Type 2 diabetes mellitus (T2DM) is a complex, chronic metabolic disorder characterized by hyperglycemia and associated with a relative deficiency of insulin production, along with a reduced response of the target tissues to insulin. It is a major public health issue and an important contributor to morbidity and mortality all over the world.¹ The top three countries with the highest number of diabetic patients are, in decreasing order, India, China, and the United States.² Epidemiology is summarized in Table 224-1.

T2DM is more common among women than men, and its prevalence increases by age. The prevalence of T2DM among youth is rising dramatically. Investigators attribute this rise to patterns of obesity and lack of physical activity. Native Americans, blacks, and Americans of Mexican or Japanese ethnicity are more commonly affected by T2DM than non-Hispanic whites (Figure 224-1).

Diabetes reduces the life expectancy of its victims by approximately 10 years. Mortality and morbidity increase because of increased risk of cardiovascular disease, heart disease and stroke, visual impairment, renal disease, and amputations. The utilization of health care, including emergency care, is higher in patients with diabetes compared with that of nondiabetic subjects. The relative risk is estimated to be 1.23 (95% confidence interval [CI], 1.08–1.39) before the diagnosis and 2.41 (95% CI, 2.18–2.66) after diagnosis is made.³

T2DM is a complex heterogeneous metabolic disorder, characterized by chronic elevation of plasma glucose levels. The pathogenesis is complex and involves interaction of both genetic (usually polygenic) and environmental (often lifestyle-related) factors. The most important pathophysiologic features of T2DM are decreased insulin sensitivity (insulin resistance) and impaired insulin secretion (Figure 224-2).

It is generally believed that, in T2DM, fasting hyperglycemia is caused by increased production of glucose by liver, which is not suppressed because of hepatic resistance to insulin action. Normally, after meals, glucose uptake in peripheral tissues increases and glucose production by gluconeogenesis and glycogenolysis decreases. Insulin acts both directly and indirectly to inhibit gluconeogenesis and glycogenolysis. In T2DM, owing to hepatic resistance to insulin, the liver is programmed to both overproduce and underuse glucose.

However, postprandial hyperglycemia results from several mechanisms: abnormal insulin secretion by pancreatic β cells in response to a meal, impaired regulation of hepatic glucose production, and reduced glucose uptake by peripheral tissues, particularly the skeletal muscle, that are insulin sensitive.⁴

Insulin resistance is the diminished tissue response to insulin at one or more sites in the complex pathways of hormone action and requires higher than normal plasma insulin levels to maintain normoglycemia. The major sites of insulin resistance in T2DM are the liver, skeletal muscle, and adipose tissue.

Insulin secretion is usually impaired and generally insufficient to compensate for insulin resistance.² The mechanism behind impaired insulin release in T2DM is complicated and includes glucotoxic and lipotoxic effects, as well as deposition of amyloid within islet cells. Glucotoxic effect refers to increased exocytosis of insulin due to increased cytosolic calcium concentration, which occurs when β-cell metabolism of glucose generates adenosine triphosphate that closes adenosine triphosphate–sensitive K⁺ channels and leads to depolarization of the membrane and hence opening of voltage-dependent Ca²⁺ channels. Exposure to increased levels of free fatty acid, as frequently found in diabetic patients, may also impair β-cell function, leading to impairment of insulin secretion (lipotoxic effect).⁵

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent inslinotropic polypeptide, secreted by intestinal L cells following glucose intake, stimulate pancreatic β cells and are responsible for 50% to 70% of total insulin secretion. In people with T2DM, the incretin system is functionally impaired,^6,7 leading to hyperglycemia.

Chronic hyperglycemia is the cornerstone of microvascular complications. The causative role of chronic hyperglycemia in the development of macrovascular complications is less well defined, and other factors such as dyslipidemia and hypertension that often accompany T2DM may also play an important part in these complications.⁸

The increased prevalence of infection is primarily attributed to phagocyte dysfunction, including impaired adherence, chemotaxis, phagocytosis, bacterial killing, and respiratory burst.⁹ Other abnormalities include nonenzymatic glycation of immunoglobulins and reduced T-lymphocyte populations.

The classic symptoms, which are usually mild and nonspecific, include fatigue, weakness, polyuria, polydipsia, polyphagia, and blurred vision. Most patients with T2DM are overweight, beyond their 30s, and suffer from other comorbid conditions such as hypertension, cardiovascular disease, dyslipidemia, and polycystic ovary syndrome. Clues in the patient’s past medical history that are suggestive of diabetes mellitus include frequent superficial infections and slow healing of skin lesions after minor trauma.

Acute complications include diabetic ketoacidosis, hyperosmolar hypertonic nonketotic state, and hypoglycemia. Diabetic ketoacidosis and hyperosmolar hypertonic nonketotic state are covered elsewhere in this book (see chapters 225 and 227), and hypoglycemia, which in most cases is actually a complication of the treatment of diabetes, is discussed separately at the end of this chapter in the “Hypoglycemia” section.

Chronic complications are categorized as microvascular, macrovascular, and nonvascular complications (Table 224-2). One of the chronic complications of diabetes may be the reason for the patient presentation to the ED or may be found during review of systems and physical examination. A brief review of the manifestations of the involvement of various organ systems by diabetes will be presented here.

CARDIOVASCULAR COMPLICATIONS

Diabetes-related atherosclerosis (macrovascular complication) affects all major vascular territories, notably the coronary, cerebral, and peripheral arteries. In individuals with diabetes, the risk of coronary artery disease is two- to fourfold of nondiabetics, and the prognosis is worse than in nondiabetics. Diabetes blunts the cardiovascular benefit of female gender. “Silent ischemia” (the absence of chest pain despite myocardial ischemia) is common in diabetic patients. It is also common for myocardial infarction to present with atypical or less impressive symptoms such as weakness, fatigue, and confusion. Patients may suffer from pain in unusual locations or with lower than expected severity. This may explain the increased incidence of medically unrecognized acute myocardial infarction in diabetics compared with nondiabetics (40% vs 25%). The risk of heart failure is increased two to five times in individuals with diabetes (age- and risk factor–adjusted hazard ratio of 1.82 in men and 3.73 in women, according to the Framingham Heart Study). Diabetic cardiomyopathy refers to changes in myocardium, distinct from ischemic myocardial injury, which render it more susceptible to ischemia and less able to recover after an ischemic insult.

The incidence of peripheral arterial disease is increased in diabetic patients by a factor of two to four. Diabetes also affects the distribution of atherosclerosis in the lower limb, affecting tibial and peroneal arteries, as well as femoral and popliteal arteries. Claudication, critical limb ischemia and tissue loss, and, finally, amputation are the manifestations of this disorder.

RENAL COMPLICATIONS

Diabetic nephropathy is a major cause of morbidity and mortality. It affects 5% to 40% of patients with T2DM and is present in approximately 7% of the cases at the time of diagnosis. Although this complication is more common in type 1 diabetes, due to the fact that the overwhelming majority of diabetics are type 2, >80% of diabetic patients in renal replacement programs have this form of the disease. Clinically, diabetic nephropathy is characterized as a triad of hypertension, proteinuria (mainly albuminuria), and ultimately renal impairment. Other renal conditions associated with diabetes include urinary tract infections and papillary necrosis. Patients with renal papillary necrosis may be asymptomatic and not notice the sloughed papillary tissue excreted in their urine, or they may present with flank pain, hematuria, fever, and chills, symptoms similar to acute pyelonephritis. Urinalysis reveals necrotic fragments of renal papilla, along with red blood cells, white blood cells, and bacteria.

NEUROLOGIC COMPLICATIONS

Diabetics have a threefold increase in the risk of stroke, and diabetes increases the risk of recurrent stroke and stroke-related dementia. Diabetic neuropathy is a set of heterogeneous clinical syndromes, affecting various regions of the nervous system, singly or combined. Clinical manifestations of diabetic neuropathy can be nonspecific and mimic those seen in many other diseases. Diabetic neuropathy is a diagnosis of exclusion and should be labeled as such only after other forms of neuropathy, such as chronic inflammatory demyelinating polyneuropathy, B₁₂ deficiency, hypothyroidism, and uremia, have been excluded. In most patients, this disorder is silent and goes undetected for long times, and less than half of patients with T2DM will develop symptomatic polyneuropathy in the 10 years after diagnosis. Neurologic disturbances in diabetes have been classified as subclinical neuropathy, diffuse clinical neuropathy, and focal neuropathy. Most common forms of diffuse neuropathies include chronic sensorimotor distal symmetric polyneuropathy and the autonomic neuropathies. Focal neuropathies consist of mononeuropathies and entrapment syndromes.

The most frequent symptoms of neuropathy are burning pain, electrical or stabbing sensations, paresthesia, hyperesthesia, and deep aching pain. Up to half of the patients are asymptomatic, and presence of neuropathy is discovered only on physical examination or when the patient presents with a painless foot ulcer. Physical examination usually reveals that perception of vibration, pressure, pain, and temperature is lost, more commonly in the feet and lower limbs with a symmetric stocking and glove pattern. The most significant morbidity associated with this type of neuropathy is foot ulceration.

Diabetic mononeuropathies usually have a sudden onset and are associated with pain. They may affect a large peripheral nerve such as ulnar, median, peroneal, or medial plantar nerves (as a result of entrapment) or an isolated cranial nerve, especially the third, fourth, or sixth cranial nerve (due to microvascular infarct). It may be difficult in the ED to differentiate the signs and symptoms of diabetic mononeuropathy from a transient ischemic attack or cerebrovascular accident, and imaging and other modalities are needed for diagnosis. The incidence of carpal tunnel syndrome is increased in diabetics.

Autonomic neuropathy may cause dysfunction of every part of the body and represents various clinical entities such as resting tachycardia, exercise intolerance, orthostatic hypotension, diarrhea, constipation, gastroparesis diabeticorum, erectile dysfunction, and neurogenic bladder. Gastroparesis is clinically manifested as nausea, vomiting, bloating, and easy satiety. Autonomic diarrhea is defined as at least 3 weeks of increased stool frequency and/or liquidity.

Proximal motor neuropathy with resultant weakness of the proximal muscles of the lower limbs and spontaneous or percussion-provoked muscle fasciculation may also be seen in diabetic patients. This disorder is believed to occur secondary to a variety of other diseases. These diseases are in turn more common in patients with diabetes mellitus than in the general population, and so proximal motor neuropathy may not be a primary component of diabetic neuropathy. Proximal motor neuropathy primarily affects the elderly and may begin, gradually or abruptly, with pain in the thighs and hips or buttocks.

INFECTIOUS COMPLICATIONS

Many common infections (such as pneumonia, soft tissue infections, and urinary tract infections) occur with greater frequency and severity in patients with diabetes. Infectious agents in these cases are usually similar to those seen in the nondiabetic population, but some organisms are more commonly encountered in these patients (Staphylococcus aureus and Mycobacterium tuberculosis in pneumonia, and Candida species in urinary tract infections). Still, there are several rare infections that almost exclusively occur in diabetics. This includes malignant otitis externa, emphysematous cholecystitis and pyelonephritis, and rhinocerebral mucormycosis. Rhinocerebral mucormycosis is an invasive fungal infection of the nasal and paranasal sinuses, sometimes involving the palate and adjacent tissues. The onset is sudden and rapidly progressive. Patients present with periorbital or perinasal pain, blood-tinged nasal discharge, unilateral headache, increased tearing, swelling of eyelids and conjunctiva, and decreased vision. Physical signs can include black eschar on the nasal mucosa or hard palate due to ischemia, proptosis, and, if the infection progresses, cranial nerve involvement or seizures. Patients with malignant otitis externa usually present with unilateral otalgia, decreased hearing, purulent ear discharge, and, sometimes, fever. Examination reveals a tender, inflamed external auditory canal with a mass of granular-appearing tissue. The infection can progress and involve the mastoid, temporal bone, or base of the skull, leading to osteomyelitis, meningitis, venous sinus thrombosis, or subdural emphysema. MRI or CT can define the extent of anatomic involvement. This infection is frequently due to Pseudomonas aeruginosa, but staphylococci, fungi, and other gram-negative organisms also have been isolated. Emphysematous cholecystitis may manifest as fever and abdominal pain. Abdominal radiographs may reveal gas within the gallbladder and biliary tree. Unexplained fever in diabetic patients, with or without abdominal pain, should be evaluated with US to search for cholecystitis. The causative agents are most frequently a Clostridium species in addition to streptococci, Escherichia coli, and Pseudomonas. Emphysematous pyelonephritis is a rare, life-threatening infection with gas production in renal parenchyma and around the kidney. Signs and symptoms include fever, clinical toxicity, flank pain, and, sometimes, a palpable mass.

FOOT AND LOWER EXTREMITY COMPLICATIONS

Diabetic foot ulceration results from interaction of many factors, including peripheral neuropathy, excessive plantar pressure, repetitive trauma, peripheral vascular disease, and wound-healing disturbances.^10,11 Ulcers act as a portal of entry for bacteria, resulting in cellulites and abscess formation. Aerobic gram-positive cocci (especially S. aureus) are the predominant pathogens in diabetic foot infections. Gram-negative rods may be encountered in patients with chronic wounds or those who have recently received antibiotic therapy. Those with foot ischemia or gangrene may be infected with obligate anaerobic microorganisms.¹²

Foot complaints in a diabetic require a thorough foot examination. Ulcer characteristics, including dimensions, depth, appearance (erythema, swelling, and purulence), and location, should be described. Hair and nail growth, calluses, corns, foot deformities, sensation, and vascular status (palpation of pedal and popliteal pulses) should be assessed. It is sometimes difficult to distinguish between lower extremity ulcers resulting from vascular insufficiency and those due to diabetes. Venous ulcers are typically present above the malleoli with irregular borders. Arterial ulcers are often found on the toes or the shins, with pale, “punched-out” borders. These ulcers are typically painful in the absence of coexisting neuropathy. Diabetic ulcers, on the other hand, usually occur at areas of increased pressure (e.g., sole of the foot) or friction (due to footwear).¹³ Any ulceration found should be unroofed and probed using a blunt-ended rigid sterile probe to determine the depth. The ability to probe to bone through the ulcer suggests the strong possibility of osteomyelitis and deep-space soft tissue infection. Purulence or inflammation suggests infection, and both aerobic and anaerobic cultures should be taken from purulent drainage or material curetted from the base of the wound. Such specimens are preferable to wound swab specimens, which are often contaminated with colonizing bacteria and often do not identify the infected organism(s).

The diagnosis of osteomyelitis in patients with diabetic foot ulcer remains a challenge. When the wound can be probed to the underlying bone, presence of osteomyelitis is almost certain. Radiographs, although not very sensitive, should be obtained in patients with deep or long-standing ulcers to exclude osteomyelitis, subcutaneous gas, foreign bodies, and Charcot joints. MRI can identify osteomyelitis if radiographs are negative but clinical suspicion is high. Table 224-3 shows the diagnostic utility of physical examination, laboratory, and basic radiographic testing in the diagnosis of osteomyelitis in patients with diabetic foot ulcer.

OPHTHALMOLOGIC COMPLICATIONS

Ocular complications of diabetes are summarized in Figure 224-3.

Retinopathy is divided into proliferative and nonproliferative forms. In the nonproliferative stage, changes in retinal vessels (vasodilation, microaneurysm formation, and leakage) occur and lead to accumulation of lipid in the outer plexiform layer (hard exudates) and hemorrhage in different layers of the retina (flame-shaped hemorrhage in the nerve fiber layer; dot-and-blot hemorrhage in deeper layers of the retina). Microinfarctions of the retina result in cotton-wool spots (soft exudates). In severe forms of the nonproliferative stage, venous tortuosity and beading occur. The proliferative stage is characterized by formation of new abnormal blood vessels (neovascularization) across the retinal surface and optic disc. These fragile new blood vessels may bleed into the vitreous, causing a vitreous hemorrhage. Ocular hemorrhage in diabetic retinopathy after thrombolytic therapy is extremely uncommon,¹⁴ and retinopathy should not be considered a contraindication. The indications and potential complications of thrombolytic therapy should be discussed with the patient before its administration. Neovascularization can also affect the iris (rubeosis iridis), leading to severe glaucoma. Traction retinal detachment may result from contraction of the fibrous tissue that accompanies neovascularization.

Other ocular manifestations of diabetes include recurrent styes, blepharoconjunctivitis, and xanthelasma, fatty deposits in the subcutaneous tissue of the lids. Impaired corneal sensitivity can predispose to bacterial corneal ulcers, neurotropic ulcers, and difficulties with contact lenses. Cataracts and open- and narrow-angle glaucoma are more common in diabetics.

DERMATOLOGIC COMPLICATIONS

Skin manifestations of diabetes generally appear in patients with known diabetes, but they may also be the first presenting sign of diabetes or even precede the diagnosis by many years.¹⁵ Protracted wound healing and skin ulcerations are the most common skin manifestations. Dermatologic complications of diabetes can be grouped as noninfectious (such as acanthosis nigricans, necrobiosis lipoidica, diabetic dermopathy, scleredema, and granuloma annulare), infectious (e.g., erythrasma, necrotizing fasciitis, and mucormycosis), and resulting from treatment of diabetes (e.g., lipoatrophy, lipohypertrophy, and various skin reactions as adverse effects of oral antidiabetics).

Common infections include cellulitis, furuncles and carbuncles, and candidiasis. Serious infections usually develop due to the combination of poorly controlled serum glucose, vascular insufficiency, and tissue hypoxia. Serious and rapidly progressive infections in diabetics include necrotizing fasciitis and Fournier’s gangrene. See chapter 152, “Soft Tissue Infections” for further discussion. Table 224-4 summarizes the cutaneous manifestations of diabetes.

Look for diabetes in the presence of symptoms suggestive of hyperglycemia, detailed above, in the undiagnosed diabetic. It is reasonable to check the glucose level in patients with certain presentations such as unexplained cellulitis, foot ulcers, frequent candidal infections, and unexplained neuropathy.

When evaluating a patient with established diabetes mellitus in the ED, in addition to complaint-directed history and physical examination, special attention can be given to diabetes-related aspects. Assessment can include questions about prior diabetes care, presence or absence of diabetes complications and diabetes-related comorbidities, and assessment of the patient’s knowledge about the disease. Elements of the history and physical examination relative to T2DM are presented in Tables 224-5 and 224-6.