Insulin is produced by beta cells in the islets of Langerhans in the pancreas. Insulin secretion is regulated by glucose influx into the beta cell, which is dependent on the serum glucose level. Insulin acts on target tissues including liver, fat, and muscle to stimulate glucose uptake and inhibit gluconeogenesis, glycogenolysis, lipolysis, and ketogenesis.

The prevalence of diabetes mellitus in the United States in youth less than 20 years of age is 0.182%.¹ Type 1 diabetes accounts for 85% of these cases, while type 2 diabetes accounts for 12%, and maturity-onset diabetes of the young (MODY) accounts for 1% to 2%. The incidences of type 1 diabetes and type 2 diabetes in children are both increasing, although the United States has seen a particularly striking increase of type 2 diabetes in children and young adults in the past several years.

PATHOPHYSIOLOGY

Hyperglycemia results from abnormal insulin production, abnormal insulin action, or both. In type 1 diabetes, autoimmune destruction of beta cells results in an absolute insulin deficiency. Approximately 90% of patients with type 1 diabetes have measurable serum antibodies against islet cells, glutamic acid decarboxylase (GAD), or insulin.² However, although autoimmunity is an essential component of the pathogenesis of type 1 diabetes, it alone is not sufficient; environmental factors including diet, prenatal influences, infectious exposures, stress, and genetic factors contribute to development of this disease.

Type 2 diabetes is characterized by insulin resistance, often due to obesity, with resulting beta cell dysfunction and glucotoxicity that results in a relative insulin deficiency despite hyperinsulinemia. Although the etiology of type 2 diabetes is multifactorial, there is a stronger genetic component than for type 1 diabetes.²

Patients with hyperglycemia often have a history of polyuria, polydipsia, polyphagia, weight loss, and/or fatigue. Depending on the duration of illness and the underlying pathophysiology, the patient may or may not have ketosis or acidosis as a consequence of absolute or relative insulin deficiency. Although more common in type 1 diabetes, ketosis and acidosis can also occur in type 2 diabetes.

Children with newly diagnosed diabetes may present to the hospital in advanced stages of metabolic decompensation because the symptoms of hyperglycemia were not recognized. Treatment of diabetic ketoacidosis (DKA) in childhood requires strict attention to fluid balance and neurologic status because of the increased risk of cerebral edema in the pediatric population. Early detection of diabetes can reduce these risks.

The cause of hyperglycemia is not always apparent at initial presentation. The differential diagnosis includes type 1 diabetes, type 2 diabetes, MODY, “stress hyperglycemia” from illness or trauma, pancreatitis, other pancreatic dysfunction (e.g. cystic fibrosis), and drug effect (glucocorticoids, antipsychotics, etc.). Less commonly, hyperglycemia may be seen in the setting of other endocrine disorders such as excess endogenous glucocorticoid, growth hormone, or catecholamine. Type 1 diabetes can also be a component of autoimmune polyendocrine syndrome type 2, which includes autoimmune primary adrenal insufficiency (Addison disease) and autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease).

Patients may experience a period of absolute insulin deficiency at the time of diagnosis and present with ketosis with or without acidosis. Younger age at presentation and Caucasian ethnicity is associated with increased likelihood of type 1 diabetes. Most patients with type 1 diabetes present before the age of 30 years, and for this reason the condition was previously termed “juvenile-onset” diabetes. It is now clear, however, that autoimmune diabetes may develop at any age. Obesity and acanthosis nigricans (thickening and darkening of the skin in flexural areas such as the axillae and posterior of the neck) should raise the possibility that a child has type 2 diabetes, even in the setting of ketoacidosis. These patients typically do not have antibodies against islet cells, GAD, or insulin. This form of diabetes was previously labeled as “adult-onset” diabetes; however, the incidence of type 2 diabetes in the pediatric population is increasing rapidly as childhood obesity has become more prevalent.^1,3

MODY is a relatively rare group of disorders of insulin secretion and glucose disposal. They vary in their severity and presentation, and management often differs from that of type 1 and type 2 diabetes. Each is caused by a single gene mutation and is inherited in an autosomal dominant pattern. Insulin resistance and obesity are not features of these disorders.⁴

Criteria for the diagnosis of diabetes include a random plasma glucose ≥200 mg/dL or hemoglobin A1c ≥ 6.5% with symptoms of diabetes, or a fasting (at least 8 hours) plasma glucose ≥126 mg/dL, or a 2-hour plasma glucose ≥200 mg/dL during an oral glucose tolerance test using a glucose load of 1.75 grams/kg (up to 75 grams).

If an asymptomatic patient is found to have a fasting plasma glucose ≥126 mg/dL or a random plasma glucose ≥200 mg/dL as part of screening labs, these should be repeated on a second day to confirm these results. However, if a patient with signs and symptoms of diabetes including polyuria, polydipsia, or weight loss is found to have a random glucose of ≥200 mg/dL, no further testing is needed for diagnosis.⁵

HYPERGLYCEMIC STATES

Patients with diabetes can present various hyperglycemic states, each with its own diagnostic criteria and management. The various ways in which diabetes can present are described below; the management will be discussed later.

Hyperglycemia with Ketoacidosis

DKA is defined by a glucose ≥200 mg/dL, venous pH <7.3 or HCO₃ <15 mM, and ketonuria or ketonemia.⁶ Patients presenting with DKA should be admitted to an intensive care unit (ICU) or a medical unit that is prepared to handle a patient requiring close monitoring of vital signs and neurologic status, frequent blood glucose monitoring, and frequent lab draws.

Hyperglycemia with Ketosis and without Acidosis

Diabetic ketosis without acidosis (DK no A) is defined by a glucose ≥200 mg/dL, venous pH ≥7.3 or HCO₃ ≥15 mM, and the presence of ketones in urine or blood. In the patient who has a history of diabetes, it is reasonable to consider emergency department management with a discharge to home if there is a good response to intravenous fluids and insulin. Most centers will admit a patient with new-onset diabetes for initiation of insulin therapy and diabetes education regardless of whether ketones are present or absent (see Management).

Hyperglycemic Hyperosmolar Syndrome

Hyperglycemic hyperosmolar syndrome (HHS), also known as hyperosmolar hyperglycemic nonketotic (HHNK) syndrome, is defined by a glucose >600 mg/dL, serum osmolality >330 mOsm, venous pH >7.3, HCO₃ >15 mM, and absent to small ketonuria or ketonemia. It is often accompanied by hypernatremia, significant dehydration, and altered mental status.^6,7 Admission to an ICU is indicated due to increased risk of cerebral edema and stroke in these patients even in comparison to DKA.

Mixed Hyperglycemic Hyperosmolar State and Ketoacidosis

Mixed hyperglycemic hyperosmolar state and ketoacidosis, defined by glucose >600 mg/dL, serum osmolality >320 mOsm, venous pH <7.3, HCO₃ <15 mM, and moderate or large ketonuria or ketonemia, often with hypernatremia, significant dehydration, and altered mental status,^6,7 warrants admission to an ICU, particularly if there is evidence of altered mental status.

INITIAL ASSESSMENT

The initial assessment of a patient with hyperglycemia includes a physical exam that pays careful attention to vital signs, status of the respiratory, cardiovascular, and neurologic systems, and to hydration status. The patient’s body mass index and the presence or absence of acanthosis nigricans may provide insight into the underlying pathophysiology.

The initial laboratory evaluation of newly diagnosed diabetes should include a venous or arterial blood gas, basic metabolic panel (to evaluate electrolytes, CO₂, BUN, and creatinine), phosphorus, magnesium, insulin, C-peptide, hemoglobin A1c, GAD-65 antibodies, islet cell antibodies, and insulin autoantibodies. Urine should be assessed for the presence of glucose and ketones. In patients with significant electrolyte abnormalities, an electrocardiogram (ECG) should be obtained. If the patient is experiencing altered mental status, a retinal exam and a head CT should be considered to evaluate for cerebral edema.

The history should include the duration of illness, precipitating factors (such as infection, trauma, stress, puberty, or pregnancy), the patient’s previous weight, and any prescription or nonprescription drugs the patient may have taken. If diabetes has previously been diagnosed, it is helpful to know the current insulin regimen, time of the last insulin dose, and the patient’s compliance with treatment. If this is the patient’s first presentation with hyperglycemia, any family history of autoimmune disease, type 1 or 2 diabetes, and gestational diabetes should be elicited. Patients with type 1 diabetes should have inappropriately low insulin and C-peptide levels. Most but not all patients with type 1 diabetes have positive diabetes antibodies. It is not uncommon for patients with type 2 diabetes to also have inappropriately low insulin and C-peptide levels given their blood glucose level, due to beta cell toxicity at the time of initial presentation; however, most patients with type 2 diabetes present with hyperinsulinemia indicative of insulin resistance (Figure 68-1).