Incidence and Prevalence

More than 240 million persons worldwide have diabetes mellitus, and health officials estimate that this figure will exceed 300 million within the next 10 years.^5,6 Nearly 26 million Americans, representing 8.3% of the entire population, are living with diabetes. Of these, 7 million cases have not been diagnosed. In 2009, 1.9 million new cases of diabetes were diagnosed among adults in the United States. The disease affects 16.1% of Native Americans and Alaska Natives, 12.6% blacks, 11.8% Hispanics, and 7.1% of whites. Diabetes mellitus accounts for about 71,000 deaths per year and is the seventh most common cause of death in the United States.^7–9

Type 2 disease is the most prevalent type of diabetes mellitus. Of patients with diabetes in the United States, 90% to 95% have type 2 disease. The incidence of type 2 diabetes increases with age, and is primarily an adult disease. In contrast, type 1 diabetes occurs in 0.3% of Americans but is more than four times more prevalent than type 2 diabetes in persons younger than 20 years of age. Currently, there are about 23 million persons with type 2 disease (90%), 2.6 million with type 1 disease (10%), 79 million who have prediabetes, and approximately 12% of the general population in the United States who have impaired glucose tolerance. It is estimated that about 210,000 people younger than 20 years of age have diabetes (0.26% of all people in this age group). The vast majority of undiagnosed cases of diabetes are of the type 2 variety.^8,10,11

The prevalence of diabetes mellitus has increased more than six-fold in the United States over the past several decades. The major reason for the dramatic increase is the obesity epidemic—especially in relation to type 2 diabetes. Recent reports indicate that more than 60% of patients with type 2 diabetes are obese at the time of diagnosis, and more than two thirds of U.S. adults are overweight or obese. Obesity is a major factor in the continual rise in the number of cases of diabetes in the United States.¹² Obesity in American youth contributes to the rising number of cases in this segment of the population. Other factors associated with the increasing prevalence of diabetes are the increasing population, increasing life expectancy, and increasing number of affected persons who are having children who will pass on the disease.^4,10,12

Etiology

Diabetes results from several pathogenic processes ranging from autoimmune destruction of pancreatic beta cells in type 1 diabetes to abnormalities that cause insulin resistance (type 2 diabetes). Type 1 diabetes is thought to be the result of genetic, autoimmune, and environmental factors. The genetic component is demonstrated by data showing concordance rates of 30% to 40% amongst identical twins. HLA genes on chromosome 6 are linked to type 1 diabetes. Autoantibodies against beta cell constituents are present in 85% to 90% of patients with type 1 diabetes, and destruction of beta cells is modulated by T cells. Viral infections (mumps, rubella, and coxsackievirus infection) are suggested environmental factors that could trigger the autoimmune response associated with type 1 disease. About 10% to 15% of cases of type 1 diabetes are of unknown etiology (i.e., idiopathic).^1,4

Type 2 diabetes has genetic, environmental, and aging components. Positive family history confers a lifetime risk of 38% to the offspring if one parent is affected, and 60% if both parents are affected.¹³ Identical twin concordance rates approach 100%.⁴ The peroxisome proliferator-activated receptor γ (PPARγ) gene, which has a key role in regulation of adipogenic differentiation, is a candidate gene of type 2 diabetes, however the disease is likely multigenic. Together the genetic and environmental factors contribute to defects in insulin receptor function, insulin receptor signal transduction, insulin secretion, glucose transport and phosphorylation, glycogen synthesis, glucose oxidation that contribute to insulin resistance, and accelerated endogenous glucose production. Obesity and lack of physical activity are the primary environmental factors involved in the pathogenesis of type 2 diabetes.^1,13,14

Other specific types of diabetes can be caused by specific gene defects, endocrine conditions such as primary destruction of islet cells through inflammation, cancer, surgery, hyperpituitarism, or hyperthyroidism. Iatrogenic disease that occurs after steroid administration is a known cause.

Gestational diabetes mellitus occurs in 5% to 7% of pregnant women during pregnancy. Obesity during pregnancy is a known risk factor for the condition. After childbirth, the mother’s glycemic control usually returns to normal, but these women have an increased risk of developing diabetes within 5 to 10 years. Gestational diabetes enhances the risk for loss of the fetus and is associated with increased size of surviving fetuses. Insulin resistance is the suggested underlying etiopathogenic mechanism. A genetic basis may play a role; however, the underlying genetic factors have not yet been identified.^15,16

Pathophysiology and Complications

Persistent elevated blood glucose levels put persons at risk for diabetes. In fact, about 11% of people with prediabetes who were followed annually developed overt diabetes each year during the average 3 years of follow-up.¹⁷ An overview of the pathophysiologic processes involved is presented next.

Glucose is rapidly taken up by the pancreatic beta cell and serves as the most important stimulus for insulin secretion. Insulin remains in circulation for only several minutes (half-life [t_1/2], 4 to 8 minutes); it then interacts with target tissues (e.g., muscle, liver, fat cells) and binds with cell surface insulin receptors. Secondary intracellular messengers are activated and interact with cellular effector systems, including enzymes and glucose transport proteins. Lack of insulin or deficient action of insulin leads to abnormalities in carbohydrate, fat, and protein metabolism (i.e, increased production of glucose from glycogen, fat, and protein). This combination of underutilization and overproduction of glucose attained through glycogenolysis and fat metabolism results in glucose accumulation in the tissue fluids and in blood¹⁸ (Figure 14-2).

FIGURE 14-2 Pathophysiology of hyperglycemia and target tissues.

(Courtesy Mary Lous Cahal, University of Kentucky.)

Hyperglycemia leads to glucose excretion in the urine, which results in increased urinary volume. The increase in fluid lost through urine may lead to dehydration and loss of electrolytes. With type 2 diabetes, prolonged hyperglycemia can lead to significant losses of fluid in the urine. When this type of severe dehydration occurs, urinary output drops, and a hyperosmolar nonketotic coma may result. This condition is seen most often in elderly persons with type 2 diabetes.¹⁸

Lack of glucose utilization by many cells of the body leads to cellular starvation. The patient often increases intake of food but in many cases still loses weight. If these events continue to progress, the person with type 1 diabetes develops metabolic acidosis. For a time, the body may be able to maintain the pH at nearly normal levels, but as the buffer system and respiratory and renal regulators fail to compensate, body fluids become more acidic (i.e., pH falls). Severe acidosis will lead to coma and death if it is not identified and treated. The primary manifestations of diabetes—hyperglycemia, ketoacidosis, and vascular wall disease—contribute to the inability of patients with uncontrolled diabetes to fight infection and to characteristic poor wound healing. The end results of these effects, as well as others yet to be identified, are that the patient with uncontrolled diabetes is rendered much more susceptible to infection, the patient’s ability to deal with an infection once it has been established is reduced, and healing of traumatic and surgical wounds is delayed.^18,19

Patients with diabetes demonstrate significant effects of the disease on long-term survival, which is affected by the type of diabetes, age at diagnosis, and compliance with therapy (Table 14-1). Few deaths occur among patients diagnosed before the age of 30 years. However, in persons diagnosed before age 40, less than half are still alive by age 55. In a recent study of 3589 diabetics, the 10-year survival rate still remained below 65%.²⁰ In addition to decreasing life expectancy by at least 5 to 10 years, the complications of diabetes mellitus lead to significant signs and symptoms that impair the quality of life.^21,22

Complications of diabetes are related to the level of hyperglycemia and pathologic changes that occur within the vascular system and the peripheral nervous system (Box 14-2). The vascular complications result from microangiopathy and atherosclerosis. The mechanisms by which hyperglycemia may lead to microvascular and atherosclerotic complications include increased accumulation of polyols through the aldose reductase pathway, advanced glycation end products, and increased production of vascular endothelial cell growth factor (VEGF).²³ Vessel changes include thickening of the intima, endothelial proliferation, lipid deposition, and accumulation of para-aminosalicylic acid–positive material. These changes can be seen throughout the body but have particular clinical importance when they occur within the retina and the small vessels of the kidney.^4,24

Retinopathy occurs in all forms of diabetes. It consists of nonproliferative changes (microaneurysms, retinal hemorrhages, retinal edema, and retinal exudates) and proliferative changes (neovascularization, glial proliferation, and vitreoretinal traction) and is the leading cause of blindness in the United States. The incidence of blindness in all persons with diabetes is 0.2% per year; it is 0.6% per year for diabetic patients with retinopathy. Proliferative retinopathy is most common among patients with type 1 diabetes; a much lower incidence is seen among those with type 2 diabetes. Cataracts occur at an earlier age and with greater frequency in those with type 1 diabetes. The typical cataract, senile cataract, is identified in 59% of persons with diabetes aged 35 to 55 years but in only 12% of those without the disease. Young people with diabetes are prone to the development of metabolic cataracts. The risk that a person with diabetes will become blind is 20 times greater than that for the general population.^4,25

Diabetics are 25 times more likely to acquire end-stage renal disease than persons without diabetes.¹² Diabetic nephropathy leads to end-stage renal disease in 30% to 40% of patients with type 1 diabetes (Figure 14-3) and in 5% of patients with type 2 diabetes. However, because type 2 diabetes is much more common than type 1, the number of persons with renal failure is the same for the two types of diabetes. Renal failure is the leading cause of death in patients with type 1 diabetes. Of all patients who undergo dialysis, 37% have diabetes. Microangiopathy in the kidney usually involves the capillaries of the glomerulus.^8,26,27

FIGURE 14-3 Diabetic nephropathy: cross section of kidney.

(Courtesy Richard Estensen, MD, Minneapolis, Minnesota.)

Macrovascular disease (atherosclerosis) occurs earlier and is more widespread and more severe in persons with diabetes. In patients with type 1 diabetes, atherosclerosis seems to develop independent of microvascular disease (microangiopathy). Hyperglycemia plays a role in the evolution of atherosclerotic plaques. Persons with uncontrolled diabetes have increased levels of low-density lipoprotein (LDL) cholesterol and reduced levels of high-density lipoprotein (HDL) cholesterol. Attainment of normal glycemia often improves the LDL-to-HDL ratio.²

A major determinant of the morbidity associated with poor glycemic control in diabetes is accelerated atherosclerosis. Atherosclerosis increases the risks of ulceration and gangrene of the feet (Figure 14-4), hypertension, renal failure, coronary insufficiency, myocardial infarction, and stroke. The most common cause of death in patients with type 2 diabetes is myocardial infarction. By age 60, a third of all persons with diabetes die of complications from coronary heart disease (CHD). Women with diabetes treated with insulin are at higher risk for CHD than non–insulin-treated women. This is not true for insulin-treated men. Also, diabetics are at a two- to four-fold greater risk for myocardial infarction and stroke than in persons without the disease, and a person with diabetes has less chance of surviving a myocardial infarction than that typical for a nondiabetic person.^2,7,28

FIGURE 14-4 Diabetic gangrene of the feet.

(From Swartz MH: Textbook of physical diagnosis: history and examination, ed 6, Philadelphia, 2010, Saunders.)

In the extremities, diabetic neuropathy may lead to muscle weakness, muscle cramps, a deep burning pain, tingling sensations, and numbness. In addition, tendon reflexes, two-point discrimination, and position sense may be lost. Some cases of oral paresthesia and burning tongue are caused by this complication.^4,29–31

Diabetic neuropathy also may involve the autonomic nervous system. Esophageal dysfunction may cause dysphagia, stomach involvement may cause a loss of motility with massive gastric distention, and involvement of the small intestine may result in nocturnal diabetic diarrhea. Sexual impotence and bladder dysfunction also may occur. Diabetic neuropathy is common with type 1 and type 2 diabetes and may occur in more than 50% of patients. Neuropathy progresses over time in type 2 diabetes, and this increase may be greater in patients with hypoinsulinemia.^4,29–31

Diabetes is associated with skin rashes, deposits of fat in the skin (xanthoma diabeticorum), decubitus ulcerations, poor wound healing, and gangrenous extremities. The relative risk that patients with diabetes will require amputation of an extremity because of diabetic complications is more than 40 times that of normal persons. Recent data show that more than 65,000 amputations are performed annually in patients with diabetes mellitus. This number represents more than 60% of all nontraumatic amputations.⁸

The severity of complications of diabetes is largely dependent on the level of glycemic control.³² In one longitudinal study conducted over a period of more than 17 years, scientists demonstrated that diabetic patients with good glycemic control (hemoglobin A_1c levels below 7%) had 42% fewer systemic complications and 57% fewer deaths than those reported for patients with diabetes and poorly controlled hyperglycemia (HbA1c levels above 8%).² Thus, a strong case can be made for early diagnosis and appropriate glycemic control to prevent or reduce progression of complications.

Signs and Symptoms

In patients with type 1 diabetes, the onset of symptoms is sudden and acute, often developing over days or weeks. Typically the diagnosis is made in nonobese children or young adults less than 40 years of age; however it may occur at any age. Signs and symptoms include polydipsia, polyuria, polyphagia, weight loss, loss of strength, marked irritability, recurrence of bed wetting, drowsiness, malaise, and blurred vision. Patients also may present with ketoacidosis, which if severe is accompanied by vomiting, abdominal pain, nausea, tachypnea, paralysis, and loss of consciousness.⁴

Type 2 diabetes generally occurs after age 40 and more often affects obese individuals. The onset of symptoms in type 2 diabetes usually is insidious, and the cardinal manifestations and symptoms (polydipsia, polyuria, polyphagia, weight loss, and loss of strength) are less commonly seen.^1,4 The signs and symptoms of type 1 and type 2 diabetes are summarized in Table 14-2 and Box 14-3.

TABLE 14-2 Clinical Features of Type 1 and Type 2 Diabetes

HLA, Human leukocyte antigen.

Other signs and symptoms related to the complications of diabetes include skin lesions, cataracts, blindness, hypertension, chest pain, and anemia. The rapid onset of myopia in an adult is highly suggestive of diabetes mellitus.

Laboratory Findings

The American Diabetes Association recommends screening tests for diabetes mellitus for all persons who are 45 years of age and older, and for persons with risk factors such as obesity, family history, belonging to an ethnic or minority group at risk for diabetes, the combination of low HDL cholesterol and high triglycerides, high blood pressure, or gestational diabetes, and for women who have delivered large babies (weighing more than 9 lb at birth) or who have had spontaneous abortions or stillbirths, or have signs and symptoms of diabetes or its complications. For persons older than age 45, screening should occur routinely at 3-year intervals. Most screenings for diabetes involve evaluation for undiagnosed type 2 diabetes.¹

The diagnostic criteria for diabetes relies on the plasma glucose level, either (1) at a random sampling, (2) after fasting, or (3) after a 75-g glucose test (oral glucose tolerance test, OGGT). Alternatively, the glycosylated hemoglobin test can be used. The American Diabetes Association criteria for diabetes are presented in Table 14-3.¹

TABLE 14-3 Diagnostic Criteria for Diabetes Mellitus*

FPG, Fasting plasma glucose; OGTT, Oral glucose tolerance test.; WHO, World Health Organization.

* Oral glucose tolerance testng generally is not recommended in clinical practice.

Data from Executive summary: standards of medical care in diabetes—2010: current criteria for the diagnosis of diabetes, Diabetes Care 33:S4-S10, 2010; Diagnosis and classification of diabetes mellitus, Diabetes Care 33(Suppl 1):S62-S69, 2010; International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes, Diabetes Care 32:1327-1334, 2009.

The primary diagnostic criterion for impaired fasting glucose is fasting plasma glucose levels of 100 to 125 mg/dL and for impaired glucose tolerance (IGT) is 140 to 199 mg/dL at 2 hours in the OGTT (Table 14-4).¹