Scope

Glucose is critical to function of the central nervous system because it is the primary fuel for these tissues. Plasma levels of glucose are strictly regulated—even after a large oral glucose load or exercise the serum level should not deviate from a range of 70 to 150 mg/dL.

Epidemiology

More than 23 million individuals in the United States have diabetes mellitus, and this number continues to increase at an accelerated rate, partially because of the worsening obesity epidemic in this country. In almost 6 million of these individuals, however, the diabetes is undiagnosed. In addition to the cost of life and morbidity associated with this disease, the financial expense is enormous. In 2007 the estimated direct and indirect cost of treating diabetes mellitus in the United States was $116 billion and $58 billion, respectively.¹

Structure and Function

Insulin is a 51–amino acid protein produced by the beta cells of the islet of Langerhans in the endocrine pancreas. After the initial protein, preproinsulin, is translated on the rough endoplasmic reticulum, it is cleaved serially first to proinsulin and then to insulin and C peptide. Insulin and its C peptide are stored in a 1 : 1 ratio in secretory granules and released primarily in response to glucose and, to a lesser extent, amino acids. Release can be further potentiated or inhibited by a number of gastrointestinal and systemic hormones.

On release, insulin binds to its membrane-spanning receptor. Binding induces a conformational change in the structure of the receptor so that it becomes enzymatically active; it is now a functional tyrosine kinase that can initiate anabolic pathways.

A newer classification system of diabetes mellitus reflects the pathophysiology of the disease and long-term treatment options. The new system identifies four types of diabetes mellitus: type 1, type 2, gestational diabetes, and “other” (Table 162.1).

Type 1 diabetes mellitus (note the Arabic numbering) has replaced older terms such as type I, insulin-dependent, and juvenile-onset diabetes mellitus. These older terms became confusing for a multitude of reasons. For example, a small subset of “type II” diabetics fail oral hypoglycemic treatment and must be treated with an insulin regimen; are these patients “insulin dependent”? With increasing worldwide childhood obesity, more and more childhood diabetics are being seen who are not “insulin dependent,” and yet their disease cannot be classified as “adult onset.”

Type 1 diabetes mellitus can best be defined as an absolute deficiency of insulin. The mechanism is complex and occurs in approximately 5% of all patients with diabetes mellitus. The process usually begins years before symptoms appear when the patient is exposed to an antigen (e.g., viral infection) that is similar in structure to a protein found in islet beta cells. The immune system begins to produce a humoral and cell-mediated assault on these antigens that leads to progressive destruction of the cells. Destruction of beta cells results in a decrease in insulin levels, and eventually a critical point is reached at which insulin requirements are no longer met and hyperglycemia ensues.

The other categories include patients with relative insulin deficiency; it is important to note that the majority of hyperglycemic patients in the remaining groups do produce insulin, and thus it is easier to conceptualize their insulin deficiency as a balance between insulin and other counterregulatory hormones (e.g., epinephrine, glucagon, cortisol, growth hormone).

Type 2 diabetes mellitus has replaced older terms such as type II, non–insulin-dependent, and adult-onset diabetes mellitus. The process leading to this type of diabetes also begins years before the onset of overt clinical symptoms. For a multitude of reasons, most commonly obesity, peripheral tissues become increasingly resistant to the effects of insulin. Such resistance leads to increased production of insulin by beta cells, which allows years of relative glucose control. Eventually, the relative insulin resistance can no longer be met by increasing beta cell production, and the patient begins to experience hyperglycemia. Additionally, the beta cells may begin to “burn out” and ultimately produce progressively less and less insulin. The onset of clinical symptoms may be insidious in an otherwise healthy patient or abrupt when significant illness produces a spike in the counterregulatory hormones (e.g., epinephrine, glucagons, cortisol, growth hormone) that tends to increase plasma glucose levels. This abrupt onset occurs because a type 2 diabetic is not able to increase insulin production to counteract this rise, as would a nondiabetic.

The third category is gestational diabetes mellitus, which occurs in about 2% to 5% of all pregnancies, most often in the second or third trimester. It is believed to occur in a manner similar to that of type 2 diabetes. Pregnancy induces increased levels of human placental lactogen, estrogen, and cortisol—all hormones that tend to increase plasma glucose levels. Pregnant women are usually able to produce insulin in sufficient quantities to combat this increase in glucose-elevating hormones; however, susceptible women cannot. This condition most often resolves after delivery, but as one would expect, these women are susceptible to the development of type 2 diabetes later in life. Gestational diabetes mellitus can cause fetal complications, mostly as a result of increased fetal plasma glucose levels. In response to this elevated glucose derived via placental blood, the fetal pancreas increases plasma insulin production, which results in increased fetal birth weight.

The fourth category—“other”—is a catchall that contains all other causes of diabetes mellitus, including genetic anomalies causing malfunctioning insulin protein, insulin receptors, and beta cells in general, as well as other immune-mediated causes. Any significant insult to the exocrine pancreas—be it trauma, chronic pancreatitis, or cystic fibrosis—may result in this type of diabetes. Many common drug-induced causes of diabetes mellitus fall into this category (Box 162.1), as well as endocrinopathies such as hyperthyroidism, Cushing syndrome, and pheochromocytoma. Infectious causes include congenital rubella and cytomegalovirus. Less common causes include genetic disorders that may be associated with diabetes mellitus, including Down syndrome, Klinefelter syndrome, Turner syndrome, Prader-Willi syndrome, Huntington chorea, and porphyria.

Clinical Presentation

The signs and symptoms of diabetes mellitus can be quite varied. The classic manifestations are discussed here, but it is important to note that many patients do not have these symptoms. Typically, patients with type 1 diabetes have had years of progressively decreasing insulin secretion as a result of beta cell destruction. However, most often an infection or other stressor acutely increases levels of the counterregulatory hormones and the patient is unable to counter this spike with an insulin surge. Hyperglycemia (generally defined as a fasting glucose level > 126 mg/dL) then ensues, and the patient suddenly seeks care in the emergency department (ED).

As the plasma glucose level increases and eventually surpasses the threshold of the kidneys to reabsorb glucose, the patient begins to spill glucose into urine. This leads to osmotic diuresis and ensuing polyuria and polydipsia.

Diagnostic Testing

All patients with a history of diabetes mellitus should have an early point-of-care glucose assay performed when seen in the ED.² At a minimum, diabetic patients with systemic complaints or complaints common to hyperglycemia require glucose testing at the time of first assessment. It is important to note that if serial tests are to be performed, there is a small but significant difference between capillary and venous blood glucose levels.³ Additionally, any patient with altered mental status or new neurologic concerns should also have glucose levels tested because patients with hypoglycemia or hyperglycemia may exhibit these changes.

The purpose of laboratory testing in a hyperglycemic patient is to differentiate simple hyperglycemia from DKA and less commonly from HHS. It is important to note that no reliable historical or physical examination findings are sensitive or specific enough to confirm or exclude these acute and serious complications of diabetes in hyperglycemic patients.⁴ A bicarbonate level below 15 mmol/L with an elevated anion gap (varies depending on the laboratory, but the upper limit is generally approximately 16 mEq/L) strongly suggests DKA. A more complete laboratory evaluation for hyper-glycemia includes venous pH, β-hydroxybutyrate (BHB), and possibly serum osmolality. Additional laboratory tests may be necessary as dictated by the clinical picture. It has recently been suggested that acetoacetate (ACA), the standard ketone assayed for by serum and urine “ketone” assays, is neither sensitive nor specific for the diagnosis of DKA.^5,6

Treatment

Patients with significant hyperglycemia, diabetic ketoacidosis (DKA), or hyperglycemic hyperosmolar state (HHS) are almost universally dehydrated and intravascularly depleted. Even though this is certainly more so in the latter two conditions, all conditions require hydration. The initial treatment is intravenous (IV) hydration with normal saline (NS). Insulin is not the initial treatment of these diabetic complications.

Pathophysiology

Hyperglycemia ensues when the endocrine pancreas cannot produce enough insulin to decrease plasma levels of glucose appropriately (>126 mg/dL in a fasting patient). In type 1 diabetes, this is due to an absolute deficiency; in the other types of diabetes, it is due to a relative deficiency of insulin in comparison with the levels of counterregulatory hormones. In this way, glucose levels increase in plasma and eventually overwhelm the renal glucose threshold, thereby resulting in spillage of glucose into urine. By osmosis, water is pulled into urine, which leads to increased urination and dehydration. This in turn leads to increased thirst and polydipsia. The degree of hyperglycemia and dehydration varies greatly from patient to patient and even in the same patient on different occasions.

Diagnosis and Diagnostic Testing

The purpose of laboratory testing in a hyperglycemic patient is to differentiate simple hyperglycemia from DKA and less commonly from HHS.

It is important to ascertain the probable cause of the hyperglycemia. Although dietary indiscretion and medication noncompliance do play a role, these diagnoses should be considered only after excluding more serious causes. The most concerning causes can be grouped into two classes: infection and infarction.

Complete a thorough evaluation for possible sources of infection in all diabetic patients.⁷ Chest radiography is indicated to search for pneumonia in patients with historical and physical examination findings suggesting pneumonia, patients in whom a thorough history and physical examination cannot be obtained, clinically ill patients, and patients at the extremes of age.

Infarction-related causes of hyperglycemia include acute coronary syndrome (acute myocardial infarction and unstable angina), pulmonary embolism, and cerebrovascular accident. It is important to note that acute coronary syndrome is very likely to be manifested in an atypical manner in diabetic patients (e.g., new-onset congestive heart failure without any history of chest pain or dyspnea without chest pain).⁸ Any hyperglycemic patient with these findings should undergo a complete ED evaluation for acute coronary syndrome. A computed tomography scan of the brain or chest may be required if cerebrovascular accident or pulmonary embolism is a concern.

Treatment

Because hyperglycemia is most often associated with some degree of dehydration, the primary modality of treatment should be rehydration with NS. Early insulin therapy is contraindicated before determining electrolyte levels. After the patient is significantly rehydrated, laboratory studies have excluded additional complications such as DKA, and electrolyte status has been stabilized, subcutaneous insulin can be administered.

IV bolus administration of insulin has no role in the treatment of hyperglycemia. Administration of insulin via a continuous drip is not indicated, except in very special circumstances in which exceedingly tight glucose control is required (e.g., during a progressing cerebral vascular accident) for the treatment of simple hyperglycemia. In fact, very tight glucose control in an ill patient has been suggested to have no effect on patient outcome other than significantly increased rates of hypoglycemia.⁹ The dose of insulin depends on the degree of hyperglycemia after hydration and the patient’s previous exposure to insulin therapy. Patients with known diabetes treated with insulin therapy may be given their usual dose after hydration. Patients new to insulin may be given low-dose subcutaneous insulin with the goal of decreasing glucose to acceptable levels at a rate of 100 mg/dL/hr.

A guideline for subcutaneous regular insulin dosing is presented in Table 162.2. This guideline is appropriate for hyperglycemic patients who have little to no previous experience with subcutaneous insulin. Those managed with insulin regimens may do better with one approximating their typical dosage. In addition, this guideline assumes that the patient has first been rehydrated and remains hyperglycemic.

Table 162.2 Regular Subcutaneous Insulin Dosing Guideline*

^* See text for a discussion of modifications of this guideline. Patients treated with regular insulin regimens should be given their usual dosage if appropriate for their condition.

It is important to note that euglycemia may not be a realistic or even appropriate goal in these patients while they are in the ED; longer-term (over a period of days to weeks) personalization of an insulin or oral hypoglycemic regimen by the patient’s primary care provider or inpatient physician is preferred. The ED goal may be simply to rehydrate the patient and then use subcutaneous insulin to further decrease the patient’s glucose level. Targeting a “normal glucose” level in patients new to insulin therapy is fraught with risks, mostly notably hypoglycemia. Moreover, no target “maximum allowable glucose level” before discharge of the patient has been established.

Treatment and Disposition

The initial medication for patients with new-onset diabetes is most often a low-dose sulfonylurea. A good choice of sulfonylurea is glyburide (1.25 to 2.5 mg orally once a day) or glipizide (2.5 to 5 mg orally once a day). These doses may not allow strict glucose control but are appropriate early therapy and pose little risk for hypoglycemia. When starting these medications, patients should be instructed to take them with an early meal or breakfast and to eat regular meals throughout the day. Metformin (850 mg orally once a day) is an appropriate choice for initiating diabetes therapy when a nonsulfonylurea drug is preferred. This drug, when used alone in initial therapy, poses a very low risk for hypoglycemia and may be a good choice for obese patients.¹⁰

All patients with new-onset diabetes should have follow-up arranged in an expedited manner. Patients with comorbid conditions or acute disease should be admitted for inpatient evaluation and treatment.