Pediatric Type 1 Diabetes Mellitus

Author: William H Lamb, MBBS, MD, FRCP(Edin), FRCP, FRCPCH; Chief Editor: Stephen Kemp, MD, PhD

Background
Most pediatric patients with diabetes have type 1 diabetes mellitus (T1DM) and a lifetime dependence on exogenous insulin. Diabetes mellitus (DM) is a chronic metabolic disorder caused by an absolute or relative deficiency of insulin, an anabolic hormone. Insulin is produced by the beta cells of the islets of Langerhans located in the pancreas, and the absence, destruction, or other loss of these cells results in type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]). A possible mechanism for the development of type 1 diabetes is shown in the image below. (See Etiology.)

Possible mechanism for development of type 1 diabetes.

Type 2 diabetes mellitus (noninsulin-dependent diabetes mellitus [NIDDM]) is a heterogeneous disorder. Most patients with type 2 diabetes mellitus have insulin resistance, and their beta cells lack the ability to overcome this resistance.[1] Although this form of diabetes was previously uncommon in children, in some countries, 20% or more of new patients with diabetes in childhood and adolescence have type 2 diabetes mellitus, a change associated with increased rates of obesity. Other patients may have inherited disorders of insulin release, leading to maturity onset diabetes of the young (MODY) or congenital diabetes.[2, 3, 4] This topic addresses only type 1 diabetes mellitus. (See Etiology and Epidemiology.)
Hypoglycemia

Hypoglycemia is probably the most disliked and feared complication of diabetes, from the point of view of the child and the family. Children hate the symptoms of a hypoglycemic episode and the loss of personal control it may cause. (See Pathophysiology and Clinical.)[5] Manage mild hypoglycemia by giving rapidly absorbed oral carbohydrate or glucose; for a comatose patient, administer an intramuscular injection of the hormone glucagon, which stimulates the release of liver glycogen and releases glucose into the circulation. Where appropriate, an alternative therapy is intravenous glucose (preferably no more than a 10%

glucose solution). All treatments for hypoglycemia provide recovery in approximately 10 minutes. (See Treatment.) Occasionally, a child with hypoglycemic coma may not recover within 10 minutes, despite appropriate therapy. Under no circumstances should further treatment be given, especially intravenous glucose, until the blood glucose level is checked and still found to be subnormal. Overtreatment of hypoglycemia can lead to cerebral edema and death. If coma persists, seek other causes. Hypoglycemia was a particular concern in children younger than 4 years because the condition was thought to lead to possible intellectual impairment later in life. Persistent hyperglycemia is now believed to be more damaging.
Hyperglycemia

In an otherwise healthy individual, blood glucose levels usually do not rise above 180 mg/dL (9 mmol/L). In a child with diabetes, blood sugar levels rise if insulin is insufficient for a given glucose load. The renal threshold for glucose reabsorption is exceeded when blood glucose levels exceed 180 mg/dL (10 mmol/L), causing glycosuria with the typical symptoms of polyuria and polydipsia. (See Pathophysiology, Clinical, and Treatment.) All children with diabetes experience episodes of hyperglycemia, but persistent hyperglycemia in very young children (age < 4 y) may lead to later intellectual impairment. [6,
7]

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is much less common than hypoglycemia but is potentially far more serious, creating a life-threatening medical emergency. Ketosis usually does not occur when insulin is present. In the absence of insulin, however, severe hyperglycemia, dehydration, and ketone production contribute to the development of DKA. The most serious complication of DKA is the development of cerebral edema, which increases the risk of death and long-term morbidity. Very young children at the time of first diagnosis are most likely to develop cerebral edema. DKA usually follows increasing hyperglycemia and symptoms of osmotic diuresis. Users of insulin pumps, by virtue of absent reservoirs of subcutaneous insulin, may present with ketosis and more normal blood glucose levels. They are more likely to present with nausea, vomiting, and abdominal pain, symptoms similar to food poisoning. DKA may manifest as respiratory distress.
Injection-site hypertrophy

If children persistently inject their insulin into the same area, subcutaneous tissue swelling may develop, causing unsightly lumps and adversely affecting insulin absorption. Rotating the injection sites resolves the condition. Fat atrophy can also occur, possibly in association with insulin antibodies. This condition is much less common but is more disfiguring.

Diabetic retinopathy

The most common cause of acquired blindness in many developed nations, diabetic retinopathy is rare in the prepubertal child or within 5 years of onset of diabetes. The prevalence and severity of retinopathy increase with age and are greatest in patients whose diabetic control is poor. Prevalence rates seem to be declining, yet an estimated 80% of people with type 1 diabetes mellitus develop retinopathy.[8]
Diabetic nephropathy and hypertension

The exact mechanism of diabetic nephropathy is unknown. Peak incidence is in postadolescents, 10-15 years after diagnosis, and it may occur in as many as 30% of people with type 1 diabetes mellitus.[9] In a patient with nephropathy, the albumin excretion rate (AER) increases until frank proteinuria develops, and this may progress to renal failure. Blood pressure rises with increased AER, and hypertension accelerates the progression to renal failure. Having diabetic nephropathy also increases the risk of significant diabetic retinopathy. Progression may be delayed or halted by improved diabetes control, administration of angiotensin-converting enzyme inhibitors (ACE inhibitors), and aggressive blood pressure control. Regular urine screening for microalbuminuria provides opportunities for early identification and treatment to prevent renal failure. A child younger than 15 years with persistent proteinuria may have a nondiabetic cause and should be referred to a pediatric nephrologist for further assessment.
Peripheral and autonomic neuropathy

The peripheral and autonomic nerves are affected in type 1 diabetes mellitus. Hyperglycemic effects on axons and microvascular changes in endoneural capillaries are amongst the proposed mechanisms. Autonomic changes involving cardiovascular control (eg, heart rate, postural responses) have been described in as many as 40% of children with diabetes. Cardiovascular control changes become more likely with increasing duration and worsening control.[10] In adults, peripheral neuropathy usually occurs as a distal sensory loss. Gastroparesis is another complication, and it which may be caused by autonomic dysfunction. Gastric emptying is significantly delayed, leading to problems of bloating and unpredictable excursions of blood glucose levels.
Macrovascular disease

Although this complication is not seen in pediatric patients, it is a significant cause of morbidity and premature mortality in adults with diabetes. People with type 1 diabetes mellitus have twice the risk of fatal myocardial infarction (MI) and stroke that people unaffected with diabetes do; in women, the MI risk is 4 times greater. People with type 1 diabetes mellitus also have 4 times greater risk for atherosclerosis.

The combination of peripheral vascular disease and peripheral neuropathy can cause serious foot pathology. Smoking, hypertension, hyperlipidemia, and poor diabetic control greatly increase the risk of vascular disease. Smoking, in particular, may increase the risk of myocardial infarction by a factor of 10.
Autoimmune diseases

Hypothyroidism affects 2-5% of children with diabetes.[11] Hyperthyroidism affects 1% of children with diabetes; the condition is usually discovered at the time of diabetes diagnosis. Although Addison disease is uncommon, affecting less than 1% of children with diabetes, it is a life-threatening condition that is easily missed. Addison disease may reduce the insulin requirement and increase the frequency of hypoglycemia. (These effects may also be the result of unrecognized hypothyroidism.) Celiac disease, associated with an abnormal sensitivity to gluten in wheat products, is probably a form of autoimmune disease and may occur in as many as 5% of children with type 1 diabetes mellitus.[12] Necrobiosis lipoidica is probably another form of autoimmune disease. This condition is usually, but not exclusively, found in patients with type 1 diabetes. Necrobiosis lipoidica affects 1-2% of children and may be more common in children with poor diabetic control.
Limited joint mobility

Limited joint mobility (primarily affecting the hands and feet) is believed to be associated with poor diabetic control.[13] Originally described in approximately 30% of patients with type 1 diabetes mellitus, limited joint mobility occurs in 50% of patients older than age 10 years who have had diabetes for longer than 5 years. The condition restricts joint extension, making it difficult to press the hands flat against each other. The skin of patients with severe joint involvement has a thickened and waxy appearance. Limited joint mobility is associated with increased risks for diabetic retinopathy and nephropathy. Improved diabetes control over the past several years appears to have reduced the frequency of these additional complications by a factor of approximately 4. Patients have also markedly fewer severe joint mobility limitations.

Pathophysiology
Insulin is essential to process carbohydrates, fat, and protein. Insulin reduces blood glucose levels by allowing glucose to enter muscle cells and by stimulating the conversion of glucose to glycogen (glycogenesis) as a carbohydrate store. Insulin also inhibits the release of stored glucose from liver glycogen (glycogenolysis) and slows the breakdown of fat to triglycerides, free fatty acids, and ketones. It also stimulates fat storage. Additionally, insulin inhibits the breakdown of protein and fat for glucose production (gluconeogenesis) in the liver and kidneys.

Hyperglycemia

Hyperglycemia (ie, random blood glucose concentration of more than 200 mg/dL or 11 mmol/L) results when insulin deficiency leads to uninhibited gluconeogenesis and prevents the use and storage of circulating glucose. The kidneys cannot reabsorb the excess glucose load, causing glycosuria, osmotic diuresis, thirst, and dehydration. Increased fat and protein breakdown leads to ketone production and weight loss. Without insulin, a child with type 1 diabetes mellitus wastes away and eventually dies due to DKA. The effects of insulin deficiency are shown in the image below.

The effects of insulin deficiency. Hypoglycemia

Insulin inhibits glucogenesis and glycogenolysis, while stimulating glucose uptake. In nondiabetic individuals, insulin production by the pancreatic islet cells is suppressed when blood glucose levels fall below 83 mg/dL (4.6 mmol/L). If insulin is injected into a treated child with diabetes who has not eaten adequate amounts of carbohydrates, blood glucose levels progressively fall. The brain depends on glucose as a fuel. As glucose levels drop below 65 mg/dL (3.2 mmol/L) counterregulatory hormones (eg, glucagon, cortisol, epinephrine) are released, and symptoms of hypoglycemia develop. These symptoms include sweatiness, shaking, confusion, behavioral changes, and, eventually, coma when blood glucose levels fall below 30-40 mg/dL. The glucose level at which symptoms develop varies greatly from individual to individual (and from time to time in the same individual), depending in part on the duration of diabetes, the frequency of hypoglycemic episodes, the rate of fall of glycemia, and overall control. (Glucose is also the sole energy source for erythrocytes and the kidney medulla.)

Etiology
Most cases (95%) of type 1 diabetes mellitus are the result of environmental factors interacting with a genetically susceptible person. This interaction leads to the development of autoimmune disease directed at the insulin-producing cells of the pancreatic islets of Langerhans. These cells are progressively destroyed, with insulin deficiency usually developing after the destruction of 90% of islet cells.

Genetic issues

Clear evidence suggests a genetic component in type 1 diabetes mellitus. Monozygotic twins have a 60% lifetime concordance for developing type 1 diabetes mellitus, although only 30% do so within 10 years after the first twin is diagnosed. In contrast, dizygotic twins have only an 8% risk of concordance, which is similar to the risk among other siblings. The frequency of diabetes development in children with a mother who has diabetes is 2-3%; this figure increases to 5-6% for children with a father who has type 1 diabetes mellitus. The risk to children rises to almost 30% if both parents are diabetic. Human leukocyte antigen (HLA) class II molecules DR3 and DR4 are associated strongly with type 1 diabetes mellitus. More than 90% of whites with type 1 diabetes mellitus express 1 or both of these molecules, compared with 50-60% of the general population. Patients expressing DR3 are also at risk for developing other autoimmune endocrinopathies and celiac disease. These patients are more likely to develop diabetes at a later age, to have positive islet cell antibodies, and to appear to have a longer period of residual islet cell function. Patients expressing DR4 are usually younger at diagnosis and more likely to have positive insulin antibodies, yet they are unlikely to have other autoimmune endocrinopathies. The expression of both DR3 and DR4 carries the greatest risk of type 1 diabetes mellitus; these patients have characteristics of both the DR3 and DR4 groups. Neonatal diabetes, including diagnosis in infants younger than age 6 months, is most likely due to an inherited defect of the iKir6.2 subunit potassium channel of the islet beta cells, and genetic screening is indicated.[14] This is particularly important, because these children respond well to sulphonylurea therapy.
Environmental factors

Environmental factors are important, because even identical twins have only a 30-60% concordance for type 1 diabetes mellitus and because incidence rates vary in genetically similar populations under different living conditions.[15] No single factor has been identified, but infections and diet are considered the 2 most likely environmental candidates. Viral infections may be the most important environmental factor in the development of type 1 diabetes mellitus,[16] probably by initiating or modifying an autoimmune process. Instances have been reported of a direct toxic effect of infection in congenital rubella. One survey suggests enteroviral infection during pregnancy carries an increased risk of type 1 diabetes mellitus in the offspring. Paradoxically, type 1 diabetes mellitus incidence is higher in areas where the overall burden of infectious disease is lower. Dietary factors are also relevant. Breastfed infants have a lower risk for type 1 diabetes, and a direct relationship is observed between per capita cow's milk consumption and the incidence of diabetes. Some cow's milk proteins (eg, bovine serum albumin) have antigenic similarities to an islet cell antigen.

Nitrosamines, chemicals found in smoked foods and some water supplies, are known to cause type 1 diabetes mellitus in animal models; however, no definite link has been made with humans. The known association of increasing incidence of type 1 diabetes mellitus with distance from the equator may now have an explanation. Reduced exposure to ultraviolet (UV) light and lower vitamin D levels, both of which are more likely found in the higher latitudes, are associated with an increased risk of type 1 diabetes mellitus.[17]
Chemical causes

Streptozotocin and RH-787, a rat poison, selectively damages islet cells and can cause type 1 diabetes mellitus.
Other causes

Additional factors in the development of type 1 diabetes mellitus include the following:

Congenital absence of the pancreas or islet cells Pancreatectomy Pancreatic damage (ie, cystic fibrosis, chronic pancreatitis, thalassemia major, hemochromatosis, hemolytic-uremic syndrome) Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness [DIDMOAD]) Chromosomal disorders such as Down syndrome, Turner syndrome, Klinefelter syndrome, or Prader-Willi syndrome (the risk is said to be around 1% in Down and Turner syndromes)

Epidemiology
Occurrence in the United States

The overall annual incidence of diabetes mellitus is about 24.3 cases per 100,000 personyears. Although most new diabetes cases are type 1 (approximately 15,000 annually), increasing numbers of older children are being diagnosed with type 2 diabetes mellitus, especially among minority groups (3700 annually).[18]
International occurrence

Type 1 diabetes mellitus has wide geographic variation in incidence and prevalence.[19] Annual incidence varies from 0.61 cases per 100,000 population in China to 41.4 cases per 100,000 population in Finland. Substantial variations are observed between nearby countries with differing lifestyles, such as Estonia and Finland, and between genetically similar populations, such as those in Iceland and Norway. A population-based, nationwide cohort study in Finland examined the short -and long-term time trends in mortality among patients with early-onset and late-onset type 1 diabetes. The results suggest that in those with early-onset type 1 diabetes (age 0-14 y), survival has improved over time. Survival of those with late-onset type 1 diabetes (15-29 y) has deteriorated since the 1980s, and the ratio of deaths caused by acute complications has increased in this group. Overall, alcohol was noted as an important cause of death in patients

with type 1 diabetes; women had higher standardized mortality ratios than did men in both groups.[20] Even more striking are the differences in incidence between mainland Italy (8.4 cases per 100,000 population) and the Island of Sardinia (36.9 cases per 100,000 population). These variations strongly support the importance of environmental factors in the development of type 1 diabetes mellitus. Most countries report that incidence rates have at least doubled in the last 20 years. Incidence appears to increase with distance from the equator.[21]
Race-related demographics

Different environmental effects on type 1 diabetes mellitus development complicate the influence of race, but racial differences are evident. Whites have the highest reported incidence, whereas Chinese individuals have the lowest. Type 1 diabetes mellitus is 1.5 times more likely to develop in American whites than in American blacks or Hispanics. Current evidence suggests that when immigrants from an area with low incidence move to an area with higher incidence, their rates of type 1 diabetes mellitus tend to increase toward the higher level.
Sex-related demographics

The influence of sex varies with the overall incidence rates. Males are at greater risk in regions of high incidence, particularly older males, whose incidence rates often show seasonal variation. Females appear to be at a greater risk in low-incidence regions.
Age-related demographics

Type 1 diabetes mellitus can occur at any age, but incidence rates generally increase with age until midpuberty and then decline.[22] Onset in the first year of life, although unusual, can occur, so type 1 diabetes mellitus must be considered in any infant or toddler, because these children have the greatest risk for mortality if diagnosis is delayed. (Because diabetes is easily missed in an infant or preschool-aged child, if in doubt, check the urine for glucose.) Symptoms in infants and toddlers may include the following:

Severe monilial diaper/napkin rash Unexplained malaise Poor weight gain or weight loss Increased thirst Vomiting and dehydration, with a constantly wet napkin/diaper

In areas with high prevalence rates, a bimodal variation of incidence has been reported that shows a definite peak in early childhood (ie, ages 4-6 y) and a second, much greater peak of incidence during early puberty (ie, ages 10-14 y).[23]

Prognosis
Apart from severe DKA or hypoglycemia, type 1 diabetes mellitus has little immediate morbidity. The risk of complications relates to diabetic control. With good management, patients can expect to lead full, normal, and healthy lives. Nevertheless, the average life

expectancy of a child diagnosed with type 1 diabetes mellitus has been variously suggested to be reduced by 13-19 years, compared with their nondiabetic peers.[24]
Morbidity and mortality

Information on mortality rates for type 1 diabetes mellitus is difficult to ascertain without complete national registers of childhood diabetes, although age-specific mortality is probably double that of the general population.[25, 26] Children aged 1-4 years are particularly at risk and may die due to DKA at the time of diagnosis. Adolescents are also a high-risk group. Most deaths result from delayed diagnosis or neglected treatment and subsequent cerebral edema during treatment for DKA, although untreated hypoglycemia also causes some deaths. Unexplained death during sleep may also occur and appears more likely to affect young males.[27] A population-based, nationwide cohort study in Finland examined the short -and long-term time trends in mortality among patients with early-onset and late-onset type 1 diabetes. The results suggest that in those with early-onset type 1 diabetes (age 0-14 y), survival has improved over time. Survival of those with late-onset type 1 diabetes (15-29 y) has deteriorated since the 1980s, and the ratio of deaths caused by acute complications has increased in this group. Overall, alcohol was noted as an important cause of death in patients with type 1 diabetes; women had higher standardized mortality ratios than did men in both groups.[20] The complications of type 1 diabetes mellitus can be divided into 3 major categories: acute complications, long-term complications, and complications caused by associated autoimmune diseases. Acute complications, which include hypoglycemia, hyperglycemia, and DKA, reflect the difficulties of maintaining a balance between insulin therapy, dietary intake, and exercise. Long-term complications arise from the damaging effects of prolonged hyperglycemia and other metabolic consequences of insulin deficiency on various tissues. Although long-term complications are rare in childhood, maintaining good control of diabetes is important to prevent complications from developing in later life.[28] The likelihood of developing complications appears to depend on the interaction of factors such as metabolic control, genetic susceptibility, lifestyle (eg, smoking, diet, exercise), pubertal status, and gender.[29, 30] Long-term complications include the following:

Retinopathy Cataracts Gastroparesis Hypertension Progressive renal failure Early coronary artery disease Peripheral vascular disease Peripheral and autonomic neuropathy Increased risk of infection

Associated autoimmune diseases are common in type 1 diabetes mellitus, particularly in children who have HLA-DR3. Some conditions may precede the development of diabetes,

and others may develop later. As many as 20% of children with diabetes have thyroid autoantibodies.[31]

Patient Education
Education is a continuing process involving the child, family, and all members of the diabetes team. (See the videos below.)[32, 33] The following strategies may be used:

Formal education sessions in a clinic setting Opportunistic teaching at clinics or at home in response to crises or difficulties such as acute illness Therapeutic camping or other organized events Patient-organized meetings Diabetes Sick Day Rules. Taking Diabetes Back to School. Carbs for Kids-Count Them In: The Constant Carbohydrates Diet.

Diabetes-related organizations and patient groups include the following:[34]

Children with Diabetes - This "online community for kids, families, and adults with diabetes" is an excellent resource with good links International Society for Pediatric and Adolescent Diabetes International Diabetes Federation Diabetes UK American Diabetes Association Juvenile Diabetes Research Foundation International Runsweet - This is a Web site devoted to giving advice on exercise management and diabetes

History
The most easily recognized symptoms of type 1 diabetes mellitus (T1DM) are secondary to hyperglycemia, glycosuria, and DKA.
Hyperglycemia

Hyperglycemia alone may not cause obvious symptoms, although some children report general malaise, headache, and weakness. Children may also appear irritable and become illtempered. The main symptoms of hyperglycemia are secondary to osmotic diuresis and glycosuria.
Glycosuria

This condition leads to increased urinary frequency and volume (eg, polyuria), which is particularly troublesome at night (eg, nocturia) and often leads to enuresis in a previously

continent child. These symptoms are easy to overlook in infants because of their naturally high fluid intake and diaper/napkin use.
Polydipsia

Increased thirst, which may be insatiable, is secondary to the osmotic diuresis causing dehydration.
Weight loss

Insulin deficiency leads to uninhibited gluconeogenesis, causing breakdown of protein and fat. Weight loss may be dramatic, although the child's appetite usually remains good. Failure to thrive and wasting may be the first symptoms noted in an infant or toddler and may precede frank hyperglycemia.
Nonspecific malaise

Although this condition may be present before symptoms of hyperglycemia or as a separate symptom of hyperglycemia, it is often only retrospectively recognized.
Symptoms of ketoacidosis

These symptoms include the following:

Severe dehydration Smell of ketones Acidotic breathing (ie, Kussmaul respiration), masquerading as respiratory distress Abdominal pain Vomiting Drowsiness and coma

Additional symptoms

Hyperglycemia impairs immunity and renders a child more susceptible to recurrent infection, particularly of the urinary tract, skin, and respiratory tract. Candidiasis may develop, especially in the groin and in flexural areas.

Physical Examination
Apart from wasting and mild dehydration, children with early diabetes have no specific clinical findings. A physical examination may reveal findings associated with other autoimmune endocrinopathies, which have a higher incidence in children with type 1 diabetes mellitus (eg, thyroid disease with symptoms of overactivity or underactivity and possibly a palpable goiter). Cataracts are rarely presenting problems ; they typically occur in girls with a long prodrome of mild hyperglycemia.

Necrobiosis lipoidica usually, but not exclusively, occurs in people with diabetes. Necrobiosis most often develops on the front of the lower leg as a well-demarcated, red, atrophic area. The condition is associated with injury to dermal collagen, granulomatous inflammation, and ulceration. The cause of necrobiosis is unknown, and the condition is difficult to manage. It is also associated with poor metabolic control and a greater risk of developing other diabetes-related complications.
Diabetic retinopathy

The first symptoms of diabetic retinopathy are dilated retinal venules and the appearance of capillary microaneurysms, a condition known as background retinopathy. These changes may be reversible or their progression may be halted with improved diabetic control, although in some patients the condition initially worsens. Subsequent changes in background retinopathy are characterized by increased vessel permeability and leaking plasma that forms hard exudates, followed by capillary occlusion and flame-shaped hemorrhages. The patient may not notice these changes unless the macula is involved. Laser therapy may be required at this stage to prevent further vision loss. Proliferative retinopathy follows, with further vascular occlusion, retinal ischemia, and proliferation of new retinal blood vessels and fibrous tissue; the condition then progresses to hemorrhage, scarring, retinal detachment, and blindness. Prompt retinal laser therapy may prevent blindness in the later stages, so regular screening is vital.

Diagnostic Considerations
Children with MODY may present as having type 1 diabetes. As they may respond better to oral hypoglycemic agents, recognizing MODY as a possibility is important. Always consider the diagnosis of MODY in the following circumstances:

A strong family history of diabetes across 2 or more generations - The age of diagnosis usually falls with each successive generation Persistently low insulin requirements, particularly with good blood glucose control Development of diabetes from birth or within the first 9 months of life

Conditions to consider in the differential diagnosis of type 1 diabetes include the following:

Type 2 diabetes mellitus MODY Psychogenic polydipsia Nephrogenic diabetes insipidus High-output renal failure Transient hyperglycemia with illness and other stress Steroid therapy Factitious illness (Mnchhausen syndrome by proxy)

Differential Diagnoses

Diabetes Insipidus Hyperthyroidism

Pheochromocytoma Renal Glucosuria Toxicity, Salicylate

Approach Considerations
The need for and extent of laboratory studies vary, depending on the general state of the child's health. For most children, only urine testing for glucose and blood glucose measurement are required for a diagnosis of diabetes. Other conditions associated with diabetes require several tests at diagnosis and at later review.
Urine glucose

A positive urine glucose test suggests, but is not diagnostic for, type 1 diabetes mellitus (T1DM). Diagnosis must be confirmed by test results showing elevated blood glucose levels. Test urine of ambulatory patients for ketones at the time of diagnosis.
Urine ketones

Ketones in the urine confirm lipolysis and gluconeogenesis, which are normal during periods of starvation. With hyperglycemia and heavy glycosuria, ketonuria is a marker of insulin deficiency and potential DKA.
Islet cell antibodies

Islet cell antibodies may be present at diagnosis but are not needed to diagnose type 1 diabetes mellitus. Islet cell antibodies are nonspecific markers of autoimmune disease of the pancreas and have been found in as many as 5% of unaffected children. Other autoantibody markers of type 1 diabetes are known, including insulin antibodies. Additional antibodies against islet cells are recognized (eg, those against glutamate decarboxylase [GAD antibodies]), but these may not be available for routine testing.
Thyroid function tests and antithyroid antibodies

Because early hypothyroidism has few easily identifiable clinical signs in children, children with type 1 diabetes mellitus may have undiagnosed thyroid disease. Untreated thyroid disease may interfere with diabetes management. Typically, hypothyroid children present with reduced insulin requirements and increased episodes of hypoglycemia; hyperthyroid children have increased insulin needs and a tendency toward hyperglycemia. Caution, therefore, is needed when initiating treatment as insulin requirements can change quite quickly. Check thyroid function regularly (every 2-5 years or annually if thyroid antibodies are present). Antithyroid antibody tests indicate the risk of present or potential thyroid disease.
Antigliadin antibodies

Some children with type 1 diabetes mellitus may have or may develop celiac disease. Positive antigliadin antibodies, especially specific antibodies (eg, antiendomysial, antitransglutaminase) are important risk markers. If antibody tests are positive, a jejunal

biopsy is required to confirm or refute a diagnosis of celiac disease. Once celiac disease is confirmed, the individual should remain on a gluten-free diet for life.
Lipid profile

Lipid profiles are usually abnormal at diagnosis because of increased circulating triglycerides caused by gluconeogenesis. Apart from hypertriglyceridemia, primary lipid disorders rarely result in diabetes. Hyperlipidemia with poor metabolic control is common but returns to normal as metabolic control improves.
Urinary albumin

Beginning at age 12 years, perform an annual urinalysis to test for a slightly increased AER, referred to as microalbuminuria, which is an indicator of risk for diabetic nephropathy.
Renal function tests

If the child is otherwise healthy, renal function tests are typically not required.

Blood Glucose
Apart from transient illness-induced or stress-induced hyperglycemia, a random whole-blood glucose concentration of more than 200 mg/dL (11 mmol/L) is diagnostic for diabetes, as is a fasting whole-blood glucose concentration that exceeds 120 mg/dL (7 mmol/L). In the absence of symptoms, the physician must confirm these results on a different day. Most children with diabetes detected because of symptoms have a blood glucose level of at least 250 mg/dL (14 mmol/L). Blood glucose tests using capillary blood samples, reagent sticks, and blood glucose meters are the usual methods for monitoring day-to-day diabetes control.

Glycated Hemoglobin
Glycosylated hemoglobin derivatives (HbA1a, HbA1b, HbA1c) are the result of a nonenzymatic reaction between glucose and hemoglobin. A strong correlation exists between average blood glucose concentrations over an 8- to 10-week period and the proportion of glycated hemoglobin. The percentage of HbA1c is more commonly measured. (Measurement of HbA1c levels is the best method for medium-term to long-term diabetic control monitoring.) An international expert committee composed of appointed representatives of the American Diabetes Association, the European Association for the Study of Diabetes, and others recommended HbA1c assay for diagnosing diabetes mellitus.[35] The committee recommended that an HbA1c level of 6.5% or higher be considered indicative of diabetes, with diagnostic confirmation being provided through repeat testing (unless clinical symptoms are present and the glucose level is >200 mg/dL). Glucose measurement should remain the choice for diagnosing pregnant women or be used if HbA1c assay is unavailable. The committee cited the following advantages of HbA1c testing over glucose measurement:

Captures long-term glucose exposure Has less biologic variability Does not require fasting or timed samples Is currently used to guide management decisions

The Diabetes Control and Complications Trial (DCCT) found that patients with HbA1c levels of around 7% had the best outcomes relative to long-term complications. Most clinicians aim for HbA1c values of 7-9%. Values of less than 7% are associated with an increased risk of severe hypoglycemia; values of more than 9% carry an increased risk of long-term complications. The International Society for Pediatric and Adolescent Diabetes (ISPAD) recommends a target level of 7.5% (58 mmol/mol) or less for all children. Normal HbA1c values vary according to the laboratory method used, but nondiabetic children generally have values in the low-normal range. At diagnosis, diabetic children unmistakably have results above the upper limit of the reference range. Check HbA1c levels every 3 months. Many different methods of measuring HbA1c are available, and the variations between the different assays can be considerable and unpredictable. A working group was established in 1995 by the International Federation of Clinical Chemists (IFCC) to find a better method of standardizing the various assays.[36] This resulted in a global standard that is gradually being implemented. As a result, HbA1c will be reported as millimole per mole (mmol/mol) instead of as a percentage. The current target range of 79% is set to be replaced with values of 53-75 mmol/mol.

Microalbuminuria
Microalbuminuria is the first evidence of nephropathy. The exact definition varies slightly between nations, but an increased AER is commonly defined as a ratio of first morning-void urinary albumin levels to creatinine levels that exceeds 10 mg/mmol, or as a timed, overnight AER of more than 20 mcg/min but less than 200 mcg/min. Early microalbuminuria may resolve. Glomerular hyperfiltration occurs, as do abnormalities of the glomerular basement membrane and glomeruli. Regular urine screening for microalbuminuria provides opportunities for early identification and treatment to prevent renal failure.

Oral Glucose Tolerance Test

Although unnecessary in the diagnosis of type 1 diabetes mellitus, an oral glucose tolerance test (OGTT) can exclude the diagnosis of diabetes when hyperglycemia or glycosuria are recognized in the absence of typical causes (eg, intercurrent illness, steroid therapy) or when the patient's condition includes renal glucosuria. Obtain a fasting blood sugar level, then administer an oral glucose load (2 g/kg for children aged < 3 y, 1.75 g/kg for children aged 3-10 y [max 50 g], or 75 g for children aged >10 y). Check the blood glucose concentration again after 2 hours. A fasting whole-blood glucose level higher than 120 mg/dL (6.7 mmol/L) or a 2-hour value higher than 200 mg/dL (11 mmol/L) indicates diabetes. However, mild elevations may not indicate diabetes when the patient has no symptoms and no diabetes-related antibodies.

A modified OGTT can also be used to identify cases of MODY (which often present as type 1 diabetes) if, in addition to blood glucose levels, insulin or c-peptide (insulin precursor) levels are measured at fasting, 30 minutes, and 2 hours. Individuals with type 1 diabetes mellitus cannot produce more than tiny amounts of insulin. People with MODY or type 2 diabetes mellitus show variable and substantial insulin production in the presence of hyperglycemia.

Approach Considerations
All children with type 1 diabetes mellitus require insulin therapy. The following are also required in treatment:

Blood glucose testing strips Urine ketone testing tablets or strips Blood ketone testing strips

A well-organized diabetes care team can provide all necessary instruction and support in an outpatient setting. The only immediate requirement is to train the child or family to check blood glucose levels, to administer insulin injections, and to recognize and treat hypoglycemia. The patient and/or family should have 24-hour access to advice and know how to contact the team. Children should wear some form of medical identification, such as a medic alert bracelet or necklace.[37, 38] Awareness of hypoglycemia becomes impaired over time, and severe hypoglycemia can occur without warning. Hypoglycemia is more likely to affect people who maintain low blood sugar levels and who already suffer frequent hypoglycemic attacks. Overzealous or inadequate treatment of hypoglycemia can lead to serious consequences. Failure to regularly examine for diabetic complications in patients with type 1 diabetes mellitus, especially renal and ophthalmic ones, can be detrimental.
Inpatient care

Where a diabetes care team is available, admission is usually required only for children with DKA. In addition, children with significant dehydration, persistent vomiting, metabolic derangement, or serious intercurrent illness require inpatient management and intravenous rehydration.
Diabetes in pregnancy

Pregnancies should be planned and carefully managed to achieve healthy outcomes for mother and infant. Preconceptual normalization of blood sugars and folic acid supplements (at least 5 mg/d) reduce the otherwise increased risk of congenital heart disease and neural tube defects. Blood sugar control during pregnancy must be strict to avoid hypoglycemia, which may damage the fetus, and persistent hyperglycemia, which leads to fetal gigantism, premature delivery, and increased infant morbidity and mortality. DKA during pregnancy may result in fetal death.

Diet
Dietary management is an essential component of diabetes care. Diabetes is an energy metabolism disorder, and consequently, before insulin was discovered, children with diabetes were kept alive by a diet severely restricted in carbohydrate and energy intake. These measures led to a long tradition of strict carbohydrate control and unbalanced diets. Current dietary management of diabetes emphasizes a healthy, balanced diet that is high in carbohydrates and fiber and low in fat. The following are among the most recent dietary consensus recommendations (although they should be viewed in the context of the patients culture)[39] :

Carbohydrates - Should provide 50-55% of daily energy intake; no more than 10% of carbohydrates should be from sucrose or other refined carbohydrates Fat - Should provide 30-35% of daily energy intake Protein - Should provide 10-15% of daily energy intake

The aim of dietary management is to balance the child's food intake with insulin dose and activity and to keep blood glucose concentrations as close as possible to reference ranges, avoiding extremes of hyperglycemia and hypoglycemia. The ability to estimate the carbohydrate content of food (carbohydrate counting) is particularly useful for children who receive fast-acting insulin at mealtimes either by injection or insulin pump, as it allows for a more precise matching of food and insulin. Adequate intake of complex carbohydrates (eg, cereals) is important before bedtime to avoid nocturnal hypoglycemia, especially for children getting twice-daily injections of mixed insulin. The dietitian should develop a diet plan for each child to suit individual needs and circumstances. Regularly review and adjust the plan to accommodate the patient's growth and lifestyle changes. Low-carbohydrate diets as a management option for diabetes control have regained popularity. Logic dictates that the lower the carbohydrate intake, the less insulin is required. No trials of low-carbohydrate diets in children with type 1 diabetes mellitus have been reported, and such diets cannot be recommended at the present.

Activity
Type 1 diabetes mellitus requires no restrictions on activity; exercise has real benefits for a child with diabetes. Current guidelines are increasingly sophisticated and allow children to compete at the highest levels in sports.[40] Moreover, most children can adjust their insulin dosage and diet to cope with all forms of exercise. Children and their caretakers must be able to recognize and treat symptoms of hypoglycemia. Hypoglycemia following exercise is most likely after prolonged exercise involving the legs, such as walking, running or cycling. It may occur many hours after exercise has finished and even affect insulin requirements the following day. A large, presleep snack is advisable following intensive exercise.

Long-Term Monitoring
Regular outpatient review with a specialized diabetes team improves short- and long-term outcomes.[45] Most teams have a nurse specialist or educator, a dietitian, and a pediatrician with training in diabetes care. Other members can include a psychologist, a social worker, and an exercise specialist. Involvement with the team is intense over the first few weeks after diagnosis while family members learn about diabetes management.[46, 47] Conduct a structured examination and review at least once annually to examine the patient for possible complications. Examination and review should include the following:

Growth assessment Injection site examination Examination of the hands, feet, and peripheral pulses for signs of limited joint mobility, peripheral neuropathy, and vascular disease Evaluation for signs of associated autoimmune disease Blood pressure

In individuals aged 11 years or older, further examination should include the following:

Retinoscopy or other retinal screening, such as photography Urine examination for microalbuminuria

Medication Summary
Insulin is always required to treat type 1 diabetes mellitus. Originally, all insulin was derived from the highly purified pancreatic extracts of pigs and cattle, and this form of insulin is still available. Human insulin was later manufactured using recombinant deoxyribonucleic acid (DNA) technology. "Designer" insulins are also now being produced; they are based on the human molecule and are tailored to meet specific pharmacologic targets, particularly duration of action. Insulin must be given parenterally, and this effectively means subcutaneous injection.[48] Alternatives to injecting insulin have been constantly sought, including an inhaled form of insulin. Several products were in development, and one (Exubera) was licensed for use but failed to generate sufficient market penetration to justify continued production. The search for alternatives continues, including oral sprays, sublingual lozenges, and delayed-absorption capsules. nsulin has basic for ulations ultra short-acting (eg, lispro, aspart, glulisine), traditional short-acting (eg, regular, soluble), medium- or intermediate-acting (eg, isophane, lente, detemir), and long-acting (eg, ultralente, glargine). Regular or soluble insulin is bound to either protamine (eg, isophane) or zinc (eg, lente, ultralente) in order to prolong the duration of action. Combinations of isophane and regular, lispro, or aspart insulins are also available in a limited number of concentrations that vary around the world, ranging from 25:75 mixtures (ie, 25% lispro, 90% isophane) to 50:50 mixtures. The following image illustrates the activity profile of various insulins.

Representation of activity profile of some available insulins.

The development of insulin analogues has attempted to address some of the shortcomings of traditional insulin.[49] Insulins lispro, glulisine, and aspart have a more rapid onset of action and shorter duration, making them more suitable for bolusing at mealtimes and for short-term correction of hyperglycemia. (See the graph below.) They are also more suitable for use with insulin pumps. An intermediate-acting insulin (detemir) has a similar profile of action to isophane but is more pharmacologically predictable and is less likely to cause weight gain, whereas glargine has a relatively flat profile of action, lasting some 18-26 hours. Despite their apparent advantages over traditional insulins, no evidence suggests a long-term advantage of the analogue insulins in terms of metabolic control or complication rates.[50]

Representation of activity profile of some available insulins.

The FDA issued an early communication to health care practitioners regarding 4 published observational studies that described the possible association of insulin glargine (Lantus) with an increased risk of cancer.[51] Insulin glargine is a long-acting human insulin analogue approved for once-daily dosing. The observational studies evaluated large patient databases, and all reported some association between insulin glargine and other insulin products with various types of cancer. The duration of the observational studies was shorter than that which is considered necessary to evaluate for drug-related cancers. Additionally, findings were inconsistent within and across the studies, and patient characteristics differed across treatment groups. These issues raised further questions about the actual risk and, therefore, further evaluation is warranted. The FDA states that patients should not stop taking their insulin without consulting their physician. An ongoing review by the FDA will continue to update the medical community and consumers with additional information as it emerges. Statements from the American Diabetes Association and the European Association for the Study of Diabetes called the findings conflicting and inconclusive and cautioned against overreaction. With so many various insulins and mixtures available, a wide range of possible injection regimens exist. These can be broadly categorized into 4 types, as follows:

Twice-daily combinations of short- and intermediate-acting insulin.

Multiple injection regimens using once-daily or twice-daily injections of long-acting or intermediate-acting insulin and short-acting insulins given at each meal A combination of the above 2 regimens, with a morning injection of mixed insulin, an afternoon premeal injection of short-acting insulin and an evening injection of intermediateor long-acting insulin Continuous subcutaneous insulin infusion (CSII) using an insulin pump

Although controlled clinical trials suggest improved short-term metabolic control in children using multiple injections or CSII,[52] international comparisons do not support any particular insulin regimen,[53, 54] and all have their advantages and disadvantages. A wide variety of insulin-injection devices are available, including a simple syringe and needle, semiautomatic pen injector devices, and needle-free jet injectors. Increasing numbers of young people use insulin pumps to deliver continuous subcutaneous insulin, with bolus doses at meal times. When prescribing, tailor the insulin dose to the individual child's needs. For instance, if using a twice-daily regimen, then, as a rule of thumb, prepubertal children require between 0.5 and 1 U/kg/d, with between 60-70% administered in the morning and 30-40% in the evening. Insulin resistance is a feature of puberty, and some adolescents may require as much as 2 U/kg/d. About one third of the administered insulin is a short-acting formulation and the remainder is a medium- to long-acting formulation. Basal bolus regimens have a higher proportion of short-acting insulin. Typically, 50% of the total daily dose is given as long- or intermediate-acting insulin. CSII uses only short-acting insulins, most often the analogues lispro or aspart. Typically, they also have around 50% of the insulin given at a basal rate; the remainder is given as food-related boluses.

Antidiabetic Agents
Class Summary

These agents are used for the treatment of type 1 diabetes mellitus, as well as for type 2 diabetes mellitus that is unresponsive to treatment with diet and/or oral hypoglycemics.
View full drug information Insulin detemir (Levemir)

This agent is indicated for daily or twice-daily subcutaneous administration for adults and pediatric patients with type 1 diabetes mellitus; it is also indicated for adults with type 2 diabetes mellitus who require long-acting basal insulin for hyperglycemic control. The duration of action ranges from 5.7 hours (low dose) to 23.2 hours (high dose). Prolonged action is a result of the slow systemic absorption of detemir molecules from the injection site. Insulin detemir's primary activity is regulation of glucose metabolism. It binds to insulin receptors and lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and fat. The drug also inhibits glucose output from the liver. It inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.

View full drug information Insulin lispro (Humalog)

Onset of action for insulin lispro is 10-30 minutes, peak activity is 1-2 hours, and duration of action is 2-4 hours.
View full drug information Regular insulin (Humulin R, Novolin R)

Onset of action is 0.25-1 hours, peak activity is 1.5-4 hours, and duration of action is 5-9 hours.
View full drug information Insulin NPH (Humulin N, Novolin N)

Onset of action is 3-4 hours, peak effect is in 8-14 hours, and usual duration of action is 1624 hours.
View full drug information Insulin aspart (NovoLog)

Onset of action is 10-30 minutes, peak activity is 1-2 hours, and duration of action is 3-6 hours. Insulin aspart is homologous with regular human insulin, with the exception of the single substitution of the amino acid proline with aspartic acid in position B28. The drug is produced by recombinant DNA technology. Insulin lowers blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. It inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis. Insulin is the principal hormone required for proper glucose use in normal metabolic processes.
View full drug information Insulin glargine (Lantus)

This is a long-acting insulin analogue. Its typical onset of action is 1-2 hours, and its duration is 20-26 hours.
View full drug information Insulin glulisine (Apidra)

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