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

Characteristics of prevalent forms of primary diabetes in children and adolescents

Features	Type 1 diabetes	Type 2 diabetes	MODY*	Atypical diabetes**
Prevalence	~85%	~12%	~1–4%	≥10% in African American
Age at onset	Throughout childhood and adolescence	Puberty; rare ‹10 years	‹25 years	Pubertal
Onset	Acute severe	Insidious to severe	Gradual	Acute severe
DKA at onset	~30%	~6%	Not typical	Common
Affected relative	5–10%	60–90%	50–90%	›75%
Female:male	1:1	1.1–1.8:1	1:1	Variable
Inheritance	Polygenic	Polygenic	Autosomal dominant	Autosomal dominant
HLA-DR3/4	Association	No association	No association	No association
Ethnicity	All, Caucasian at highest risk	All¶	All	African American/Asian
Insulin (C-peptide) secretion	Decreased/absent	Variable	Variably decreased	Variably decreased
Insulin sensitivity	Normal when controlled	Decreased	Normal	Normal
Insulin dependence	Permanent	Variable	Variable	Intermittent
Obesity	No†	›90%	Uncommon	Varies with population
Acanthosis nigricans	No	Common	No†	No†
Islet autoantibodies	Yes§	No	No	No

• MODY is maturity-onset diabetes in the young or monogenic diabetes. **Atypical diabetes is also referred to as Flatbush diabetes, type 1.5 diabetes, ketosis-prone diabetes, and idiopathic type 1 diabetes. ¶In North America, type 2 diabetespredominates in African American, Hispanic,Native American, and Canadian First Nations children and adolescents and is also more common in Asian and South Asian than in Caucasian individuals. †Mirrors rate in general population. §Diabetes-associated (islet) autoantibodies to insulin, islet cell cytoplasmic, glutamic acid decarboxylase, or tyrosine phosphatase (insulinoma-associated) antibody (IA-2, ICA512, ZnT8 antibodies in 85–95%) at diagnosis.

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.

Staging of type 1 diabetes

Stage	Features
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. Diagnostic criteria: ›2 autoantibodies; No IGT or IFG
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. Diagnostic criteria: ›2 autoantibodies; Dysglycemia: IFG and/or IGT; FPG 100–125 mg/dL (5.6–6.9 mmol/L); 2-h PG 140–199 mg/dL (7.8–11.0 mmol/L); A1C 5.7–6.4% (39–47 mmol/mol) or ≥10% increase in A1C
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. Diagnostic criteria: Clinical symptoms; Diabetes by standard criteria

• 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

• Genetics: 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.

• Non-Genetics: 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.

Hypoglycemia

• Hypoglycemia, a blood glucose concentration less than 60 mg/dL (3.3 mmol/L), occurs frequently in children treated for type 1 diabetes. It is caused by the inability to match the minute-to-minute changes in insulin requirements with current therapy, resulting in periods when insulin action exceeds insulin requirements. Patients who have lower average blood glucose concentrations may have more frequent episodes of hypoglycemia. The severity of hypoglycemic symptoms depends on both the degree of hypoglycemia and the rapidity of its development. The adrenergic symptoms of hypoglycemia include sweating, trembling, hunger, and palpitations; the neuroglycopenic symptoms include headache, lightheadedness, dizziness, diplopia, and confusion. With severe hypoglycemia, coma and seizures can occur.

• Mild-to-moderate hypoglycemia is treated by ingesting 10 to 15 g of glucose (eg, 4 oz of juice or nondiet soft drink). Hypoglycemia in infants and young children and moderate reactions resulting in confusion in older children require that caregivers, teachers, coaches, and others be prepared to assist in the recognition and treatment of hypoglycemia. Severe reactions require treatment with intramuscular or subcutaneous glucagon (1 mg, except for infants �10 kg, in whom 0.5 mg is given). Because hypoglycemia can occur away from home, a source of glucose to treat it (eg, a tube of cake frosting) and a glucagon emergency kit always should be available.

Ketonemia and Ketonuria

• The presence of urine or blood ketones should be assessed whenever there is persistent, significant hyperglycemia (eg, blood glucose�250 mg/dL [13.9 mmol/L] in spite of the administration of corrective doses of insulin). Urine or blood ketones also should be tested whenever the child feels ill, particularly with nausea and vomiting.
• Aggressive treatment with additional insulin is necessary once ketosis develops to prevent deterioration into DKA. Rapid-acting insulin at doses of 10% to 20% of the total daily requirement should be given every 3 to 4 hours until the ketones are cleared. Care must be taken to avoid causing hypoglycemia in a child who is not able to take sufficient caloric intake because of illness. Blood glucose and ketones should be measured frequently (at least every 3 to 4 h). Extra fluids are given to maintain hydration, which also helps excrete excess glucose and ketoacids. If solid foods cannot be eaten, sugar-containing foods such as soda, juice, gelatin dessert, and popsicles can be given to maintain some caloric intake and prevent hypoglycemia. During some illnesses, the usual daily insulin doses, adjusted for intake and glucose concentrations, can be continued. For illnesses in which oral intake is more disrupted, when ketones have developed, or for more significant illnesses, it may be best to treat with more frequent, small doses of insulin; typical doses may be 5% to 10% of the total daily dose every 3 to 4 hours, increasing to 10% to 20% of the total daily dose every 3 to 4 hours if ketones are present.
• Persistent vomiting, or a refusal or inability to take fluids or food orally, requires an emergency department or office visit. Glucagon must be available to treat hypoglycemia during an illness. The usual dose is administered for significant hypoglycemia. Because such doses of glucagon frequently cause significant nausea and vomiting, further compromising the ability to ingest food, smaller doses may be more effective for less severe hypoglycemia due to poor intake: 10 mcg/year of age (minimum 20 mcg, maximum 150 mcg); if there is no response in 30 minutes, a repeat at twice the dose can be attempted.

Diabetes Ketoacidosis

• DKA is a state of metabolic decompensation that results from profound insulin deficiency. DKA is the most common cause of death in children who have type 1 diabetes and is associated with a significant risk of morbidity. Early identification and treatment are key to minimizing the risks. For a child who is not known to have diabetes, the diagnosis of DKA must be considered with the presentation of vomiting and dehydration, particularly in the presence of an altered sensorium or in the absence of other indicators of a viral infection (such as fever and diarrhea). Diabetes mellitus always should be considered when there is a preceding history of polydipsia and polyuria. For a child who has a known diagnosis of diabetes mellitus, ketones should be measured when the child is significantly ill, if there is vomiting, or if there is persistent hyperglycemia. During a ketotic illness, referral for medical care (rather than continued home management) should be considered if the patient begins to vomit. Medical attention is necessary if the patient has deep respirations or is unable to stand.

Associated autoimmune disease

• Associated autoimmune disease, particularly thyroid dysfunction, occurs with greater frequency in individuals who have type 1 diabetes. Thyroid-stimulating hormone (TSH) should be measured shortly after diagnosis and may be measured subsequently every 1 to 2 years. TSH also should be measured whenever any thyroid-related signs or symptoms occur. Thyroxine concentrations and thyroid antibodies also may be assessed. Although rare, autoimmune adrenal hypofunction can occur, and symptoms to suggest this disorder should prompt appropriate testing.

• Celiac disease also occurs more frequently in children who have type 1 diabetes; all patients should be screened for this disorder at least once and any time poor growth and gastrointestinal symptoms occur. Tissue transglutaminase and antiendomysial antibodies are more sensitive and specific than antigliadin antibodies. Also, because these are immunoglobulin A (IgA) antibodies, it is important to assure that the individual patient is not IgA-deficient by measuring IgA concentrations.

Growth Disturbance

• Linear growth is affected negatively by poor diabetic control. Decreased growth velocity, crossing percentiles downward for height and weight, eventual short stature, and delayed skeletal and sexual maturation are associated with chronic undertreatment with insulin. An extreme form of this effect—the Mauriac syndrome or diabetic dwarfism—occurs rarely and usually is associated with hepatomegaly. Height and weight should be measured at every appointment and plotted on growth curves so deviations from normal velocities can be detected early. Alternatively, treatment with excessive insulin doses often leads to excessive weight gain, causing the weight curve to cross percentiles upward. Maintenance of normal growth curves for height and weight is an important goal of diabetes management.

Retinopathy

• Retinopathy usually is not seen before 5 to 10 years of diabetes duration. Recommendations from the American Diabetes Association are for the first ophthalmologic examination to occur once the child is at least 10 years old and has had diabetes for 3 to 5 years. Yearly follow-up examinations generally are recommended. Poor metabolic control, elevated blood pressure, smoking, albuminuria, and elevated lipid values are risk factors for retinopathy. Diabetes duration and pregnancy also are associated with increased risk.

Nephropathy

• A significant minority of patients who have type 1 diabetes eventually develops end-stage renal disease, necessitating dialysis or transplantation. All patients who have type 1 diabetes should be monitored by urine microalbumin determination at least annually beginning after the child is 10 years old and has had diabetes for 5 years. Because hypertension accelerates the progression of nephropathy, blood pressure should be monitored several times a year, and hypertension should be treated aggressively. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are recommended for treatment of hypertension. If hypertension, overt proteinuria, or elevation in serum creatinine or urea nitrogen values is found, monitoring of renal function several times each year and consultation with a nephrologist are warranted. Microalbuminuria (30 to 299 mg of albumin per gram of creatinine on spot urine) is a marker for early nephropathy. Two of three urine specimens that have elevated values, measured on different days, are needed for confirmation. Whether using angiotensin-converting enzyme inhibitors in normotensive individuals prevents or retards nephropathy is not known. Patients should avoid other risk factors for nephropathy, such as smoking.

Neuropathy

• Symptomatic diabetic neuropathy, peripheral or autonomic, is uncommon in children and adolescents who have type 1 diabetes. Changes in nerve conduction, however, may be seen after 4 to 5 years of having diabetes. Overall, neuropathy is a common type 1 diabetes complication, and its frequency increases with the duration of disease and degree of hyperglycemia. Improvements in glycemic control may improve neuropathic symptoms.

Macrovascular Complications

• Patients who have type 1 diabetes tend to have coronary artery, cerebrovascular, and peripheral vascular disease more often, at an earlier age, and more extensively than the nondiabetic population. Hypertension, elevated blood lipid concentrations, and cigarette smoking are other risk factors for developing macrovascular complications. Risk factors should be analyzed, including lipid panels, blood pressure measurements, and determination of smoking status, and treatment instituted as indicated. A strong admonition against smoking and referral to an appropriate program for patients who already are smokers is crucial. Studies continue to show that lower lowdensity lipoprotein (LDL) values are beneficial in lowering the risk of vascular disease, and recommendations continue to evolve. Screening with fasting lipid measurements should begin in children at age 12 years if there is no concerning family history and at diagnosis (after establishing metabolic control) when there is a positive family history for lipid abnormalities or early cardiovascular events.

• Current recommendations are to treat children older than age 10 years who have LDL cholesterol concentrations at or above 160 mg/dL (4.14 mmol/L) and to consider treatment if the LDL value is at or above 130 mg/dL (3.37 mmol/L) if other risk factors are present. The goal is to achieve an LDL value below 100 mg/dL (2.59 mmol/L) . Although bile acid sequestrants may be recommended as the first treatment in children, they are poorly tolerated, and effective therapeutic data are lacking. Thus, statins should be considered, with appropriate monitoring. Of course, dietary counseling and blood glucose control are important parts of management.

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.

Treatment

• The management requires a diabetes healthcare team consisting of the medical provider, nurse, diabetes educator, dietician, social worker, and psychologist. However, not all specialties are always available, convenient, or covered by insurance.
• During an initial phase of management, frequent contact between the child and family and medical team through in-office visits is required while being treatment is adjusted; and the family learns the daily management tasks of caring for a child with diabetes as it needs a long-term day to day treatment decisions.
• Social worker: Involved to ensure that the child has adequate support and finances for treatment.
• Exercise specialist: Teach the child about beneficial exercises.
• Diabetic nurse: Assess the child's growth, blood pressure and injection site at every home visit; and assist with the care coordination between the patient and family with the medical providers. A mental health nurse provide counseling if a child with diabetes become depressed.
• All diabetics should be referred to an ophthalmologist, nephrologist, cardiologist and a neurologist for baseline workup of their respective organ systems.

Type 1 Diabetes Mellitus

• Insulin delivery: It is done by multiple daily injections (MDI) or an insulin pump to simulate endogenous insulin physiology.
  • Multiple daily injections: Basal insulin is given once or twice daily, and bolus insulin typically injected at meals three or more times daily based on carbohydrate content and current blood glucose.
  • Insulin pumps: They 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.
• Honeymoon period: Patients usually have some remaining beta cells at the time of diagnosis of the diabetes. Hence, insulin requirements often decline temporarily 1 to 3 months after diagnosis. During this honeymoon period, dose requirements may drop to less than 0.5 units/kg/day which may lasts several months occasionally for 12 months or more. However, most patients who have type 1 diabetes have no significant insulin production except during the honeymoon period; therefore, most preadolescent children need about 0.5 to 1.0 units/kg/day and adolescents usually requires about 0.8 to 1.2 units/kg/day due to increased insulin resistance during puberty.
• Insulin: All insulin is manufactured by recombinant DNA technology based on the amino acid sequence of human insulin which are elaborated in Table 3.

Table 3: Types of insulin preparations and approximate insulin action profiles

Insulin type	Onset of action (h)	Peak of action (h)	Duration of action (h)
Rapid-acting analogs Aspart (Novolog) Lispro (Humalog) Glulisine (Apidra)	0.25–0.5 0.25–0.5 0.25–0.5	1–3 1–3 1–3	3–5 3–5 3–5
Regular insulin	0.5–1	2–4	5–8
Intermediate-acting: NPH	2–4	4–8	12–18
Long-acting analogs Detemir (Levemir) Glargine (Lantus, Basaglar, Toujeo) Degludec (Tresiba)	2–4 2–4 2–4	none none none	12–24 up to 24 ›24

• Split/mixed regimens: It require at least two injections per day of short- and intermediate-acting insulin (a mix of NPH and regular/rapid) being administered shortly before breakfast and dinner to achieve satisfactory metabolic control. When split/mixed regimens are used, patients usually need about two thirds of their total dose in the morning and one third in the evening. The doses usually are split between one-third regular/rapid-acting insulin and two thirds NPH to one-half/one-half. More regular/rapid-acting insulin may be required in the morning because of the dawn phenomenon which is caused by normal nocturnal increases in some counter-regulatory hormones that lead to reduced insulin sensitivity in the early morning.

• Basal/bolus regimens: It aims to achieve more physiologic insulin concentrations with less between-meal insulin action.
  • Basal insulin: It provides baseline or fasting insulin needs, which are usually about 50% of total daily insulin requirements, by either rapid-acting insulin given with the basal rate of an insulin pump or with once- or twice daily injections of detemir or glargine.
  • Bolus insulin: It is provided by acute doses of rapid-acting insulin either through injections or through bolus doses given by an insulin pump to cover food requirements and to correct hyperglycemia. It has two parts to the dose: the amount of insulin needed to cover the carbohydrates in the meal and the amount of insulin needed to correct for a blood glucose concentration outside of the target range.
  • The Basal/bolus doses are based on empiric formulas, and modifications can be made once responses to starting doses are assessed.
  • The insulin-to-carbohydrate ratio, which may differ for each patient and for different times of day, is the insulin requirement for each gram of carbohydrate in a meal.
  • The correction or sensitivity factor is how much the individual patient’s blood glucose values fall when given 1 unit of insulin.
  • Thus, the premeal bolus dose equals the insulin-to-carbohydrate ratio multiplied by the grams of carbohydrate to be eaten plus the insulin sensitivity factor multiplied by the amount that the blood glucose needs to fall from the preprandial value to reach the target range.
  • Target ranges, for example, may be set at 80 to 120 mg/dL (4.4 to 6.7 mmol/L) for daytime and 100 to 150 mg/dL (5.6 to 8.3 mmol/L) at bedtime. When converting a child from a two- or three-injection regimen with NPH to a basal/bolus regimen, the total daily dose is usually lower, and recommendations are to use 50% to 80% of the NPH dose for the initial basal insulin dose, with the lower percentages used for younger children.

• Automated Insulin Delivery: The combination of continuous glucose sensors with insulin pumps has enabled the development of automated insulin delivery systems (“closed-loop” or “artificial pancreas” devices). “Hybrid” closed-loop systems, which modulate basal insulin delivery based on sensor glucose levels, have increased time spent within target glucose ranges, reduced hyper- and hypoglycemia exposure, lowered A1C levels, and improved measures of quality of life in both adult and adolescent subjects. However, transition of automated insulin delivery from research to clinical care will require patient and provider education to optimize outcomes.

• Adjunctive therapies: Pramlintide, an analog of the pancreatic polypeptide amylin, has been shown to improve glycemic control when added to insulin in adults with type 1 diabetes primarily through dampening glycemic excursions by suppressing glucagon secretion and delaying gastric emptying. However, neither pramlintide nor other potentially useful adjuncts, such as glucagon like peptide 1 receptor agonists (e.g., liraglutide, exenatide) or sodium–glucose cotransporter 2 inhibitors, have been thoroughly studied in the pediatric population with type 1 diabetes, and none have been approved yet for use in this population by the FDA.

Type 2 Diabetes Mellitus

• Pharmacological agents: Metformin and insulin are the only medications for use in children and adolescents.
  • Metformin: It is first-line therapy along with in combination with diet and exercise in children 10 years and older. It should be initiated at a dosage of 500 mg per day, regardless of the patient’s weight, then titrated in 500 mg intervals over four weeks to the maximum dosage of 2,000 mg per day. The gradual increase of the medication and taking it with food helps to prevent gastrointestinal side effects.
  • Insulin: Insulin may be beneficial for these patients on a short-term basis; subsequently can be discontinued after initiating metformin therapy and lifestyle changes. A basal/bolus regimen like in T1DM may be used, but typically T2DM patients require higher doses (2-3 unit/kg/day). However, it must be initiated in the following scenarios:
    • Patient has signs of ketosis or ketoacidosis
    • Random plasma glucose levels of 250 mg/dL (13.9 mmol/L) or greater
    • A1C level is greater than 9%
    • Diagnosis of type 1 vs. type 2 is not clear.

Lifestyle management

• Lifestyle management is important for pediatric patients with diabetes to enable health maintenance, CVD prevention, and glycemic control.

Nutrition

• Dietary management should be individualized: family habits, food preferences, religious or cultural needs, schedules, physical activity, and the patient’s and family’s abilities in numeracy, literacy, and self-management level.
• Dietitian visits should include assessment for changes in food preferences over time, access to food, growth and development, weight status, cardiovascular risk, and potential for eating disorders.
• Current consensus recommends the following:
  • Carbohydrates: 50-55% of the daily energy intake but simple carbohydrates like sucrose should not make up more than 10% of the total.
  • Fats: ~30% of the daily energy intake.
  • Protein: 10-15% of the daily energy intake.
• Most carbohydrate calories should be complex carbohydrates, and the fat portion should emphasize low amounts of cholesterol and saturated fats.
• Split/ mixed insulin regimens: For patients using this regimen, timing of meals is important to minimize blood glucose variability.
  • In addition to the usual three meals, mid-afternoon snacks are necessary because they coincide with the typical peak of the morning NPH insulin dose and with most after-school sports activities.
  • Bedtime snacks are important for most children receiving evening NPH doses.
  • Midmorning snacks are useful in preschool-age children, but most school-age children find such snacks disruptive to their school routine. This snack usually is not recommended after a child begins elementary school.

Physical activity and Exercise

• Exercise is recommended for all youth with type 1 diabetes with the goal of 60 min of moderate- to vigorous intensity aerobic activity daily, with vigorous muscle-strengthening and bone-strengthening activities at least 3 days per week.
• Hypoglycemia during exercise: The type, intensity, and duration of exercise trigger multiple hormones (insulin, glucagon, catecholamines, and glucocorticoids) that mediate fuel metabolism. Pancreatic islet cells achieve euglycemia by balancing peripheral glucose uptake and hepatic glucose production. In type 1 diabetes, this intrinsic balance does not exist. Exogenous insulin administration inhibits hepatic glucose production and promotes exercise-induced glucose uptake, both triggering hypoglycemia. Intense exercise increases hypoglycemia risk during, immediately following, and 6–12 h after physical activity, the “lag effect”. This lag likely results from a combination of improved insulin sensitivity following exercise, blunted counterregulatory hormone release, and increased glucose uptake bythe liver and skeletal muscles to replenish glycogen stores. Impaired counterregulatory hormone release in pediatric patients may include blunting during sleep, antecedent hypoglycemia, and autonomic failure. Delayed hypoglycemia often occurs at night following afternoon physical activities. Therefore, exercise-induced hypoglycemia and fear of hypoglycemia may limit desire to participate in exercise.
• Hyperglycemia during exercise: It may occur during high-intensity exercise such as sprints or resistance training when there is inadequate delivery of exogenous insulin and/or an excess of counterregulatory hormones that increase hepatic glucose production and inhibit glucose uptake into skeletal muscle. Intense activity should be postponed with marked hyperglycemia (glucose$350mg/dL [19.4mmol/L]), moderate to large urine ketones, and/or b-hydroxybutyrate.1.5 mmol/L. Caution may be needed when b-hydroxybutyrate levels are $0.6 mmol/L.
• Education about prevention and management of potential hypoglycemia during and after exercise is essential, including pre-exercise glucose levels of 90–250 mg/dL (5–13 mmol/L) and accessible carbohydrates, individualized according to the type/intensity of the planned physical activity.
• Strategies to prevent hypoglycemia during exercise, after exercise, and overnight following exercise include reducing prandial insulin dosing for the meal/snack preceding exercise, increasing carbohydrate intake, eating bedtime snacks, using CGM, and/or reducing basal insulin doses. For low- to moderate-intensity aerobic activities (30260 min), and if the patient is fasting, 10215 g of carbohydrate may prevent hypoglycemia. After insulin boluses (relative hyperinsulinemia), consider 0.5– 1.0 g of carbohydrates/kg per hour of exercise (;30260 g), which is similar to carbohydrate requirements to optimize performance in athletes without type 1 diabetes.
• Frequent glucose monitoring before, during, and after exercise, with or without CGM use, is important to prevent, detect, and treat hypoglycemia and hyperglycemia with exercise.

Education and Family involvement

• Diabetes education is life-long, for patients, families, and the diabetes team.
• Lifestyle changes are most successful when the patient’s entire family is involved. Engaging family members also improves medication adherence. Because type 2 diabetes disproportionately affects minorities, clinicians should ensure that family-centered education is culturally appropriate.
• Patients and families need to understand all aspects of diabetes, including acute and long-term complications. They must understand details of insulin action, including duration and timing and dose adjustments, injection and insertion techniques, electronics and mechanics of insulin pumps, dietary information, blood glucose monitoring and interpretation, and urine ketone checks and appropriate interventions.
• Education about diabetes must be appropriate to the child’s age and the family’s educational background, and it must be ongoing. Responsibility for diabetes self-care skills (eg, insulin injections) should be shifted gradually from parent to child and when the child shows interest and readiness to take responsibility. Premature shifting of responsibility may result in deterioration of metabolic control. Management of diabetes involves the whole family because the life of the entire family is affected by having a child who has type 1 diabetes. Sharing responsibilities and attending support groups and camps for children who have type 1 diabetes can help with psychological adjustment.
• The psychosocial effects of diabetes should be addressed to help children and adolescents cope with the disease.
• All patients and their families need comprehensive education about the disease and its potential complications.

Assessment of Glycemic control

• A1C monitoring: It should be measured in all children and adolescents with type 1 diabetes at 3-month intervals to assess their overall glycemic control. An A1C target of ,7.5% should be considered in children and adolescents with type 1 diabetes but should be individualized based on the needs and situation of the patient and family. With increasing use of continuous glucose monitoring (CGM) devices, outcomes other than A1C, such as time with glucose in target range and frequency of hypoglycemia, should be considered in the overall assessment of glycemic control.
• Blood glucose monitoring: All children and adolescents with type 1 diabetes should have blood glucose levels monitored multiple times daily (up to 6–10 times/day), including premeal and pre-bedtime, and as needed for safety in specific situations such as exercise, driving, illness, or the presence of symptoms of hypoglycemia.
• Blood/Urinary Ketone Monitoring: Blood or urine ketone levels should be monitored in children with type 1 diabetes in the setting of prolonged/severe hyperglycemia or acute illness to determine if adjustment to treatment or referral to urgent care is needed.
• Continuous glucose monitoring: CGM should be considered in all children and adolescents with type 1 diabetes, whether using injections or insulin pump therapy, as an additional tool to help improve glycemic control. Benefits of CGM correlate with adherence to ongoing use of the device.

Anticipatory Guidance

• Immunization: Children with diabetes should receive all immunizations in accordance with the recommendations of the Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention, including annual vaccination against influenza for children with diabetes who are at least 6 months of age. Once administer one dose of 23-valent pneumococcal polysaccharide vaccine (Pneumovax) at least eight weeks after previous dose of 13-valent pneumococcal conjugate vaccine (Prevnar 13). The child and adolescent vaccination schedule is available at www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html. Large studies have shown no causal relationship between childhood vaccination and type 1 diabetes.

• Growth: Normal linear growth and appropriate weight gain throughout childhood and adolescence are excellent indexes of general health and reasonable markers of metabolic control. Height and weight should be measured at each visit and tracked via appropriate height and weight growth charts (www.cdc.gov/growthcharts/clinical_charts.htm). Overweight and obesity are emerging issues in youth with type 1 diabetes and should be considered as part of dietary counseling.

• Multidisciplinary evaluation: All people with diabetes should have regular dilated eye exams (to examine for diabetic retinopathy), urine microalbumin screening at appropriate intervals (evaluated for renal involvement), hyperlipidemia screens/treatment, hypertension screening/treatment, liver function tests, sleep apnea evaluation, and regular assessment of psychosocial adherence, self-management skills, dietary needs, and physical activity level.

• Smoking: Elicit a smoking history at initial and follow-up diabetes visits, and discourage smoking in youth who do not smoke and encourage smoking cessation in those who do smoke.

• Transition from pediatric to adult care: Pediatric diabetes providers should begin to prepare youth for transition in early adolescence and, at the latest, at least 1 year before the transition to adult health care. Both pediatric and adult diabetes care providers should provide support and resources for transitioning young adults.