Diabetes in children
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Jaspinder Kaur, MBBS[2]
Synonyms and keywords: Pediatric Diabetes Mellitus (DM)
Overview
DM1 is considered an immuno-mediated disease that develops as a result of gradual destruction of insulin-producing pancreatic beta cells that eventually results in their total loss and complete dependence on exogenous insulin. Clinical presentation can occur at any age, but most patients will be diagnosed before the age of 30 years. The disease process begins months to years before the onset of clinical signs such as polyuria, polydipsia, weight loss, and diabetic ketoacidosis. However, the etiology and natural history of DM1 are not yet completely known, with genetic and environmental factors believed to participate. The genetic effect probably contributes 70 to 75% in the susceptibility to DM1, with environmental factors possibly initiating or stimulating the process that will lead to the destruction of the beta cells and the onset of the disease.
Diabetes mellitus is a disorder of the metabolic homeostasis controlled by insulin, resulting in abnormalities of carbohydrate and lipid metabolism. Type 1 diabetes (also called juvenile-onset diabetes mellitus and insulin-dependent diabetes mellitus) is caused by an absolute insulin deficiency, the result of a loss of the insulin-producing beta cells of the pancreas. Type 2 diabetes mellitus is characterized by two underlying defects. The earliest abnormality in an individual who develops type 2 diabetes mellitus is insulin resistance, which initially is compensated for with an increase in insulin secretion. Type 2 diabetes mellitus then develops due to a defect in insulin secretion that prevents such secretion from matching the increased requirements imposed by the insulin-resistant state. Thus, diabetes mellitus always is caused by insulin deficiency: in type 1 diabetes mellitus, the deficiency is absolute; in type 2 diabetes mellitus, the deficiency is relative. Although the percentage of cases of diabetes in children and adolescents caused by type 2 diabetes has risen in the past 1 to 2 decades, type 1 diabetes remains the most common form of diabetes mellitus in children. Recombinant insulin analogs, insulin pumps, and newer devices for home monitoring have drastically improved the ability to control glucose concentrations in patients who have diabetes. However, the feedback control in the healthy state that allows minute-to-minute regulation of insulin secretion cannot be recapitulated with current diabetes therapies, making full metabolic normalization not yet possible. Thus, some degree of hyperglycemia persists in virtually all patients who have diabetes. Long-term complications, including renal failure, retinopathy, neuropathy, and cardiovascular disease, are related to and likely caused by the hyperglycemia.
Historical Perspective
- 400–500 A.D.: Indian physicians called it madhumeha (‘honey urine’) because it attracted ants. The ancient Indian physician, Sushruta, and the surgeon Charaka were able to identify the two types, later to be named Type I and Type II diabetes.
- 1889: Von Mering and Minkowski, when experimenting on dogs, found that removal of the pancreas led to diabetes.
- 1921: Banting, Best and Collip, working in Macleod’s laboratory, ligated the pancreatic duct, causing the destruction of the exocrine pancreas while leaving the islets intact. In their elegant animal experiments, by using canine insulin extracts to reverse induced diabetes, they conclusively established that the deficiency of insulin was the cause of diabetes.
- 1922: One of the miracles of the last century was the discovery of insulin by Canadian surgeon Banting and his assistant Best. Following experimentation on dogs, their life-saving infusion of a bovine extract of insulin (made by their biochemist colleague, Collip) to a 14-year-old boy, Leonard Thompson, in 1922 at the Toronto General Hospital, proved to be a sensation in the world of diabetic therapy.
- 1960-1969: Urine strips in the 1960s and the automated ‘doit-yourself’ measurement of blood glucose through glucometers, produced by Ames Diagnostics in 1969, brought glucose control from the emergency room to the patient’s living room.
- 1980: The first human insulin was manufactured by Graham Bell.
- 1982: the first biosynthetic insulin (humulin) was developed.
- 1986: Eisenbarth proposed the pathophysiological model of DM1 as a gradual deficiency of insulin production resulting from the destruction of pancreatic beta cells due to an autoimmune process mediated by T cells in individuals genetically susceptible to the disease, who were born with a normal number of beta cells but undergo a process of cell destruction, most likely after exposure to precipitating environmental factors.
- November 14: Banting’s colossal contribution has been globally recognised by the declaration, since 2007, of his birthday (14th November) as World Diabetes Day.
Classification
- Type 1 Diabetes mellitus
- Type 2 Diabetes mellitus
- Monogenic diabetes: Neonatal diabetes, MODY-maturity onset diabetes of the young, mitochondrial diabetes, and lipoatrophic diabetes
- Diabetes secondary to other pancreatic diseases, endocrinopathies, infections and cytotoxic drugs
- Diabetes related to certain genetic syndromes
Pathophysiology
Type 1 Diabetes Mellitus
- 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.
- 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). Follow-up studies have documented the association of chronic hyperglycemia with macrovascular complications as well as all-cause mortality. Iatrogenic hypoglycemia, however, was identified as the major limiting factor to intensive glucose control.
- 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.
Type 2 Diabetes Mellitus
- Obesity leads to peripheral insulin resistance, which in turn leads to hyperglycemia as discussed. Independent of obesity, certain ethnicities have higher risks of insulin resistance and beta cell dysfunction. Hyperglycemia leads to an osmotic diuresis (polyuria), which increases thirst (polydipsia). This diuresis causes moderate to severe dehydration. Prolonged hyperglycemia can produce two distinct emergent states in type 2 diabetes mellitus in children.
- Diabetic ketoacidosis: much more common in children with type 2 diabetes mellitus compared to adults. Lack of insulin inhibits the body's ability to use glucose for energy and reverts to breaking down fat for energy. This leads to ketosis, acidosis, and electrolyte abnormalities and may lead to coma and death.
- Hyperglycemic Hyperosmolar State (HHS): characterized by hypertonicity, extreme hyperglycemia (> 600 mg/dl), and severe dehydration. The profound hyperglycemia results in continued osmotic diuresis and intravascular depletion.
Etiology
Type 1 Diabetes Mellitus
- 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:Pre-symptomatic DM1 with positive autoimmunity (two or more autoantibodies against the islet) and normal blood glucose. This corresponds to the immunological disease phase and, in many cases, progression to the clinical disease occurs in a period between 8 to 10 years.
- Stage 2: Pre-symptomatic DM1 with positive autoimmunity (two or more autoantibodies against the islet) and pre-diabetic dysglycemia (abnormal fasting glucose and/or reduced glucose tolerance in the OGTT). This corresponds to the almost irreversible stage of the disease, with functional loss of beta cells and the beginning of metabolic disease. The risk of symptomatic disease within a period of 5 years is approximately 75%, reaching 100% over a lifetime.
- Stage 3: Symptomatic DM1, with positive autoimmunity (two or more autoantibodies against the islet) and diabetic dysglycemia (diabetic fasting glucose and/or diabetic OGTT, increase in HbA1c). This corresponds to the autoimmune acceleration stage of the disease, with the presence of typical signs and symptoms of DM1. Progression of the symptomatic phase of DM1 can further be classified as: a) initial phase); b) established DM1 phase; c) established DM1 phase with chronic complications.
- 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.
Type 2 Diabetes Mellitus
- Hyperglycemia results when there is a relative lack of insulin compared to glucose in the blood. In type 2 diabetes mellitus, insulin resistance first leads to increased insulin production by the beta cells of the pancreas. When the beta cells are unable to produce enough insulin to maintain euglycemia, hyperglycemia results. Hyperglycemia has damaging effects to multiple organs, including kidneys, eyes, heart, and nerves. Further, hyperglycemia puts children at risk for other electrolyte disturbances
Differentiating [disease name] from other Diseases
- Salicylate toxicity
- Pheochromocytoma
- Diabetes insipidus
- Hyperthyroidism
Epidemiology and Demographics
Type 1 Diabetes Mellitus
- 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. 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%.
Type 2 Diabetes Mellitus
- Type 1 diabetes remains the most prevalent form of diabetes in children. However, type 2 diabetes mellitus is estimated to occur in one in three (20% to 33%) of new diagnoses of diabetes in children today. The rate of type 2 diabetes mellitus in children continues to rise even as the obesity rates have plateaued in these age groups. Risk factors include high-risk ethnicity (African American, Hispanic, Native Americans, Pacific Islanders, Asian Americans), a positive first-degree relative with the disorder, obesity, low birth weight, mother with gestational diabetes, and female sex. It is more likely to be diagnosed during adolescence when insulin resistance is common due to multiple factors including hormonal changes.
Risk Factors
Type 1 Diabetes Mellitus
- Despite HLA genes exerting a greater role in the etiology, other genes also contribute to the genetic effect, although the type of inheritance still remains unknown. Currently, the main markers of susceptibility to DM1 are considered to be class II HLA haplotypes DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2 serotype) and DRB1*0401-DQA1*0301-DQB1*0302 (DR4-DQ8 serotype), while DRB1*0403 is negatively associated with DM1, and may protect or slow the progression to clinical disease.
- Recurrence among siblings of a patient with DM1 is 5%, which means a risk 15 times higher, reaching 65-70% between monozygotic twins, or even higher if the index case has developed the disease in childhood.
- Genome-wide association studies have already identified more than 40 gene loci associated with the DM1 phenotype, generally involved in autoimmunity, the production and metabolism of insulin, and also the survival of the pancreatic beta cells.
- Genes such as IL2, CD25, INS, IL18RAP, IL10, IFH1, and PTPN22 appear to exert an influence on the speed of progression to DM1 after the onset of autoimmunity against the islet,24 and predictive algorithms for DM1 that also incorporated non-HLA genetic markers such as the PTPN22 or the INS gene increased the capacity to predict risk, especially in individuals with the DR3/DR4 haplotype in the general population.
- Some potential risk factors such as early fetal events, viral infections during the intrauterine or postnatal period, early exposure to the components of cow’s milk, and other nutritional factors could trigger the autoimmune process.
- Systematic reviews of observational studies have identified certain protective factors against the development of DM1, such as breast milk, atopy, and attending day care as indicative of early infections. There are also some risk factors, such as advanced maternal age, birth by cesarean section, and lower birth order.
- On the other hand, the role of the metabolism of vitamin D remains unclear. The frequency of DM1 in childhood has already been associated with estimates of the wealth of populations, such as the gross domestic product, suggesting that lifestyle habits related to wealth may be responsible for changes in these trends.
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Criteria
- Metabolic tests that evaluate insulin secretion ability and glycemic state are also used as criteria for predicting the functional reserve of beta cells and the clinical onset of DM1; they include: a) the intravenous glucose tolerance test (IGTT); b) the oral glucose tolerance test (OGTT); c) glycated hemoglobin concentrations (HbA1c). The diagnostic criteria of glucose disorders according to the American Diabetes Association (ADA) – 20165 are presented in Table 1.
| Diagnosis | Fasting blood glucose (mg/dL) | 2H-OGTT (mg/dL) | HbA1c (%) |
|---|---|---|---|
| Normal | 70 to 99 | < 140 | 4.5 to 5.6 |
| Prediabetes | 100 to 125 | 140 to 199 | 5.7 to 6.4 |
| Diabetes mellitus | ≥ 126 | ≥ 200 | ≥ 6.5 |
2H-OGTT: 120 minute time of the oral glucose tolerance test; HbA1c: glycated hemoglobin evaluated by laboratory test aligned with that used by the Diabetes Control and Complications Trial (DCCT).