eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Diabetes Mellitus, Type 1

Author: William H Lamb, MBBS, MD, FRCP(Edin), FRCP, Clinical Lecturer, Department of Child Health, The General Hospital, Bishop Auckland, UK
Contributor Information and Disclosures

Updated: Jul 2, 2009

Introduction

Background

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]). Most children with diabetes have type 1 diabetes mellitus (T1DM) and a lifetime dependence on exogenous insulin.

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. 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.^1,2

This topic addresses only type 1 diabetes mellitus.

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 both liver and kidneys.

Hyperglycemia (ie, random blood glucose concentration 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 diabetic ketoacidosis (DKA).

An excess of insulin prevents the release of glucose into the circulation and results in hypoglycemia (blood glucose concentrations of <60 mg/dL or 3.5 mmol/L). Glucose is the sole energy source for erythrocytes, kidney medulla, and the brain.

Frequency

United States

The overall annual incidence has risen from approximately 16 cases per 100,000 population in the 1990s to 24.3 per 100,000 population currently and is probably still increasing. 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).³

International

Type 1 diabetes mellitus has wide geographic variation in incidence and prevalence.⁴ 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. 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 or more in the last 20 years. Incidence appears to increase with distance from the equator.⁵

Mortality/Morbidity

Information on mortality rates is difficult to ascertain without complete national registers of childhood diabetes, although age-specific mortality is probably double that of the general population.^6,7 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.⁸

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 reflect the difficulties of maintaining a balance between insulin therapy, dietary intake, and exercise. Acute complications include hypoglycemia, hyperglycemia, and DKA.
• 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.⁹ 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.¹⁰ Long-term complications include the following:
  • Retinopathy
  • Cataracts
  • Hypertension
  • Progressive renal failure
  • Early coronary artery disease
  • Peripheral vascular disease
  • Neuropathy, both peripheral and autonomic
  • Increased risk of infection
• Associated autoimmune diseases are common with type 1 diabetes mellitus, particularly in children who have the human leukocyte antigen DR3 (HLA-DR3). Some conditions may precede development of diabetes; others may develop later. As many as 20% of children with diabetes have thyroid autoantibodies.

Race

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

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

Generally, incidence rates increase with age until mid-puberty then decline after puberty, but type 1 diabetes mellitus can occur at any age. Onset in the first year of life, although unusual, can occur and must be considered in any infant or toddler because these children have the greatest risk for mortality if diagnosis is delayed. Their symptoms 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

Neonatal diabetes, including diagnosis in infants younger than 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.¹¹

In areas with high prevalence rates, a bimodal variation of incidence has been reported that shows a definite peak in early childhood (ie, 4-6 y) and a second, much greater peak of incidence during early puberty (ie, 10-14 y).¹²

Clinical

History

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

• Hyperglycemia: Hyperglycemia alone may not cause obvious symptoms, although some children report general malaise, headache, and weakness. They may also appear irritable and become ill-tempered. 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
  • Severe dehydration
  • Smell of ketones
  • Acidotic breathing (ie, Kussmaul respiration), masquerading as respiratory distress
  • Abdominal pain
  • Vomiting
  • Drowsiness and coma
• Other nonspecific findings
  • 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 groin and flexural areas.

Physical

• 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 and 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.

Causes

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 developing in children with a diabetic mother is 2-3% and 5-6% if the father 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 one or both of these molecules, compared with 50-60% in 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.
• 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.¹³
  • 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,¹⁴ 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 insulin-dependent diabetes mellitus (IDDM), 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 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.¹⁵
• Chemical causes: Streptozotocin and RH-787, a rat poison, selectively damage islet cells and can cause type 1 diabetes mellitus.
• Other causes
  • Congenital absence of the pancreas or islet cells
  • Pancreatectomy
  • Type 1 diabetes mellitus secondary to 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.)

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