Pediatric Type 1 Diabetes Mellitus

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Type 1 diabetes is a chronic illness characterized by the body’s inability to produce insulin due to the autoimmune destruction of the beta cells in the pancreas. Most pediatric patients with diabetes have type 1 and a lifetime dependence on exogenous insulin. [1] The image below depicts the effects of insulin deficiency.

Signs and symptoms of type 1 diabetes in children include the following:

Hyperglycemia

Glycosuria

Polydipsia

Unexplained weight loss

Nonspecific malaise

Symptoms of ketoacidosis

See Clinical Presentation for more detail.

Blood glucose

Blood glucose tests using capillary blood samples, reagent sticks, and blood glucose meters are the usual methods for monitoring day-to-day diabetes control.

Diagnostic criteria by the American Diabetes Association (ADA) include the following [2] :

A fasting plasma glucose (FPG) level ≥126 mg/dL (7.0 mmol/L), or

A 2-hour plasma glucose level ≥200 mg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test (OGTT), or

A random plasma glucose ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis

Glycated hemoglobin

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. [3]

See Workup for more detail.

Glycemic control

The ADA recommends using patient age as one consideration in the establishment of glycemic goals, with different targets for preprandial, bedtime/overnight, and hemoglobin A1c (HbA1c) levels in patients aged 0-6, 6-12, and 13-19 years. [4] Benefits of tight glycemic control include not only continued reductions in the rates of microvascular complications but also significant differences in cardiovascular events and overall mortality.

Insulin therapy

All children with type 1 diabetes mellitus require insulin therapy. Most require 2 or more injections of insulin daily, with doses adjusted on the basis of self-monitoring of blood glucose levels. Insulin replacement is accomplished by giving a basal insulin and a preprandial (premeal) insulin. The basal insulin is either long-acting (glargine or detemir) or intermediate-acting (NPH). The preprandial insulin is either rapid-acting (lispro, aspart, or glulisine) or short-acting (regular).

Diet and activity

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 following are among the most recent dietary consensus recommendations (although they should be viewed in the context of the patient’s culture) [5] :

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

Exercise is also an important aspect of diabetes management. It has real benefits for a child with diabetes. Patients should be encouraged to exercise regularly.

See Treatment and Medication for more detail.

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.)

Type 2 diabetes mellitus (non–insulin-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. [6] 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. [7, 8, 9] This topic addresses only type 1 diabetes mellitus. (See Etiology and Epidemiology.)

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.) [10]

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.

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. [11, 12]

Diabetic ketoacidosis (DKA) is much less common than hypoglycemia but is potentially far more serious, creating a life-threatening medical emergency. [13] 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.

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.

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. [14] Prevalence rates seem to be declining, yet an estimated 80% of people with type 1 diabetes mellitus develop retinopathy. [15]

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. [16]

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.

The peripheral and autonomic nerves are affected in type 1 diabetes mellitus. [17] Hyperglycemic effects on axons and microvascular changes in endoneural capillaries are amongst the proposed mechanisms. (In adults, peripheral neuropathy usually occurs as a distal sensory loss.)

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. [18] In a study by 253 patients with type 1 diabetes (mean age at baseline 14.4 y), Cho et al reported that the prevalence of cardiac autonomic dysfunction increases in association with higher body mass index and central adiposity. [19]

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.

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.

Hypothyroidism affects 2-5% of children with diabetes. [20] 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. [21]

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 (primarily affecting the hands and feet) is believed to be associated with poor diabetic control. [22]

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.

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 (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.

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.)

A study by Chan et al indicated that in pediatric patients with type 1 diabetes, the presence of hypoglycemia is a sign of decreased insulin sensitivity, while hyperglycemia in these patients, especially overnight, signals improved sensitivity to insulin. In contrast, the investigators found evidence that in pediatric patients with type 2 diabetes, markers of metabolic syndrome and hyperglycemia are associated with reduced insulin sensitivity. Patients in the study were between ages 12 and 19 years. [23]

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.

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. [24] This is particularly important, because these children respond well to sulphonylurea therapy.

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. [25] 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, [26] 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. [27]

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

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)

The overall annual incidence of diabetes mellitus is about 24.3 cases per 100,000 person-years. 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). [28]

A study by Mayer-Davis et al indicated that between 2002 and 2012, the incidence of type 1 and type 2 diabetes mellitus saw a significant rise among youths in the United States. According to the report, after the figures were adjusted for age, sex, and race or ethnic group, the incidence of type 1 (in patients aged 0-19 years) and type 2 diabetes mellitus (in patients aged 10-19 years) during this period underwent a relative annual increase of 1.8% and 4.8%, respectively. The greatest increases occurred among minority youths. [29]

Type 1 diabetes mellitus has wide geographic variation in incidence and prevalence. [30] 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.

Also 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. [31]

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.

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.

Type 1 diabetes mellitus can occur at any age, but incidence rates generally increase with age until midpuberty and then decline. [32] 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). [33]

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. [34]

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. [35, 36] 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. [37]

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. [38]

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. [39] 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. [40, 41] 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. [42]

Type 1 diabetes in pediatric patients has been linked to changes in cognition and brain structure, with a study by Siller et al finding lower volume in the left temporal-parietal-occipital cortex in young patients with type 1 diabetes than in controls. The study also indicated that in pediatric patients, higher severity of type 1 diabetes presentation correlates with greater structural differences in the brain at about 3 months following diagnosis. The investigators found that among study patients with type 1 diabetes, an association existed between the presence of diabetic ketoacidosis at presentation and reduced radial, axial, and mean diffusivity in the major white matter tracts on magnetic resonance imaging (MRI). In those with higher glycated hemoglobin (HbA1c) levels, hippocampal, thalamic, and cerebellar white matter volumes were lower, as was right posterior parietal cortical thickness, while right occipital cortical thickness was greater. Patients in the study were aged 7-17 years. [43]

A study by Dabelea et al found that in teenagers and young adults in whom diabetes mellitus had been diagnosed during childhood or adolescence, diabetes-related complications and comorbidities—including diabetic kidney disease, retinopathy, and peripheral neuropathy (but not arterial stiffness or hypertension)—were more prevalent in those with type 2 diabetes than in those with type 1 disease. [44]

Education is a continuing process involving the child, family, and all members of the diabetes team. [45, 46] (See the videos below.) 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-related organizations and patient resources include the following: [47]

Children with Diabetes 

International Society for Pediatric and Adolescent Diabetes

International Diabetes Federation

Diabetes UK

American Diabetes Association

Juvenile Diabetes Research Foundation International

Runsweet 

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William H Lamb, MD, MBBS, FRCP(Edin), FRCP, FRCPCH Consultant Paediatric Diabetologist, The Great North Children’s Hospital, The Royal Victoria Infirmary; Honorary Clinical Lecturer, University of Newcastle upon Tyne; Honorary Clinical Lecturer, University of Durham School of Medicine and Health, UK

William H Lamb, MD, MBBS, FRCP(Edin), FRCP, FRCPCH is a member of the following medical societies: British Medical Association, British Society of Paediatric Endocrinology and Diabetes, International Society for Pediatric and Adolescent Diabetes, Royal College of Paediatrics and Child Health, Royal College of Physicians

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children’s Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Sasigarn A Bowden, MD Associate Professor of Pediatrics, Section of Pediatric Endocrinology, Metabolism and Diabetes, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Associate Fellowship Program Director, Division of Endocrinology, Nationwide Children’s Hospital; Affiliate Faculty/Principal Investigator, Center for Clinical Translational Research, Research Institute at Nationwide Children’s Hospital

Sasigarn A Bowden, MD is a member of the following medical societies: American Society for Bone and Mineral Research, Central Ohio Pediatric Society, Endocrine Society, International Society for Pediatric and Adolescent Diabetes, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Arlan L Rosenbloom, MD Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida College of Medicine; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, Florida Chapter of The American Academy of Pediatrics, Florida Pediatric Society, International Society for Pediatric and Adolescent Diabetes

Disclosure: Nothing to disclose.

The author would like to thank Dr. Tim Cheetham and Dr. Debbie Matthews, Colleagues at the Royal Victoria Infirmary, Newcastle upon Tyne, for reading through the manuscript and for years of support.

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