Diabetes mellitus can lead to many acute and chronic complications. The chronic complications are mainly the result of longstanding damage to blood vessels. These complications are grouped as microvascular due to basement membrane thickening or macrovascular due to accelerated atherosclerosis. The major microvascular complications are diabetic retinopathy, nephropathy, and neuropathy. The diabetic foot ulcer shown is the result of longstanding peripheral neuropathy.
Diabetic retinopathy is progressive damage to the retina from longstanding diabetes mellitus that, if untreated, will lead to progressive vision loss and blindness. Microvascular basement membrane thickening impairs the diffusion of oxygen and nutrients to the retina, activating a cascade of events leading to neovascular proliferation. The abnormal growth of friable blood vessels on the retina produces microaneurysms (short arrow) that may rupture, leading to blot or flame-shaped hemorrhages (arrowhead). Hard exudates (long arrow) are caused by the breakdown of the blood-retina barrier allowing for serum proteins and lipids to leak out and accumulate on the retinal surface.
Fluorescein angiograms allow for a better examination of the retinal vasculature. Sodium fluorescein is injected into the venous system and serial photographs of the retina are taken over time. The photographs are taken in black-and-white to provide better contrast for the vasculature. The angiogram shown demonstrates leakage of dye secondary to poor capillary integrity.
Macular edema is presumed to be the result of functional damage and necrosis to the retinal capillaries. It is a sign of longstanding retinal disease and over time leads to blindness. Macular edema is characterized by retinal thickening and the presence of hard exudates near the fovea, as shown. In the United States, diabetic retinopathy is the most common cause of blindness and macular edema is the major contributor.
Diabetic retinopathy is classified on a spectrum from nonproliferative to proliferative depending on the extent of retinal changes and the degree of microvascular growth. In advanced disease, progressive hemorrhage obscures a patient's visual fields, leading to vision loss. The image shown is an example of what a patient with advanced diabetic retinopathy may see when looking at a scene of 2 young children. Image courtesy of the National Institute of Health.
Laser photocoagulation provides a noninvasive means of treating microvascular retinal disease. A high-focused beam of light energy creates localized coagulation of the retina. A grid pattern of laser burns is produced to coagulate leaky blood vessels while still retaining enough retinal tissue to allow for normal vision. Image courtesy of the National Institute of Health.
Diabetic nephropathy is the most common cause of kidney failure in the United States. Medical management focuses on controlling hyperglycemia and high blood pressure, and keeping patients on a low protein diet. Eventually these patients will die if they do not receive peritoneal dialysis, hemodialysis, or a renal transplantation. Renal transplantation offers the best chance for medical rehabilitation but not all patients are candidates. Image courtesy of Wikimedia Commons.
In the 1930s, Kimmelstiel and Wilson first described the classic diabetic lesions of nodular glomerulosclerosis that bear their names. Three major histologic changes occur. First, mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycosylation of matrix proteins. Second, glomerular basement membrane thickening occurs. Third, glomerular sclerosis is caused by intraglomerular hypertension (induced by renal vasodilatation or ischemic injury from hyaline narrowing of the vessels supplying the glomeruli).
Diabetic nephropathy is a clinical syndrome characterized by angiopathy of the capillaries in the kidney glomeruli, leading to progressive albuminuria, loss of glomerular filtration, and hypertension. These changes develop slowly over many years, and overt signs or symptoms may not develop until very late in the disease course. The earliest detectable changes are only evident on biopsy specimens, but as the disease advances microscopic and then gross amounts of albumin are leaked into the urine. Formal classification requires > 300 mg/day of albumin confirmed on at least 2 occasions at least 3 months apart, a progressive decline in the glomerular filtration rate, and an elevated arterial blood pressure.
The exact mechanism of extracellular matrix accumulation and proteinuria is multifactorial and incompletely understood. Hyperglycemia directly leads to glycosylation product buildup, which causes extracellular matrix crosslinking. But the metabolic environment that leads to hyperglycemia is also responsible for an elevation in protein kinase C, tumor growth factor-beta, vascular endothelial growth factor, and other cytokines that lead to cellular hypertrophy, enhanced collagen synthesis, and increased vascular permeability.
Diabetic neuropathy is characterized by progressive loss of nerve fibers. The exact pathophysiologic mechanism is incompletely understood, but is most likely the combined result of oxidative stress, excessive neuronal intracellular glucose, and glycation end product disruption of cellular metabolism in the setting of microvascular injury. Diabetic neuropathy affects the peripheral nerves (left image), in a stocking-and-glove distribution, and the autonomic neurons (right image), within the gastrointestinal tract, bladder, and blood vessels. Patients with autonomic neuropathy may suffer from hypotension, gastroparesis, diarrhea, urinary incontinence, or urinary retention. Images courtesy of the National Institute of Health.
Diabetic peripheral neuropathy causes sensorial and motor symptoms. Sensorial symptoms include loss of vibration sense, temperature sense, proprioception, and reflexes as well as numbness and painful paresthesias. Because patients cannot feel their extremities, they are at risk of developing unrecognized injuries, fractures, and infections that can lead to severe ulcers or gangrene. Loss of motor function causes weakness, ocular dysfunction, and contractures. The long nerves are affected first because of the disproportionate delay in nerve conduction.
Neuropathic osteoarthropathy, also known as a Charcot joint, is a late complication of diabetic neuropathy. As patients lose sensation, progressive degeneration of weight-bearing joints occurs, leading to bony destruction, bone resorption, and deformity. The process is believed to be the result of the loss of proprioception and deep sensation causing recurrent trauma. Disease progression may be insidious and patients present with unsalvageable destruction.
Peripheral neuropathy is assessed with careful neurologic examination. Monofilament pricks are a standardized means of assessing sensorial loss. Vibration sense and reflexes are tested with a tuning fork and reflex hammer, respectively. Nerve conduction studies and electromyography may be used to detect deficits before they are clinically apparent and to rule out other etiologies. Nerve biopsies are rarely used.
Treatment for diabetic neuropathy begins with excellent glycemic control and regular surveillance for injuries. For pain, tricyclic antidepressants, gabapentin, pregabalin, duloxetine, topical lidocaine, or capsaicin may be used. For patients with diabetic foot ulcers, the cause of the injury should be first removed, such as poorly fitting shoes. Patients should be instructed to limit weight-bearing to the affected area. Special shoes, as shown, are designed to evenly distribute weight over the foot to prevent pressure ulcers from developing. For patients with advanced disease, antibiotics, surgical debridement, or even amputation may be necessary.
