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Complications of Diabetes Mellitus

By Erika F. Brutsaert, MD, Assistant Professor;Attending Physician, Albert Einstein College of Medicine;Montefiore Medical Center

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(See also Diabetes Mellitus.)

In patients with diabetes mellitus (DM), years of poorly controlled hyperglycemia lead to multiple, primarily vascular, complications that affect small vessels (microvascular), large vessels (macrovascular), or both.

The mechanisms by which vascular disease develops include

  • Glycosylation of serum and tissue proteins with formation of advanced glycation end products

  • Superoxide production

  • Activation of protein kinase C, a signaling molecule that increases vascular permeability and causes endothelial dysfunction

  • Accelerated hexosamine biosynthetic and polyol pathways leading to sorbitol accumulation within tissues

  • Hypertension and dyslipidemias that commonly accompany diabetes mellitus

  • Arterial microthromboses

  • Proinflammatory and prothrombotic effects of hyperglycemia and hyperinsulinemia that impair vascular autoregulation

Immune dysfunction is another major complication and develops from the direct effects of hyperglycemia on cellular immunity.

Microvascular disease underlies 3 common and devastating manifestations of diabetes mellitus:

  • Retinopathy

  • Nephropathy

  • Neuropathy

Microvascular disease may also impair skin healing, so that even minor breaks in skin integrity can develop into deeper ulcers and easily become infected, particularly in the lower extremities. Intensive control of plasma glucose can prevent or delay many of these complications but may not reverse them once established.

Macrovascular disease involves atherosclerosis of large vessels, which can lead to

Immune dysfunction is another major complication and develops from the direct effects of hyperglycemia on cellular immunity. Diabetic patients are particularly susceptible to bacterial and fungal infections.

Diabetic Retinopathy

Diabetic retinopathy is the most common cause of adult blindness in the US. It is characterized initially by retinal capillary microaneurysms (background retinopathy) and later by neovascularization (proliferative retinopathy) and macular edema. There are no early symptoms or signs, but focal blurring, vitreous or retinal detachment, and partial or total vision loss eventually develop; rate of progression is highly variable.

Screening and diagnosis are by retinal examination, which should be done regularly (usually annually) in both type 1 and type 2 DM. Early detection and treatment are critical to preventing vision loss. Treatment for all patients includes intensive glycemic and blood pressure control. More advanced retinopathy may require panretinal laser photocoagulation or more rarely vitrectomy. Vascular endothelial growth factor (VEGF) inhibitors are promising new drugs for macular edema and as adjunctive therapy for proliferative retinopathy.

Diabetic Nephropathy

Diabetic nephropathy is a leading cause of chronic kidney disease in the US. It is characterized by thickening of the glomerular basement membrane, mesangial expansion, and glomerular sclerosis. These changes cause glomerular hypertension and progressive decline in GFR. Systemic hypertension may accelerate progression. The disease is usually asymptomatic until nephrotic syndrome or renal failure develops.

Diagnosis is by detection of urinary albumin. Once diabetes is diagnosed (and annually thereafter), urinary albumin level should be monitored so that nephropathy can be detected early. Monitoring can be done by measuring the albumin:creatinine ratio on a spot urine specimen or total urinary albumin in a 24-h collection. A ratio > 30 mg/g or an albumin excretion of 30 to 300 mg/day signifies moderately increased albuminuria (previously called microalbuminuria) and early diabetic nephropathy. An albumin excretion > 300 mg/day is considered severely increased albuminuria (previously called macroalbuminuria), or overt proteinuria, and signifies more advanced diabetic nephropathy. Typically a urine dipstick is positive only if the protein excretion exceeds 300 to 500 mg/day.

Treatment is rigorous glycemic control combined with blood pressure control. An ACE inhibitor or an angiotensin II receptor blocker should be used to treat hypertension and, at the earliest sign of albuminuria, to prevent progression of renal disease because these drugs lower intraglomerular blood pressure and thus have renoprotective effects. These drugs have not been shown to be beneficial for primary prevention (ie, in patients who do not have albuminuria).

Diabetic Neuropathy

Diabetic neuropathy is the result of nerve ischemia due to microvascular disease, direct effects of hyperglycemia on neurons, and intracellular metabolic changes that impair nerve function. There are multiple types, including

Symmetric polyneuropathy is most common and affects the distal feet and hands (stocking-glove distribution); it manifests as paresthesias, dysesthesias, or a painless loss of sense of touch, vibration, proprioception, or temperature. In the lower extremities, these symptoms can lead to blunted perception of foot trauma due to ill-fitting shoes and abnormal weight bearing, which can in turn lead to foot ulceration and infection or to fractures, subluxation, and dislocation or destruction of normal foot architecture (Charcot joint). Small-fiber neuropathy is characterized by pain, numbness, and loss of temperature sensation with preserved vibration and position sense. Patients are prone to foot ulceration and neuropathic joint degeneration and have a high incidence of autonomic neuropathy. Predominant large-fiber neuropathy is characterized by muscle weakness, loss of vibration and position sense, and lack of deep tendon reflexes. Atrophy of intrinsic muscles of the feet and foot drop are common.

Autonomic neuropathy can cause orthostatic hypotension, exercise intolerance, resting tachycardia, dysphagia, nausea and vomiting (due to gastroparesis), constipation and diarrhea (including dumping syndrome), fecal incontinence, urinary retention and incontinence, erectile dysfunction and retrograde ejaculation, and decreased vaginal lubrication.

Radiculopathies most often affect the proximal L2 through L4 nerve roots, causing pain, weakness, and atrophy of the lower extremities (diabetic amyotrophy), or the proximal T4 through T12 nerve roots, causing abdominal pain (thoracic polyradiculopathy).

Cranial neuropathies cause diplopia, ptosis, and anisocoria when they affect the 3rd cranial nerve or motor palsies when they affect the 4th or 6th cranial nerve.

Mononeuropathies cause finger weakness and numbness (median nerve) or foot drop (peroneal nerve). Patients with DM are also prone to nerve compression disorders, such as carpal tunnel syndrome. Mononeuropathies can occur in several places simultaneously (mononeuritis multiplex). All tend to affect older patients predominantly and usually abate spontaneously over months; however, nerve compression disorders do not.

Diagnosis of symmetric polyneuropathy is by detection of sensory deficits and diminished ankle reflexes. Loss of ability to detect the light touch of a nylon monofilament identifies patients at highest risk of foot ulceration (see Figure: Diabetic foot screening.). Alternatively, a 128-Hz tuning fork can be used to assess vibratory sense on the dorsum of the first toe.

Electromyography and nerve conduction studies may be needed for all forms of neuropathy and are sometimes used to exclude other causes of neuropathic symptoms, such as nondiabetic radiculopathy and carpal tunnel syndrome.

Management of neuropathy involves a multidimensional approach including glycemic control, regular foot care, and management of pain. Strict glycemic control may lessen neuropathy. Treatments to relieve symptoms include topical capsaicin cream, tricyclic antidepressants (eg, amitriptyline), serotonin-norepinephrine reuptake inhibitors (eg, duloxetine), and anticonvulsants (eg, pregabalin, gabapentin). Patients with sensory loss should examine their feet daily to detect minor foot trauma and prevent it from progressing to limb-threatening infection.

Diabetic foot screening.

A 10-g monofilament esthesiometer is touched to specific sites on each foot and is pushed until it bends. This test provides a constant, reproducible pressure stimulus (usually a 10-g force), which can be used to monitor change in sensation over time. Both feet are tested, and presence (+) or absence () of sensation at each site is recorded.

Macrovascular disease

Large-vessel atherosclerosis is a result of the hyperinsulinemia, dyslipidemias, and hyperglycemia characteristic of diabetes mellitus. Manifestations are

Diagnosis is made by history and physical examination; the role of screening tests, such as coronary calcium score, is evolving. Treatment is rigorous control of atherosclerotic risk factors, including normalization of plasma glucose, lipids, and blood pressure, combined with smoking cessation and daily intake of aspirin and ACE inhibitors. A multifactorial approach that includes management of glycemic control, hypertension, and dyslipidemia may be effective in reducing the rate of cardiovascular events. In contrast with microvascular disease, intensive control of plasma glucose alone has been shown to reduce risk in type 1 diabetes but not in type 2.

Cardiomyopathy

Diabetic cardiomyopathy is thought to result from many factors, including epicardial atherosclerosis, hypertension and left ventricular hypertrophy, microvascular disease, endothelial and autonomic dysfunction, obesity, and metabolic disturbances. Patients develop heart failure due to impairment in left ventricular systolic and diastolic function and are more likely to develop heart failure after myocardial infarction.

Infection

Patients with poorly controlled diabetes mellitus are prone to bacterial and fungal infections because of adverse effects of hyperglycemia on granulocyte and T-cell function. In addition to an overall increase in risk for infectious diseases, individuals with diabetes have an increased susceptibility to mucocutaneous fungal infections (eg, oral and vaginal candidiasis) and bacterial foot infections (including osteomyelitis), which are typically exacerbated by lower extremity vascular insufficiency and diabetic neuropathy. Hyperglycemia is a well-established risk factor for surgical site infections.

Other Complications

Diabetic foot complications (skin changes, ulceration, infection, gangrene) are common and are attributable to vascular disease, neuropathy, and relative immunosuppression.

Patients with diabetes mellitus have an increased risk of developing some rheumatologic diseases, including muscle infarction, carpal tunnel syndrome, Dupuytren contracture, adhesive capsulitis, and sclerodactyly. They may also develop ophthalmologic disease unrelated to diabetic retinopathy (eg, cataracts, glaucoma, corneal abrasions, optic neuropathy); hepatobiliary diseases (eg, nonalcoholic fatty liver disease [steatosis and steatohepatitis], cirrhosis, gallstones); and dermatologic disease (eg, tinea infections, lower-extremity ulcers, diabetic dermopathy, necrobiosis lipoidica diabeticorum, diabetic systemic sclerosis, vitiligo, granuloma annulare, acanthosis nigricans [a sign of insulin resistance]). Depression and dementia are also common.

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