Advances in Diabetes for the Millennium: New Treatments for Diabetic Neuropathies

Abstract

Diabetic neuropathies are not a single disorder but a heterogeneous group of conditions that involves different parts of the somatic and autonomic nervous systems. Neuropathies may be focal or diffuse, proximal or distal. The focal neuropathies are either entrapment syndromes that occur in 30% of patients with diabetes, and if recognized can be treated with diuretics, splinting local steroids, and unentrapment. The focal mononeuritides are vascular assaults and heal spontaneously and need supportive therapy. The proximal neuropathies are, for the most part, inflammatory demyelinating conditions that occur 11 times more frequently in the diabetic population and respond well to intravenous immunoglobulin (Ig)G or immunosuppressive treatments.

The distal symmetric polyneuropathies are usually a mixed picture of sensorimotor dysfunction, and recent evidence based on intraepidermal nerve-fiber changes has identified a subset of painful neuropathies that are associated with impaired glucose tolerance and dysmetabolic syndrome, and precede the onset of diabetes. Pain in neuropathy is also multifactorial and can occur at different levels, starting at the peripheral sympathetic nervous system in the skin (C fibers) and migrating to involve A-beta and A-delta fibers to produce allodynia, continuing with reorganization at the cord-level, cold allodynia, and finally, within the central nervous system, spontaneously as opposed to provoked pain. This is best treated with agents that target the different levels of pain production.

It now seems that the pathogenesis of diabetic neuropathy is also heterogeneous with causative factors, including microvascular insufficiency, oxidative stress, nitrosative stress, defective neurotrophism, and autoimmune-mediated nerve destruction. New therapies are aimed at the underlying pathogenesis as well as the symptom complex. If attention is directed toward a pathogenetic approach, much can be done to alleviate the symptoms, alleviate the mitigation of quality of life, and now it would seem to address the underlying biological disturbance.

Introduction

"All we can do for diabetic neuropathy (DN) is make the diagnosis and commiserate with the patient" (The Lancet editorial 1994). We have come a long way since then and, with increasing sophistication in our understanding of the true nature of diabetic neuropathies, have developed new strategies for treatment. Because we now have real therapies to offer, it behooves us to do our utmost to make these diagnoses on the basis of pathogenic mechanisms when therapeutic endeavors can result in real gains. To do this, we need first to briefly review what we have come to know about neuropathies. Diabetic neuropathy (DN) is the most common and troublesome complication of diabetes mellitus, leading to great morbidity and mortality, and resulting in a huge economic burden for diabetes care.[1-4]

It is the most common form of neuropathy in the developed countries of the world, accounts for more hospitalizations than all the other diabetic complications combined, and is responsible for 50% to 75% of nontraumatic amputations. DN is a heterogeneous disorder that encompasses a wide range of abnormalities affecting proximal and distal peripheral sensory and motor nerves as well as the autonomic nervous systems. DN is a set of clinical syndromes that affects distinct regions of the nervous system, singly or combined. It may be silent and go undetected while exercising its ravages. Neuropathic complications occur equally in type 1 and type 2 diabetes mellitus, and in various forms of acquired diabetes.[5]

The major morbidity associated with somatic neuropathy is foot ulceration, the precursor of gangrene and limb loss.[6] Neuropathy increases the risk of amputation 1.7-fold, 12-fold if there is deformity (itself a consequence of neuropathy), and 36-fold if there is a history of previous ulceration. There are 85,000 amputations in the United States each year, 1 every 2 minutes, and neuropathy is considered to be the major contributor in 87% of cases. It is also the most life-spoiling of the diabetic complications and has tremendous ramifications for the quality of life of the person with diabetes. Once autonomic neuropathy sets in, life can become quite dismal and the mortality rate approximates 25% to 50% within 5-10 years.[7,8]

Subclinical neuropathy is diagnosed on the basis of (1) abnormal electrodiagnostic tests with decreased nerve-conduction velocity or decreased amplitudes; (2) abnormal quantitative sensory tests for vibration, tactile, and thermal warming and cooling thresholds; and (3) quantitative autonomic function tests revealing diminished heart-rate variation with deep breathing, Valsalva maneuver, and postural testing.[9,10] The results of quantitative autonomic function tests also include diminished sudomotor function, increased pupillary latency, and abnormalities in gastrointestinal function as well as disturbed skin neurovascular responses.

DNs have been classified in different ways. The most convenient is 1 that is based on differences in pathogenesis and thereby treatment modalities.

DNs are:

1. Focal;

2. Mononeuritis;

3. Entrapment;

4. Diffuse;

5. Proximal;

6. Distal;

7. Small-fiber (these include the autonomic neuropathies); and

8. Large-fiber.

The mononeuritides are always sudden in onset; they may involve cranial nerves C3, 6, and 7, and the peripheral nerves -- median, ulnar, peroneal, and posterior tibial -- with the medial and lateral plantar nerves. Pain is localized to the nerve distribution but may spread, and weakness is confined to the muscles supplied. The etiology is vascular and recovery is usually complete within 6 weeks. The tendency of diabetic platelets to hyperaggregate and the increased thrombogenicity (elevated fibrinogen, PAI-1) need to be targeted for prevention of these occurrences.

There is, however, a trap for the unwary. These same nerves tend to be caught up in an entrapment process. There are key differences in the clinical presentation. For example, entrapment is a chronic insidious process, whereas mononeuritides tend to occur out of the blue like many other vascular insults. Entrapments, of course, require an entirely different form of intervention (see Table 1).

Table 1.

Contrast of Mononeuritis and Entrapment

Mononeuritis	Entrapment
Onset sudden	Onset gradual
Usually single nerves but may be multiple nerves	Single nerves exposed to trauma
Common nerves: C3, 6, and 7; and ulnar, median, and peroneal	Common nerves: median, ulnar, peroneal, medial, and lateral plantar
Not progressive and resolves spontaneously	Progressive
Treatment: symptomatic	Treatment: rest, splints, diuretics, steroid injections, and surgery for paralysis

Diffuse Proximal Neuropathies

Diffuse proximal neuropathies were once called diabetic amyotrophy. The process resolves spontaneously over a protracted period of months to years. New evidence suggests that about 90% of these cases are chronic inflammatory demyelinating polyneuropathies, vasculitides, monoclonal gammopathies, and immune-mediated demyelination with apoptosis of neurons.[11-13] Many of these conditions are now treatable with salutary responses. Only about 10% remain that can be ascribed to the diabetes per se and pursue a chronic, relentless course.

Distal Symmetric Polyneuropathies

Diffuse distal symmetric polyneuropathies (DSPNs) are the most common of the neuropathic syndromes in diabetes. There is no consensus as to the pathogenesis because many conditions probably contribute. The major factors in pathogenesis include metabolic events, microvascular insufficiency, oxidative stress, loss of neurotrophism, and autoimmune-mediated nerve destruction. Just as diabetes in general now requires polypharmacy to reduce the impact on complications, it seems that no single therapy will be sufficient to mitigate all these participating components. Metabolic events that contribute include hyperglycemia, polyol accumulation, accumulation of advanced glycation end products, deficiencies of antioxidants, and certain fatty acids. Successful treatment of hyperglycemia has already been shown to slow the rate of progression of DSPNs. Promising results have been obtained with aldose reductase inhibitors, the antioxidant alpha-lipoic acid, and dihomo gamma-linolenic acid. Nontoxic agents that can break advanced glycosylation end products are sorely needed.

Microvascular Insufficiency and DN

Microvascular insufficiency rears its head in a multitude of different forms. Overactivity of the beta-2 protein kinase C has been implicated in increased vessel permeability, smooth muscle contraction, and endothelial cell proliferation, thereby impairing blood supply via the vasa nervorum.[14] An ongoing, multicenter worldwide trial of a specific beta-2 protein kinase C inhibitor will be completed early next year. The microvasculature in the diabetic patient reacts poorly to vasodilatory stimuli and may overreact to vasoconstrictive stimuli.[15]

These microcirculatory defects have been found in type 2 diabetes before the onset of the diabetes, in family members, and cosegregate with other components of the metabolic syndrome, including hypertension, dyslipidemia with a raised triglycerides level, and insulin resistance. There appears to be a reduction in the responses to nitric oxide (NO) (and prostacyclin ) as well as the vasodilatory neuropeptides and overactivity in the responses to the vasoconstrictors endothelin and angiotensin. Insulin itself is a vasodilator, operating through the NO mechanism, and this response is defective in type 2 diabetes. (See the review by Dandona in this symposium.) As the condition progresses, there is a loss of the thinly myelinated C fibers in the skin with the disappearance of the vasodilating neurotransmitters substance P and calcitonin gene-related peptide. Of interest, it has been reported that a 68% reduction in the development of autonomic neuropathy occurs with a program of intensification of blood pressure reduction; controlling blood glucose and lipids; and providing aspirin, an angiotensin-converting enzyme (ACE) inhibitor, and the antioxidants, vitamin C and E. This reemphasizes the need for polypharmacy for even this component of DSPN. Immune-mediated damage is more difficult to recognize, but a number of research laboratories have now established assays of the effects of sera on immune-mediated apoptosis that may become clinically available, thus providing an alternative approach to these neuropathies. This appears to be particularly relevant in motor neuropathies but needs further exploration.

Neurotrophism in DNs

The loss of neurotrophism is probably the single most exciting (and frustrating) prospect for the treatment of DSPN. It not only offers the possibility of slowing progression but also causes nerves to regenerate. There is ample evidence of the loss of neurotrophic support in the diabetic nerve, eg, human nerve growth factor, IGF I and II, NT3, and brain-derived neurotrophic factor, among others.[16]

These trophic factors, however, target specific nerve fibers; eg, human nerve growth factor targets only those fibers that subserve warm thermal perception and pain, whereas NT3 targets larger myelinated fibers important for position sense, vibration, reflexes, and motor power. It is naive to think that a single trophic agent could embrace all these fibers. A way in which this may be overcome in the future is to make hybrid molecules that contain the core components of each neurotrophic agent. Alternatively, it seems that the immunophilins and the prosaposides may be small molecules that either release these trophic agents or mimic their proliferative and differentiative effects.[17,18]

An alternate strategy is to stimulate the receptors, eg, Trks A, B, and C, responsible for small fibers, large fibers, and motor function, respectively. New drugs are anticipated that would enter the arena beyond the receptor, eg, acting on the signal-transduction pathway of cell growth and proliferation that could be a small-molecule, eg, p38 kinase or the cyclic adenosine monophosphate response, binding protein.

Adult neurons require a trophic milieu to survive and in the absence undergo apoptosis or programmed cell death. One of the new and exciting areas is finding ways and means of combating this influence. For example glutamic acid is an excitatory neurotransmitter that via metabotropic pathways can cause cell death. Blocking its synthesis with NAALADase inhibitors may be able to prevent this. Such compounds are in the pipeline.

Basement-membrane proteins are also essential for the viability of these nerves and laminin via its binding to integrins, and various cytokines, eg, interleukin (IL)-6, have been shown to actively inhibit apoptosis in tissue culture. It will be interesting to follow this area with interest and enthusiasm. Some of the compounds discovered by chance even appear to be able to stimulate Schwann cell remyelination of nerves with promise for reversal of the large-fiber neuropathies.

Pain in DNs

Pain in DNs remains a vexing problem. There are different types of pain, eg, superficial dysesthetic or allodynic, which is quite different from the deep-seated gnawing, and lightning pains, which afflict certain individuals. Each type of pain requires its own form of intervention, but none of the agents currently available are without significant side effects that bar their use for protracted periods or in high doses in diabetes. Some of the agents can be quite addicting. Understanding the pain pathways and better tailoring of drugs to meet these needs is required. Gabapentin (Neurontin) is one of the most successful agents, but doses required for pain relief also cause somnolence. The development of pregabalin, a potential successor to gabapentin, has been held up by possible findings of animal carcinogenicity.

Measurements of the Nature and Extent of the Deficits

Paralleling our increased understanding of the pathogenesis of DN, there must be refinements in our ability to quantitatively measure the different types of deficits that occur in this disorder, so that appropriate therapies can be targeted to specific fiber types. These tests must be validated and standardized to allow comparability between studies and a more meaningful interpretation of study results.[19]

Several recent studies have failed to show benefit in DN and have been interpreted as failure of the drug to be effective. These studies include most notably the aldose reductase inhibitor studies and the nerve growth factor studies.[20]

The drugs have not necessarily failed. It may be that our ability to demonstrate meaningful change was insufficient. Perhaps we need more success in uncovering the pathogenic processes underlying this disorder.

Caveats in the Management of DN

There are a number of treatments for neuropathy that are based on limited observations, for example, magnets. Although it is difficult to refute the power of magnetism, it is almost impossible to test the efficacy in a double-blind, placebo-controlled manner. One only has to use a compass to discover whether you are in the active or placebo group. Similarly, the use of transcutaneous electrical stimulation, electrical contraction of muscles, and infrared radiation to increase NO all need to be tested in a controlled manner, but the study design requires some ingenuity.

Conclusion

There is much on the horizon in the area of DN. Key elements are the need for understanding the diversity and heterogeneity of the condition and the differences in the pathogenesis of each of the manifestations. Current strategies could be optimized with more attention to the different aspects of the condition and correct application of the available agents. There are prospective agents for the metabolic, vascular, and autoimmune components of DNs. The new advances in the development of neurotrophic factors herald a host of potentially combined treatments. The use of neurotrophic factors appears to be the most exciting approach because of the potential for the reversibility and regeneration of nerves.

This diversity of potential approaches will undoubtedly dictate a need for polypharmacy if we are to embrace the entire spectrum of DNs. Certainly, the cost of such multiple treatments will be high. Yet, if successful, we hope to see reasonable success in treating DN, the neglected Cinderella of diabetes complications.