The natural history of diabetes mellitus is associated with complications affecting numerous functions of the body. The complications of diabetes mellitus that affect the nervous system belong to the category of metabolic neuropathies. It is estimated that 60-70 percent of people with diabetes will develop some form of neuropathy during the course of their illness. While not precise, the presentation of neuropathy appears to occur after about five years of elevated blood glucose levels (hyperglycemia) and reaches a peak after 25 years of hyperglycemia. Some individuals with documented nerve damage will not have symptoms, while others will report pain, tingling or numbness in the hands, arms, feet or legs that suggest involvement of peripheral sensory pathways. Diabetic neuropathy can also affect organ systems, including the cardiovascular, genital-urinary, digestive and vision systems.(1)

Although the key factor in both type 1 and type 2 diabetes is the defective activation of insulin-sensitive pathways, either from lack of insulin or from insulin resistance, respectively, the major resulting metabolic derangement is the persistence of hyperglycemia.(2) The long-term high levels of blood glucose lead to multiple metabolic alterations such as generation of oxidative stress in a variety of tissues, the hyperactivation of pathways such as the polyol pathway or activation of poly(ADP-ribose) polymerase (PARP), the generation of reactive oxygen species and the production and downstream actions of modified moieties such as advanced glycation end products (AGE-s) and receptor for advanced glycation endproducts (RAGE).(3)(4)

All these factors, implicated in the pathophysiology of diabetes, lead to altered neural function and, eventually, to the demise overtime of nerve cells. Therefore, the neuropathic complications of diabetes are multifactorial in nature and their manifestations either in peripheral or autonomic neuropathies are the result of the inimical effects of these factors. The identification of symptoms, the assessment of the development of diabetic neuropathy and the analysis of treatment options need to take into account this multifactorial process.

Symptoms and Signs Associated With Diabetic Neuropathies

The type of symptoms and signs experienced by patients with diabetic neuropathy will depend on the nerves involved.(5) For example, many individuals will first notice numbness, tingling or pain in the feet. These symptoms are initially mild but, typically, worsen over the years, and then decrease with progressive damage and loss of the affected nerves. Some individuals will report muscle weakness associated with wasting involving the hands or feet. Others present with impaired function involving the autonomic or involuntary nervous system. These individuals may report progressive problems with constipation or diarrhea, nausea with or without vomiting and feeling full after eating, dizziness with or without fainting related to a drop in blood pressure after standing or sitting up, erectile problems in men and vaginal dryness in women, and problems with urination.

Peripheral neuropathy is first noticed as a distal symmetric neuropathy or sensorimotor neuropathy involving the hands and feet that progresses proximally. Individuals will report either hyper- or hyposensitivity that appears to depend on the duration of diabetes. Some individuals will present with problems involving specific nerves and muscles, for example, double vision, pain or weakness in the face, thigh, chest or abdomen.

Autonomic neuropathy involves the nervous system innervating the heart and blood vessels, gastrointestinal tract and genital-urinary system including the system that monitors and restores blood glucose levels to normal after a hypoglycemic episode. Therefore, individuals with autonomic neuropathy may be unaware of palpitations, shakiness and sweating that can accompany episodes of low blood sugar. When innervation of the heart and blood vessels are affected, individuals may loose their ability to adjust blood pressure and heart rate associated with changes in position, resulting in light-headedness and, possibly, loss of consciousness.

When the gastrointestinal tract is involved, constipation is often the first complaint. Later, individuals may experience diarrhea associated with small bowel bacterial overgrowth or, uncommonly, a high volume secretory diarrhea associated with impaired sympathetic regulation of secretory function. Involvement of the upper GI tract can present with nausea with or without vomiting and loss of appetite associated with abdominal bloating, distension and early satiety, especially after meals. This constellation of symptoms is observed in patients with slow emptying of the stomach (gastroparesis). Some individuals may complain of swallowing problems.

Autonomic neuropathy may also affect urinary and sexual function. Incomplete emptying of the bladder increases risk for urinary tract infections. Some individuals will experience urinary incontinence. Males can experience problems with erections, ejaculation and orgasm, while females may have problems with arousal, vaginal dryness and experiencing a normal orgasm.

Individuals with autonomic neuropathy may also develop an abnormal sweat response, resulting in dysfunctional regulation of body temperature or profuse sweating at inappropriate times. Vision can be affected as a result of abnormal pupillary response to changes in ambient light or dysfunction of the muscles that coordinate eye movement resulting in blurry or double vision.

Diagnosis of Diabetic Neuropathy

The diagnosis of autonomic neuropathy is based on the clinical history, physical examination and targeted diagnostic testing.(6) The physical examination may reveal abnormalities in blood pressure, heart rate, muscle strength, reflexes and sensory response to light touch, position, temperature and vibration. Careful examination of the feet is an important part of any evaluation of a patient with diabetes because neuropathic changes often involve the feet early in the natural history of this disorder. Additional testing may include direct measurement of nerve conduction and electromyography which can help assess the type and extent of nerve damage, as well as, how well specific muscles respond to electrical stimulation.

Other tests are used to examine the presence of abnormal variability in the heart rate in response to deep breathing or changes in posture which, if present, supports the presence of autonomic neuropathy. Some clinical research studies quantify sweat output in response to the application of a topical stimulant and counts of sensory nerve fiber terminals in the epidermis on skin biopsies. Reduction in the number of nerve terminals in the epidermis is gaining acceptance as a barometer of early sensory neuropathy in diabetes.

All diabetics should undergo an annual eye exam to check for abnormalities. If gastroparesis is suspected a solid-phase gastric emptying study may help confirm this diagnosis. The diagnosis of autonomic neuropathy involving the urinary tract can be assisted by obtaining targeted imaging and cystometric studies.

Role of Endocrine and Metabolic Factors in the Development of Peripheral Neuropathy

The key derangement of diabetes is persistent hyperglycemia. The inability of the body to regulate and maintain normal levels of glucose may arise from lack of insulin such as the insulinopenia in type 1 diabetes as a consequence of the destruction of the beta cells of the pancreas, or, in type 2 diabetes, from the diminished ability of insulin to lower blood glucose (insulin resistance) through activation of cellular signaling pathways that lead to the uptake and utilization of blood glucose. In either case, the excessive glucose levels trigger a panoply of cellular derangements that are the major cause of diabetic complications.

A large body of research on diabetes and diabetic neuropathy(1)(2)(5) has investigated the role of factors such as anomalies in lipid levels and composition, genetic factors and age-related risks (e.g. decreased metabolic rates in the elderly). Dyslipidemias are well known to increase significantly the pathophysiology of diabetes. The contribution of lipids and fatty acids to oxidative stress and inflammatory responses is a major focus in current research on diabetic complications. A recent report(7) suggests that elevated triglycerides correlate with progression of peripheral neuropathy independent of disease duration, age, diabetes control or other variables. However, it has become clear that early detection of hyperglycemia and proper glycemic control are critical to prevent the development of diabetic neuropathy and the other complications of diabetes.

The presence of abnormally high glucose levels in neural tissues affects a wide variety of cell functions and pathways. The more salient alterations include:

Increased Oxidative Stress

Uncontrolled hyperglycemia eventually leads to a variety of alterations in cell metabolism, as well as, protein expression and activity. Much research has identified the stimulatory effect of high glucose on the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as the major, if not the single, most important alteration in the cellular milieu.(8)(9) The generation of ROS and RNS in hyperglycemia is originally driven by alterations such as the over-activity of aldose reductase and concomitant increased polyol pathway flux. The enhanced polyol pathway, in turn, results in sorbitol accumulation and a plethora of alterations including increased superoxide production, enhanced production of nitrosative stressors such as peoxynitrite, increased poly(ADP-ribose) polymerase (PARP) activity, and reduced antioxidant function involving events such as depletion of glutathione (GSH), increased GSS/GSH ratios, superoxide dismutase downregulation, abnormal catalase and glutathione peroxidase function, and excess production of oxidative stressors by mitochondria.

A major feature of the metabolic derangements in diabetic neuropathy is the cross-talk and global cross-dysfunctions among pathways that regulate nerve cell, metabolism, growth and survival.(10) There is growing interest in the observation that the excessive oxidative intracellular environment activates a variety of cytoprotective responses to cope with the inimical environment. These cytoprotective events include stimulation of autophagic processes, which mammalian cells utilize to remove and degrade, during conditions of stress, abnormal proteins and organelles in lysosomes.(11)(12) For example, overactive mitochondria and oxidative stressors trigger engulfment of mitochondria by macroautophagic mechanisms that prevent further damage to the nerve cell. However, if uncontrolled, the stressful environment can lead to pathophysiological responses, development of apoptosis, a reduction in the number of nerve cell fibers in peripheral nerves and eventual impairment of nerve function.

Abnormal Production of Glycated Compounds

Hyperglycemia and the resulting hexose flow through the polyol pathway lead to high sorbitol and fructose concentrations inside the nerve cell. The excessive levels of sugars contribute to the non-enzymatic formation of advanced glycation end products (AGE). The presence and cellular effects of AGE and its receptor (RAGE) are active areas of research in a variety of degenerative diseases, including neuropathies.(13) The presence of high levels of AGE-modified proteins is known to stress the cellular milieu. Research has demonstrated co-localization of AGE and RAGE in diabetic peripheral nerve. AGE/RAGE-modified myelin contributes to the inflammatory environment of diabetic nerve and, therefore, can add to the oxidative stress milieu in diabetic neuropathies.(14) Given these observations, the inhibition of AGE formation and AGE/RAGE interactions are active ongoing areas of research with therapeutic potential.

Abnormal Activation of Key Regulatory Enzymes

As mentioned previously, numerous cellular derangements have been identified in diabetic neural tissue and the number of reported alterations in enzymatic activity is likely to increase. Current research focusing on the pathophysiology of diabetic neuropathies has identified derangements involving increased expression and/or activity on numerous enzymatic pathways(10) including, among the more thoroughly characterized:

Aldose reductase Poly(ADP-ribose) polymerase (PARP) Isoforms of protein kinase C Inducible nitric oxide synthetase (iNOS) Mitogen activated kinase (MAPK) NFκB which is an important marker and mediator of cellular stress responses Cyclooxygenase-2 (COX-2) and lipooxygenase

There is a robust literature that discusses these pathways and the reader is encouraged to review the pertinent references and in-depth reviews.(10) However, their roles can be encapsulated as follows:

Aldose reductase, whose hyperactivity leads to the enhanced polyol pathway hexose flux; Poly(ADP-ribose) polymerase (PARP) whose most widely known function is DNA repair and has also been shown to be involved in oxidative stress mechanisms; Isoforms of protein kinase C with tissue and cell type specific effects related to diabetic complications; Inducible nitric oxide synthetase (iNOS), which appears critical for the microvascular derangements in peripheral nerve and perhaps most importantly, for the generation of nitrosative oxidants; Mitogen activated kinase (MAPK) whose role in stress responses is amply documented; NFκB which is an important marker and mediator of cellular stress responses; Cyclooxygenase-2 (COX-2) and lipooxygenase which have been shown to increase the inflammatory environment and impair microvascular function in peripheral nerve.

One of the most comprehensively studied enzymes is aldose reductase, which mediates the conversion of glucose to sorbitol and enhances flux through the polyol pathway.(15) Increased sorbitol and its subsequent conversion to fructose have inimical pleiotropic effects, triggering oxidative stress, osmotic stress and increased non-enzymatic glycation of cellular proteins.(10) Studies with aldose reductase inhibitors have shown amelioration of many of the cellular derangements, including oxidative stress in diabetic animal models. Several studies suggest that the over-activity of this enzyme leads to oxidative stress through increases in peroxide production, decreased antioxidant activity, enhanced cytosolic NAD/NADH ratios and dysfunctional mitochondrial oxidative status.

Inhibition of aldose reductase as a potential therapeutic intervention has been an active area of research.(16) In general, the benefits of aldose reductase inhibitors demonstrated clearly in animal models have proved challenging to replicate in human studies.

Poly(ADP-ribose) polymerase (PARP), usually known because of its function in DNA repair, has been found to be activated and contribute to diabetic complications. Its role in the pathophysiology of diabetic neuropathy is thought to arise from over-activation of oxidative/nitrosative-related stress damage (e.g. secondary to peroxynitrite-induced injury) and the generation of free radicals.(17)

PARP has a variety of roles affecting cell metabolism. PARP activation in peripheral nerve has been shown to affect many processes.(10) For example, it has been shown to lead to a deficit in activation of glyceraldehyde 3-phosphate dehydrogenase, a glycolytic enzyme.(18) The full characterization of PARP effects in the diabetic nerve cell needs to be comprehensively characterized.

Specific isoforms of protein kinase C have been shown to be overactive in diabetic complications.(19) This is particularly the case in diabetic retinopathy. Although the role of protein kinase C in diabetic neuropathy is complex,(10) its effects appear to be primarily mediated through the well-documented reduction of blood supply in peripheral diabetic nerve.(20) The role and level of expression of the different isoforms of PKC in specific neural tissues and cell types remain to be fully elucidated.

It is quite possible that disturbances in other enzymatic pathways will be implicated in the neuropathic complications of diabetes. Should this be the case, it will complicate the development of successful single-modality treatments.

Depletion of Key Metabolites in Diabetic Neuropathy

Recent advances in cell biology have highlighted the importance of characterizing the constellation of metabolites, collectively known as the metabolome, in a variety of diseases. Potentially significant disturbances in a number of compounds that comprise the metabolome have been identified in diabetic neuropathy. The metabolites that have received the most attention are myo-inositol and the amino acid taurine. Both general and compartmentalized reductions in intracellular myo-inositol concentrations have been described in diabetic nerve tissue.(21) Decreased taurine transporter expression, with a concomitant deficit of intracellular taurine, has also been reported in diabetic peripheral neuropathy.(22) Taurine appears to have a role in the proper functioning of healthy nerve tissue and its deficit may contribute to cell stress in diabetic neuropathy.

Contribution of Microvascular Dysfunction to Diabetic Neuropathy

A larger question than the nerve-specific derangements in diabetic nerve is the interaction between neural and non-neural tissues. These interactions are particularly relevant with respect to the blood supply to peripheral nerve.(23) Research suggests that microvasculature function is impaired in diabetic peripheral neuropathy. Improving blood flow has been shown to ameliorate many of the defects observed in diabetic peripheral neuropathy.

The specific interaction between the microvascular structures such as the vasa nervorum and the supply of blood and nutrients to the nerve cells is pathophysiologically significant on two major levels. First, we have a limited understanding of how chronic hyperglycemia affects the structure and function of the neuronal microvasculature longitudinally. Second, once blood flow is impaired, the deficit may interfere with the delivery of potentially therapeutic compounds to nerve tissue. This difficulty may explain the suboptimal efficacy of single modality therapeutic approaches in management of diabetic neuropathy and supports the need for more research using multi-modality interventions.

Preventive Strategies and Therapeutic Resources

Longitudinal studies indicate that the best way to prevent the neuropathic changes associated with long-term diabetes mellitus is to maintain blood sugar (glucose) levels as close to the normal range as possible. In addition, research indicates that acute fluctuations in the blood glucose level in the hyperglycemic range is also associated with abnormal function of the autonomic nervous system.(24) Preventive strategies also include maintenance of body weight in the optimal range for an individual's height, avoidance of tobacco products and excessive use of alcohol.(25)(26)(27)

Treatment of Diabetic Neuropathies

The cornerstone of managing diabetes mellitus and minimizing the development of neuropathic complications is maintenance of blood glucose levels as close as possible to the normal range.(28)(29)

Painful neuropathy can respond to treatment with tricyclic antidepressants such as nortriptyline, other members of the antidepressant family such as duloxetine and anticonvulsants such as gabapentin and pregabalin.(30) It is noteworthy that relatively low doses of these drugs can be effective. Opioids and opioid-like drugs such as tramadol can also be effective but should be used judiciously because of their side-effects, which can exacerbate other complications of diabetic neuropathy such as constipation.

Autonomic neuropathy associated with gastroparesis can respond to metoclopramide, which promotes gastric emptying but has central nervous system side effects that limit its use in some patients. Domperidone is an alternative treatment available outside the United States whose principle advantage is fewer CNS side effects than metoclopramide. Patients with diarrhea related to bacterial overgrowth are treated with a broad spectrum antibiotic such as tetracycline or rifaximin, which acts primarily inside the digestive tract. Patients with constipation will typically respond to polyethylene glycol (PEG) 3350 products. Dosing is titrated to produce one formed bowel movement a day to every other day.

Individuals with problems involving the genital-urinary tract or vision should be evaluated by the relevant specialist to determine the optimal management.

Summary

In summary, to avoid the neuropathic complications associated with diabetes mellitus, afflicted individuals should be advised to adhere to the following recommendations:

• Maintain blood glucose as close to the normal range as possible.
• Limit alcohol consumption.
• Don't smoke.
• Take particular care of feet and tell their doctor about any skin problems, especially poorly healing sores.
• Tell the doctor about any problems they have with:
  • Hands, arms, feet or legs such as changes in sensation or muscle weakness.
  • Stomach, bowels, or bladder such as bloating, distention, constipation, diarrhea or difficulties with urination.
• Tell the doctor if they:
  • have problems with sex, such as erectile dysfunction, difficulty achieving an orgasm or vaginal dryness.
  • cannot always tell when their blood glucose is low.
  • feel dizzy when they move from lying down to a sitting or standing position.

On-line Resources

The sites below are provided by the leading organizations in the field of diabetes that are involved in the ongoing development of potential therapies for diabetes and its complications. The participant is advised to visit their sites.

American Diabetes Association:
http://www.diabetes.org/diabetes-research/clinical-trials/trials-home.jsp

Juvenile Diabetes Research Foundation:
http://www.jdrf.org

National Institutes of Health:
http://www.diabetes.niddk.nih.gov

Food and Drug Administration:
http://www.fda.gov/diabetes