of tolerance to islet autoantigens, with or without immunosuppression, is an area of intensive research.

B. Type 2 Diabetes

The Diabetes Prevention Program in adults with impaired glucose tolerance 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%.

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 ~40%, a sign of poor provider and community awareness. More than half of DKA patients were seen by a provider in the days preceding diagnosis, and obvious symptoms and signs were missed. In contrast, only 10%–20% of newly diagnosed children in Scandinavia or Canada present with DKA. The correct diagnosis could be improved with better history taking and point-of-care urine analysis. Initial diagnosis can be easily confirmed by blood glucose and ketones measurement using widely available and inexpensive meters.

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

Acanthosis nigricans, a thickening and darkening of the skin over the posterior neck, armpits, or elbows, is present in many obese children and is not specific for the diagnosis of T2D.

B. Laboratory Findings

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 the presentation is mild and an outpatient diabetes education service is available, hospitalization is usually not necessary.

In the presence of typical symptoms, a random blood glucose level above 200 mg/dL (11 mmol/L) (confirmed on a CLIA [Clinical Laboratory Improvement Amendments]-certified instrument) is sufficient to make the diagnosis of diabetes. An oral glucose tolerance test is rarely necessary in children. In borderline or asymptomatic cases, a fasting plasma glucose level >125 mg/dL (7 mmol/L) or a plasma glucose level above 200 mg/dL (11.1 mmol/L) 2 hours after an oral glucose load (1.75 g glucose/kg up to a maximum of 75 g) on 2 separate days confirms the diagnosis. Impaired (not yet diabetic) fasting glucose values are 100–125 mg/dL (5.5–6.9 mmol/L) and impaired 2-hour values are 140–200 mg/dL (7.8–11.1 mmol/L). Children with impaired fasting glucose or impaired glucose tolerance and no islet autoantibodies are at high risk of T2D and require careful follow-up and lifestyle modification with weight loss, if obese. An HbA_1c ≥ 6.5 (48 mmol/L) is also diagnostic of diabetes. However, 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.

A combination of polyuria, polydipsia, and weight loss in a child is unique to diabetes.

Transient, “stress-” or steroid-induced hyperglycemia can occur with illness. 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. Testing such children for islet autoantibodies can help to rule out ongoing islet autoimmunity. The absence of the three most available autoantibodies (to insulin, GAD, and IA-2) provides 80% negative predictive value. 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 dinner 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 under age 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, signs of insulin resistance such as acanthosis nigricans and pubertal status. It should be noted that up to 10% of children with T2D present in DKA.

A. Diabetic Ketoacidosis

Acidosis (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, acidosis 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 ketoacidosis 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 completion of the 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 ~100 mg/dL per hour. An IV insulin bolus is not recommended as it may increase the risk of brain edema. Fast-acting insulin analogs have no advantage over regular insulin when given intravenously. The insulin solution should be administered by pump and can be made by diluting 30 units of regular insulin in 150 mL of 0.9% saline (1 U/5 mL). If necessary, the insulin dosage can be reduced, but it should not be discontinued before the venous blood pH reaches 7.30 and there is sufficient level of insulin from subcutaneous injections. 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 < 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.

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. 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 (HHS)

Hyperosmolar hyperglycemic state (HHS) is 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 kidney failure, hypokalemia and hypocalcemia with cardiac arrhythmia or arrest and muscle swelling 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. Risk of thrombosis, however, is much greater than in DKA. Similar to reports in adults, HHS in the pediatric population is more common in obese, male African Americans. While the adult literature describes HHS as a complication of T2D, in the pediatric population, it has been reported in individuals with both type 1 and type 2 diabetes.

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. The risk versus benefit of central venous pressure monitoring should be considered due to heightened thrombotic risk, and if instituted, prophylactic measures should be considered. Labs should be monitored every 2–3 hours including serum electrolytes, blood urea nitrogen, creatinine, osmolality and creatine kinase (to evaluate for evolving rhabdomyolysis). Additionally, serum calcium, phosphate and magnesium should be evaluated every 3–4 hours.

1. Restoration of fluid volume

Because of initial severe dehydration, as well as the ongoing osmotic diuresis that persists following onset of care, aggressive fluid replacement is necessary to restore renal perfusion, promote gradual decline in serum sodium concentration and osmolality, and to avoid vascular collapse and associated morbidity. A minimum initial bolus of 20 mL/kg of normal saline (0.9%) should be followed by additional boluses as needed to restore peripheral perfusion. Typical fluid deficits of 12%–15% of body weight should be replaced using hypotonic fluids (0.45%–0.75% NaCl) over the next 24–48 hours, with a goal of gradual normalization of serum sodium and osmolality. Isotonic fluids may be restarted if there is hemodynamic decompensation with declining osmolality. Replacement of urinary losses is also recommended. There are no data on optimal rate of decline for serum sodium; however, a rate of 0.5 mEq/L/h has been recommended. Serum glucose should decline by 75–100 mg/dL/h (4.1–5.5 mmol/L/h), with the exception of the first few hours, which may show a more rapid decline. Lack of glucose decline may indicate renal dysfunction or presence of large amounts of glucose-containing fluids in the stomach.

2. Insulin therapy

As HHS is not typically associated with significant ketosis, early insulin administration is not necessary and may be detrimental. Overly rapid decline in blood glucose may lead to decreased circulation and increased thrombotic risk. Further, insulin may exacerbate severe whole-body potassium deficits by shifting potassium to the intracellular space and increasing risk of arrhythmia. Insulin should be considered when serum glucose is no longer declining substantially with rehydration alone (< 50 mg/dL/h, < 3 mmol/L/h) or in the case of more severe ketosis and presence of acidosis. Initial continuous infusion rate of 0.025–0.05 units/kg/h can be titrated to achieve a serum glucose decrease of 50–75 mg/dL/h (2.7–4.1 mmol/L/h). Insulin should be suspended if serum glucose drops faster than 100 mg/dL/h (5.5 mmol/L/h).

3. Replacement of electrolytes

Electrolyte changes, particularly in potassium, phosphate and magnesium, can also be more severe than in DKA. Potassium should be replaced as soon as renal function has been confirmed and potassium is < 5 mEq/L. IV fluids should contain half (20 mEq/L) as potassium chloride and the other half as potassium phosphate (20 mEq/L). Magnesium replacement should be considered in patients with hypocalcemia and low magnesium with a recommended dose of 25–50 mg/kg/dose every 4–6 hours for a total of 3–4 doses (maximum infusion rate 150 mg/min and 2 g/h).

C. Hypoglycemia

Hypoglycemia (or “insulin reaction”) 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, the 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, continuous glucose monitoring (CGM) and “artificial pancreas” insulin pumps which 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 age 5 years; 0.5 mL (50 units) to those older than age 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 non-diabetic illness (gastroenteritis, respiratory infections).

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 35–1 summarizes routine tests helpful in preventing long-term complications.

1. Hypertension

Elevated blood pressure is prevalent among children with diabetes and strongly predicts micro- and macrovascular complications. Treatment of blood pressure is critical in reducing these complications in adults with diabetes and presumably in children and adolescents as well. Blood pressure should be checked and reviewed at each clinic visit. Hypertension is defined as systolic or diastolic blood pressure (measured on at least three separate days) above the 95th percentile for the child’s age, sex, and height. If hypertension or high-normal blood pressure (≥90th percentile for age) is confirmed, non-diabetic causes should first be excluded (see Chapter 20 Cardiovascular Disease). Angiotensin-converting enzyme inhibitors are the first-line agents for hypertension; if not tolerated well, angiotensin II receptor blockers can be used. 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. 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. The screening for dyslipidemia should commence after the age of 10 years and, if normal, should be repeated every 3–5 years. In children with a significant family history of cardiovascular disease, screening should begin at 2 years of age. 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 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 fails after 6 months, statin therapy should be considered in children with 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. The treatment goals are LDL less than 100 mg/dL (2.6 mmol/L), HDL more than 35 mg/dL (0.9 mmol/L), and triglycerides less than 150 mg/dL (1.7 mmol/L). Statins are teratogenic, therefore prevention of unplanned pregnancies is critically important in postpubertal girls.

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). Screening for microalbuminuria with a random spot urine sample should occur annually in children once they are 10 years of age and have had diabetes for more than 3–5 years. If values are abnormal or borderline, two timed overnight collections should occur. 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, non-diabetic 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

The first dilated ophthalmologic examination should be obtained by an ophthalmologist or optometrist trained in diabetes-specific retinal examination once the child is ≥ 10-years old and has had diabetes for 3–5 years. The frequency of subsequent examination is generally every 1–2 years, depending on the patient risk profile and advice of the eye care provider. 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 begin at age 10 years or the start of puberty, whichever is earlier, in children who have had T1D for at least 5 years. This 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.

Thyroid-stimulating hormone (TSH) level should be measured at diagnosis and every 1–2 years in all patients with T1D. Thyroid peroxidase autoantibody (TPO) is usually the first test to become abnormal in the autoimmune thyroiditis affecting up to 20% of children 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. Risk of celiac disease is most strongly associated with the HLA-DR3-DQ2 haplotype. Routine screening is recommended at diagnosis of diabetes and, if negative, screening should be repeated at least at 2 and 5 years post diagnosis. Screening should also be considered, every 1–2 years, in those with a first-degree relative with celiac disease, poor growth or poor weight gain, abdominal pain, signs of malabsorption, frequent unexplained hypoglycemia or deteriorating glycemic control. About 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).

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 35–1). 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).

Treatment of both type 1 and type 2 diabetes 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 Priniciples 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. 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 injections, 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 Understanding Diabetes and Understanding Insulin Pumps, Continuous Glucose Monitors, and the Artificial Pancreas) 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. Persisting 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. Regular 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 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—and more frequently in patients who have glucose-control problems or intercurrent illnesses. Blood glucose levels can be monitored using any downloadable meter. Target levels when no food has been eaten for 2 or more hours vary according to age (Table 35–2).

The frequency of self-monitoring of blood glucose correlates with improved HbA_1c. Blood glucose results, insulin dosage, and events, for example, illness, parties, exercise, menses, and episodes of hypoglycemia or ketonuria/ketosis should be recorded in a logbook or downloaded. Regular evaluation by the family helps to see patterns, adjust insulin dosage and, if needed, communicate with health care providers. If more than 50% 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 by telephone, fax, email or via data shared in the cloud 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 (see Table 35–1).

CGM is now routinely available and can tremendously 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 6–7 days. A transmitter sends glucose levels via radio waves or Bluetooth from the sensor to a receiver that can be inside an insulin pump, smartphone, or separate receiver device. As with insulin pump therapy, intensive education and follow-up is 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 personalized range. Low and high blood glucose alarms can be set and in some systems CGM data may be used to automatically change insulin pump delivery rate. At the time of consultation, data from CGM devices and pumps are routinely downloaded for analysis of patterns.

The FDA has now approved insulin dosing based on the Dexcom 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.

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 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. Alternatively to a precise carb counting, “exchanges” are 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 have adequate oral intake, the initial insulin dose can be administered subcutaneously as 0.2 U/kg of short-acting insulin (regular) or, preferentially, rapid-acting analog: lispro (Humalog), aspart (NovoLog), or glulisine (Apidra). At the same time, 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. 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 (q2–4h) 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 > 12% commonly require 1.0–1.5 U/kg/day of insulin during the initial week of treatment. Children younger than age 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 multiple daily injections (MDI). This usually consists of 3–4 injections (boluses) of rapid-acting analog before meals and 1–2 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 1 or 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 is often 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. Analog insulin (glargine, detemir) works more efficiently than NPH. 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 which include: insulin-to-carbohydrate ratios, insulin sensitivity factor, glycemic target, and duration of insulin action (set at 3–4 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 the 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 which 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 2 hours. Other systems react to predicted, rather than current, low or high blood glucose levels. Finally, the MiniMed 670G hybrid closed loop became available in 2017. It 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 and insulin therapy

Hypoglycemia during exercise or in the 2–12 hours after exercise can be prevented by careful monitoring of blood glucose before, during, and after exercise; reducing the dosage of the insulin active at the time of (or after) the exercise; and by 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 3–4 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/Poweraid or other glucose-containing beverages.

Mild ketonuria/ketonemia secondary to fasting or acute gastrointestinal upset and associated with normal or low blood/CGM glucose does not require supplemental insulin treatment. Of note, the brain uses β-hydroxybutyrate as the alternate fuel to glucose in the setting of hypoglycemia. Overtreatment with insulin during a sick day that begins with hyperglycemia and ketosis may lead to severe hypoglycemia resulting in loss of consciousness and/or seizures.

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 intervention is a cornerstone of T2D management in adults; however, results have been more mixed in the pediatric population. This may reflect the complex family and environmental context for T2D in youth, which may be resistant to individual-level interventions. 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

Current pharmacologic therapy is limited to two approved medications: metformin and insulin. With HbA_1c ≤ 9.0% and no 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 more than 9.0%, random blood glucose levels ≥ 250 mg/dL, or uncertainty regarding the distinction between T1D and T2D, initial treatment should include insulin. Metformin can be initiated after ketosis has resolved. An attempt to wean insulin can be started once fasting and postprandial glucose levels have reached normal or near-normal levels. Clinical trials are underway examining the safety and efficacy of other pharmacologic therapies, but none are currently approved in the pediatric population.

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 as well as assessment of outcomes are summarized yearly in the American Diabetes Association’s position statement, Standards of Medical Care in Diabetes, available online and in mobile format. (http://professional.diabetes.org/content/clinical-practice-recommendations.)

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. At present, the safest recommendation for glycemic control in children is to achieve an HbA_1c less than 7.5%. Unfortunately less than 30% of the US children and youth with T1D meet this goal.

The long-term prognosis of children diagnosed with T1D has improved tremendously 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 four to ten times higher, especially in diabetic women. 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 made the prevention of acute and long-term complications achievable. However, comprehensive and continuing education of patients and their families remains the foundation of a healthy and quality life with diabetes.