Type 1 Diabetes in Children

Etiology

Both genetic and environmental contributions lead to immune-mediated loss of beta cell function resulting in hyperglycemia and life-long insulin dependence. In an individual at risk (human leukocyte antigen (HLA) haplotype accounts for 30% to 50% of their genetic risk. More than 50 other genes have been found through candidate gene and genome-wide association studies.  A "triggering" insult (e.g., maternal and intrauterine environment, exposure to viruses, host microbiome, diet and many other factors are thought to contribute to disease susceptibility) is suspected to initiate a process that recruits antigen-presenting cells to transport beta cell self-antigens to autoreactive T cells. Through failures of self-tolerance, these T cells mediate beta-cell killing and inflammation leading to insulinopenia and symptomatic diabetes. Recently, preclinical stages of type 1 diabetes have been recognized. Stage 1 is defined by the presence of beta cell autoimmunity, but normal glucose-handling, stage 2 is defined by abnormal glucose handling but no overt symptoms, and finally stage 3 is defined by clinically-apparent symptoms of insulinopenia. Progression through these stages may take years. Although the pre-clinical staging is not usually clinically relevant, research focusing on interventions in the pre-clinical groups may prove to delay or prevent the onset of type 1 diabetes.[3][2]

Epidemiology

Type 1 diabetes may be diagnosed at nearly any age, though peaks in presentation occur between ages 5 to 7 and around puberty. There appears to be seasonal variation with more cases diagnosed in fall and winter. Unlike most autoimmune disorders, type 1 diabetes is slightly more common in boys and men. In the past several decades, type 1 diabetes incidence and prevalence has increased in most age, sex, and race/ethnic groups with some of the fastest growth in young children. There is significant variability in incidence based on geography and ethnicity. For example, the incidence in Finland is 60 per 100,000 person-years, while in China it is 0.1 per 100,000. In the United States, there are approximately 20 to 30 new diagnoses per 100,000 person-years. These incidences have increased by 200% to 300% in the past several decades. In the United States, there are now more than 1.25 million people living with type 1 diabetes., and around 500,000 are children.[4]

If a child has type 1 diabetes, concordance in another sibling is around 5%. In fraternal twins, it is around 10% to 30%, and with identical twins, it is 40% to 50%. Children of adults with type 1 diabetes are at an approximately 5% to 8% risk. In the United States, the general population risk is approximately 0.3%.[5]

Pathophysiology

Insufficient endogenous insulin leads to hyperglycemia, hyperglucagonemia, glucosuria, and without treatment, eventually ketosis, acidosis, dehydration, and death. About one-third of patients with newly-diagnosed type 1 diabetes present with diabetic ketoacidosis (DKA) which has a mortality rate of around 0.3-0.5%, despite aggressive treatment.[6][2]

The Diabetes Control and Complications Trial was the pivotal study published in 1993 documenting the clear association of chronic hyperglycemia with long-term microvascular complications such retinopathy, neuropathy, and microalbuminuria (as a surrogate for nephropathy). [7] Follow-up studies have documented the association of chronic hyperglycemia with macrovascular complications as well as all-cause mortality.[8] Iatrogenic hypoglycemia, however, was identified as the major limiting factor to intensive glucose control.[9]

For the last several decades, therapies have focused on normalizing glucose while minimizing the risk of hypoglycemia while at the same time monitoring for chronic complications and acknowledging the important psychosocial factors that affect a growing and developing children with a chronic disease.

Toxicokinetics

Insufficient insulin and/or poor oral intake may lead to the development of ketosis. If not recognized and treated appropriately, ketoacids increase and cause acidosis which if severe, may require hospitalization. Rates of admission for diabetic ketoacidosis are low with most children never requiring admission, though approximately 5% of children are admitted per year, and approximately 1% are admitted multiple times each year.[6] Rates are highest among adolescents, females, and those with poor social support.[10]

History and Physical

At presentation, children usually have a history of polyuria, polydipsia and weight loss for days to months. If the diagnosis is delayed, there may be vomiting, lethargy, altered mental status, dehydration, and acidosis. After diagnosis, and initiation of insulin therapy, follow-up management is typically coordinated by a pediatric endocrinologist on approximately a quarterly basis.

Some children will present with ketoacidosis that is associated with the following features:

• Smell of ketones
• Dehydration
• Abdominal pain
• Kussmaul breathing
• Vomiting
• Coma
• Altered mental status

At regular visits, the provider will assess changes in diabetes status and life circumstances affecting diabetes management, for example, school experience, changes in patterns of exercise and diet, the developmental stage of the child, their participation in diabetes care tasks, family and home life changes, and adherence to therapy. History and physical also focus on assessing issues related to glucose monitoring, insulin delivery (e.g., lipodystrophy, skin tolerance to medical adhesives on diabetes technology), and screening for symptoms of associated medical issues such as thyroid dysfunction or celiac disease. [2][11] As most children with type 1 diabetes are otherwise healthy, history and physical is usually limited to assessment of pertinent diabetes care.

Evaluation

Particular attention is paid to home glucose monitoring to learn the patterns of glucose variability and their relation to life circumstances such as school, exercise, and physical stresses such as illness and menses. Insulin dose adjustment is performed with child and family input, as appropriate.

Hemoglobin A1c is typically measured at clinic visits as a measure of average glucose over the prior two to three months. The American Diabetes Association recommends Hemoglobin A1c be less than 7.5%, although large population studies suggest only 20% to 25% of children and adolescents achieve this.[12] Diabetes organizations in other developed countries may suggest lower Hemoglobin A1c targets and are somewhat more successful at achieving these targets.[13]

Continuous glucose monitoring (CGM) has become more common in children and adolescents, and measures of "time in range" and glucose variability are likely to be even more valuable than Hemoglobin A1c, although insurance does not universally cover CGM and is not always desired by patients.

Screening for thyroid disorders is performed at regular intervals and screening for celiac disease is typically done as well, although the frequency is not established. Regular screening for lipid disorders, microalbuminuria, and retinopathy are recommended based on the duration of diabetes. Assessment of mental health and psychosocial factors are also important.[2]

Islet cell antibodies are not usually measured to make the diagnosis of type 1 diabetes. These antibodies are only found in about 5% of children and are not specific markers. One should obtain a baseline lipid profile. In addition, urinary albumin should start at age 12 as these children are susceptible to end-stage renal disease.

Treatment / Management

A diabetes healthcare team may include the medical provider, nurse, diabetes educator, dietician, social worker, and psychologist; However, not all specialties are always available, convenient, or covered by insurance. Contact between the child and family and medical team between in-office visits is frequent, at least initially, while treatment is adjusted and the family learns the daily management tasks of caring for a child with diabetes. The patient and family make long-term day to day treatment decisions.

Insulin delivery is by multiple daily injections (MDI) or an insulin pump to simulate endogenous insulin physiology. Multiple daily injections include basal insulin once or twice daily, and bolus insulin typically is given at meals three or more times daily and is based on carbohydrate content and current blood glucose. Insulin pumps deliver rapid-acting insulin only and provide a basal rate of insulin that is either programmed or automatically adjusted based on continuous glucose monitor input in some pumps, and mealtime insulin is typically calculated based on mealtime inputs of carbohydrate and current blood glucose.

The provider will also screen for associated disorders (e.g., thyroid disease, celiac disease, dyslipidemia), ensure screening for complications of chronic hyperglycemia (e.g., retinopathy, neuropathy, nephropathy), and ongoing healthcare maintenance such as influenza vaccine. A detailed description of diabetes care is documented in the American Diabetes Association Standards of Medical Care in Diabetes publication which is updated each January in the journal Diabetes Care.[2]

Strategies should be established to allow the parent to achieve the best glycemic management. Behavior intervention has been found to help with medication compliance and improve outcomes.

The parent should be educated about hypoglycemia, the signs, and its management.

A recent study revealed that probiotic supplementation before age 3 in infants with type 1 diabetes led to a reduction in the development of pancreatic islet cell autoimmunity.

A dietary consult is an essential component of diabetes management. Current consensus recommends the following:

Carbohydrates should provide 50-55% of the daily energy intake, but simple carbohydrates like sucrose should not make up more than 10% of the total.

Fats should provide about 30% of the daily energy intake

Protein should provide 10-15% of the daily energy intake.

Differential Diagnosis

• Salicylate toxicity
• Pheochromocytoma
• Diabetes insipidus
• Hyperthyroidism

Treatment Planning

Current Guidelines

• When glycosuria/hyperglycemia is noted, consult with an endocrinologist
• Differentiate between type 1 and type 2 disease
• Children usually require intense insulin regimens, with multiple daily injections
• Assess A1c every 3 months
• The blood glucose should be monitored 5-10 times every day
• Continuous blood glucose monitors should be recommended for children
• Monitor for ketones when the child is ill or has an infection
• Optimize nutrition
• Daily exercise for 60 mins is recommended; check blood glucose before and after exercise to detect hypoglycemia and hyperglycemia
• Remain compliant with medication; insulin omission is a leading cause of DKA
• Screen for albuminuria after age 10
• Ensure the child has annual eye exams at age 10 and annually thereafter
• Monitor BP; of high use ACE inhibitors
• Monitor LDL cholesterol and if abnormal, treat with diet; if that fails, use a statin.
• Maintain A1C to less than 7.5%
• Carry sugar snacks in case of hypoglycemia
• Monitor thyroid function if there is growth variability
• Screen for celiac disease
• Educate about harms of smoking

Prognosis

Type 1 diabetes has high morbidity and mortality. The life expectancy is reduced by 10-20 years for many individuals. The disorder is associated with numerous complications including hypoglycemia and diabetic ketoacidosis. For children, managing diabetes can lead to enormous stress and depression is common. Children particulary die from DKA chiefly due to delayed diagnosis. 

Complications

• Cataracts
• Retinopathy
• Gastroparesis
• Renal failure
• Hypertension
• Premature coronary disese
• Peripheral vascular disease
• Neuropathy
• Increased susceptibility to infections