Diabetes in children

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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.
• The autoimmune destruction of beta cells probably occurs over the course of months to years before diabetes develops. It is believed that more than 80% of beta cells must be lost before glycemic control is impaired significantly. As beta-cell loss progresses beyond that point, insulin is insufficiently present to maintain glucose and lipid homeostasis. When glucose concentrations in the blood rise above approximately 180 mg/dL (10.0 mmol/L), glucosuria occurs, leading to an osmotic diuresis that causes polyuria. The polyuria stimulates polydipsia to maintain euvolemia. With further insulin deficiency, there is an increase in lipolysis from fat cells as well as protein breakdown, an exaggeration of the normal fasting state designed to provide alternative sources of fuel. These mechanisms, along with the caloric loss from glucosuria, result in the hyperphagia and weight loss typical of the undiagnosed diabetic state. With profound insulin deficiency, the process devolves into ketoacidosis, with marked hyperglycemia, dehydration driven by the glucosuric osmotic diuresis, and accumulation of ketoacids from the hepatic metabolism of the liberated fatty acids.

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 and Prognosis

• The natural history of diabetes involves increased risk for acute and severe complications alongwith chronic microvascular and macrovascular complications that negatively affect the quality of life and survival of these patients. Because the risk of diabetes-related complications is related to the duration of the disease, prompt diagnosis and appropriate therapy are important.
• The psychosocial impact of living with diabetes can be a challenge for any child and any family but is particularly burdensome to those with maladaptive coping skills. The result can sometimes be manifest as poor glucose control.
• Approximately 1 million people die every year as a result of diabetes, two-thirds of which in developing countries.
• Type 1 diabetes has high morbidity and mortality. The life expectancy is reduced by 10-20 years for many individuals. Children particulary die from DKA chiefly due to delayed diagnosis.

Complications

• DKA and hypoglycemia are the most significant acute complications of diabetes and its treatment, and both complications pose a significant risk of morbidity and mortality. Diabetes mellitus causes damage to the microvascular circulation, which results in tissue and organ damage, most notably in the retina, kidneys, and nerves. Due to these microvascular complications, diabetes mellitus is a leading cause of blindness, end-stage renal disease, and neuropathy. There also is a significant increase in the risk of atherosclerotic vascular disease in individuals who have diabetes. This macrovascular disease is responsible for strokes and heart attacks being the most common causes of death in these patients.

• Risk reduction: Both the microvascular and macrovascular complications of diabetes are related to the hyperglycemia that persists even with disease treatment. The development of chronic complications also depends on the duration of diabetes, generally taking decades for clinically significant complications to appear. Therefore, although some late adolescents who have early onset of diabetes may show early evidence of complications (eg, nonproliferative retinopathy, microalbuminuria [urinary albumin excretion of 30 to 300 mg/d], or changes in nerve conduction), it is extremely uncommon for a child to have significant diabetic microvascular or macrovascular complications. Nonetheless, glycemic control should be maximized in children who have diabetes to minimize their risk of long-term complications as they age. Clinical trials, including the Diabetes Control and Complications Trial (DCCT), have demonstrated that the lower the hemoglobin A1c (HbA1c) that a patient maintains, reflecting a lower average blood glucose concentration, the lower the risk of microvascular complications. An improvement in HbA1c of 1% (reflecting a decrease in mean glucose concentrations of 30 to 35 mg/dL [1.67 to 2.9 mmol/L]) decreases the risk of long-term complications by approximately 20% to 50%. There is no threshold for this effect; that is, a lower HbA1c always is better in terms of lowering the risk of long-term complications. However, the absolute risk reduction is less at lower HbA1c values, and lower average glucose values increase the risk of the acute complications of hypoglycemia. Therefore, diabetes management involves a balancing of the long-term benefit of lowering the average glucose concentration with avoiding the acute complication of hypoglycemia.

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.

Diagnostic criteria of glucose disorders according to the American Diabetes Association (ADA) – 2016

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).

History and Physical Examination

• At presentation, children usually have a history of polyuria, polydipsia and weight loss for days to months. Re-emergence of bedwetting, nocturia, and a need to leave classes in school to use the bathroom are complaints that suggest polyuria.
• If the diagnosis is delayed, there may be vomiting, lethargy, altered mental status, dehydration, and acidosis.
• Some children will present with ketoacidosis that is associated with the smell of ketones, dehydration, abdominal pain, Kussmaul breathing, vomiting, coma and altered mental status.
• Children with type 2 diabetes mellitus most often present during asymptomatic screening. Children with type 2 diabetes mellitus are more likely than adults with the disorder to present in DKA (5% to 13%), especially if they are of ethnic minority descent. Adolescents with type 2 diabetes mellitus may also present in Hyperosmolar Hyperglycemic State (HHS).
• Physical exam findings can include acanthosis nigricans (dark, velvety rash present in the axillae and neck). The American Diabetes Association recommends screening children at 10 years old or at the start of puberty in children who are obese (> 95th percentile BMI for age) or are overweight (BMI > 85th percentile for age or > 120% ideal body weight) and have two risk factors. These factors can be positive family history, high-risk ethnicity, signs of insulin resistance (polycystic ovary syndrome (PCOS), acanthosis, symptoms), or history of maternal gestational diabetes mellitus
• 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. As most children with type 1 diabetes are otherwise healthy, history and physical is usually limited to assessment of pertinent diabetes care.
• 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.

Diagnostic Evaluation

• The American Diabetes Association recommends screening for type 2 diabetes mellitus every three years starting at age ten years (or at the onset of puberty) for patients who are:
  • Obese (body mass index (BMI) greater than or equal to the 95th percentile for age)
  • Overweight (BMI greater than or equal to the 85thpercentile) and have at lease two risk factors (positive family history, higher risk race or ethnicity, signs of insulin resistance, maternal history of gestational DM).

• Diagnostic criteria:
  • Random plasma blood glucose 200 mg/dl or greater with symptoms of polyuria, polydipsia, or weight loss.
  • Fasting blood glucose of 126 mg/dl or higher in an asymptomatic patient.
  • Oral glucose tolerance test with blood sugar 200 mg/dl or greater at two hours post ingestion.
  • Hemoglobin A1c > 6.5%.

• If the diagnosis between type 1 and type 2 diabetes mellitus is not clear, helpful labs include fasting insulin or c peptide (both usually high or normal in type 2 diabetes mellitus, low in type 1 diabetes mellitus ), and autoantibodies for type 1 diabetes mellitus.
• 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.
• 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.