Diabetic Microvascular Complications Part 2

Extracellular Matrix Accumulation and Proteinuria 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 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 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.

Charcot Joint Neuropathic Osteoarthropathy 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.

Charcot Knee Joints Another example of a Charcot joint from repetitive damage to the bilateral knee joints. Fragmentation and collapse of the chondral and osseous structures are shown.

Neuropathic Arthropathy Ankle Charcot Joint Computed tomography scan through the level of the ankle of a Charcot joint secondary to long standing neuropathic arthropathy. Note the destruction of the articular surface (yellow arrow), disorganization of the joint, and fragmentation (red arrow).

Monofilament Neurologic Examination 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.

Diabetic Neuropathy Preventing Pressure Ulcers 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.

Diabetic Impotence Diabetic-induced vascular disease is a major etiology of male impotence. It is estimated that erectile dysfunction will develop in approximately 50% of men with diabetes mellitus, but good glycemic control can help to reduce this risk. Unfortunately, many of the medications used to treat the hypertension that develops in diabetics exacerbates the erectile dysfunction.

Erectile Dysfunction ED In the normal erectile process, arterial dilation and venous compression causes a buildup of blood within the corpora cavernosa. The microvascular changes secondary to longstanding hyperglycemia cause arterial insufficiency and defective smooth muscle relaxation. Arterial insufficiency prevents dilation of the penile artery, thus reducing blood inflow and defective smooth muscle relaxation prevents compression of the penile vein thus increasing blood outflow. The net result is a decrease in the volume of blood within the corpus cavernosa, causing patients to suffer from progressively flaccid erections of shorter duration.