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ORIGINAL ARTICLE

Improving Prognosis in Type 2 Diabetes

Diabetic neuropathy is in trouble

John Dale Ward, MD, FRCP

Painful sensory syndromes and the anesthetic foot result in much clinical morbidity and patient unhappiness in diabetes. As yet, a satisfactory and fundamental therapy is not available to us to help patients. Effective blood glucose control and vigilant screening programs for foot problems are all we have to offer. Clinical observation of neuropathic syndromes and measures of nerve function have not led to significant understanding of pathogenesis. The primary source of understanding of pathways to nerve damage come from animal studies, despite the fears that the model in diabetes in no way reflects the human situation. Therapeutic hope at the moment from such animal work must focus on the interference of pathways known to lead to neural blood-flow abnormalities and a variety of metabolic abnormalities, as well as the possibility that addition of nerve growth factor will assist repair and regeneration. The understanding of these multiple pathways in the animal model underlines the likely enormous complexity in the final picture of understanding in diabetic neuropathy. Modern imaging techniques such as magnetic resonance imaging should, in the future, allow more significant investigation of the human subject.

Diabetes Care 22 (Suppl. 2):B84–B88, 1999

This short review highlights the great difficulties encountered in the study of peripheral nerves in diabetes and the resulting damage leading to diabetic neuropathy. The situation is outlined pragmatically and should be regarded as a realistic but not pessimistic view of the situation. Indeed, there is a very urgent need for more thought and detailed research into the pathogenetic mechanisms leading to diabetic neuropathy.

The results of damage to nerves in diabetes—diabetic neuropathy—cause considerable morbidity and unhappiness (1). Sensori-peripheral neuropathic symptoms are extremely unpleasant and only partially helped by sedative therapy. The massive number of male diabetic subjects who are impotent is a tragic statistic of diabetes (2). Moreover, neuropathic damage contributes significantly to morbid foot problems. Despite this sad state of affairs, we have no effective therapy for many aspects of diabetic neuropathy; and despite years of research, we are far from a detailed understanding of the pathogenetic mechanisms that lead to nerve damage. With regard to the autonomic nervous system, we are aware of the large number of abnormalities in autonomic function testing but do not have a precise understanding of their meaning (3). There is a suggestion that the presence of abnormal cardiac autonomic function tests does predict mortality, but there is no obvious way of proving autonomic dysfunction (4).

It would therefore be fair to say that patients with diabetic neuropathy are in trouble, for their medical advisers have little to offer them.

WHAT DO WE HAVE TO OFFER?

Blood glucose control
The Diabetes Control and Complications Trial provided the evidence that nerve function is protected by meticulous blood glucose control, both in terms of symptomatology and in minimizing the degree of nerve conduction deterioration (5). All those running clinical diabetes units are striving to improve the metabolic control of their patients, but this is not always possible for a significant number of patients for a variety of reasons. Moreover, in type 2 diabetes, the recognition of the disease may occur far into its natural history. In addition, there does not seem to be such a clear-cut relationship between blood glucose levels and the presence of neuropathy. Much neuropathy is present at the diagnosis of type 2 diabetes. However, every attempt should be made to achieve the best blood glucose levels possible in individual patients.

Foot care
At the present time, the greatest benefit in improving prognosis in type 1 diabetes with regard to neuropathy would be to organize efficient and comprehensive screening for the presence of neuropathic foot problems and ischemia. Provision of foot care services has been shown to reduce the occurrence of ulceration and amputation, and simple screening procedures likewise produce great reductions in amputation rate (6,7). Because foot problems in diabetes are the single most common cause of admission to the hospital, any attempt to reduce this will pay big dividends, which is the objective of the impressive St. Vincent Declaration and Initiative. Screening for foot problems is inexpensive, requiring only knowledgeable, trained hands and eyes, and will result in massive savings in money and unhappiness.

Apart from these two clinical organizational strategies we have little else to offer those with diabetic nerve damage apart from sedatives such as tricyclic antidepressants to ease their nocturnal pains (8). We owe it to the patients to educate professionals who care for people with diabetes about the common nature of the condition. Surveys by pharmaceutical companies over the years have shown an abysmal lack of knowledge of diabetic neuropathy in physicians and nurses outside the diabetes world, and even poor perceptions within diabetes clinics.

CLINICAL OBSERVATION— The clinical features of diabetic neuropathy have been beautifully and meticulously documented for both the peripheral and autonomic nervous system (9). Clinical descriptions have been given in enormous detail, more so than in any other complication of diabetes. However, such meticulous clinical description has not led to any detailed understanding of mechanisms. When coupled with epidemiological studies, clinical descriptions simply tell us that diabetic neuropathy is very common and that its presence is related to the age of the patient, the duration of the diabetes, and the quality of metabolic control. The EURODIAB study has pointed to new clinical associations with microalbuminuria and diastolic blood pressure (10). None of these, however, gives us a lead to that basic initial insult that progresses to neuropathy.

Over the years, clinical understanding of diabetic neuropathy has been hampered by the lack of an agreed-on and clinically useful definition. A variety of definitions have led to variable reports of prevalence, and indeed there are those who diagnose diabetic neuropathy on the basis of delayed nerve conduction or abnormal autonomic function tests. The definition of the Peripheral Nerve Society is acceptable only for those in research: "a diffuse symmetrical polyneuropathy mainly affecting the legs" (11). Moreover, the needs of the epidemiologist regarding definition may not be those of the clinician. However, a standardized scoring system has now been developed and should be adopted by all those describing and studying groups of patients with diabetic neuropathy (12). By agreeing to such a system, at least workers in different centers will understand what they are each describing by providing a clinical score based on symptoms, signs, and functional measurements.

MEASUREMENT OF NERVE FUNCTION— At the risk of continuing to sound negative, it must be said that our measures in diabetic neuropathy are relatively inaccurate surrogates for what is actually occurring in nerve structure and function. We certainly do not have at our disposal a direct view of the damaged tissue as we do in the retina or access to a functional measure, such as microalbuminuria, which has been shown to be an accurate marker of progress to renal impairment and renal failure. Moreover, such a marker can be scored as improving under various therapeutic procedures, such as blood glucose control and hypotensive therapy.

Conduction velocities
Motor and sensory conduction velocities (CVs) are the most commonly used measures in the study of diabetic neuropathy (13). They give an assessment of function in large myelinated fibers, i.e., only 25% of peripheral nerve fibers. Seventy-five percent of small myelinated and unmyelinated fibers are not assessed in any way with these measures. Velocities deteriorate with time, and although there is broad agreement that a degree of CV delay is related to pathology in cross-sectional studies, there is no absolute evidence that in serial studies improved CV indicates improved function or structure (14). Indeed, the prevailing view in neuropathy circles is that our ability to return damaged nerves to normal is likely to be very limited and that perhaps the best we can hope for is to minimize the known deterioration in CV that occurs in most diabetic patients. If, of course, it can be demonstrated that an impaired CV predicts the eventual development of a neuropathic problem (sensory syndrome or foot ulcer), then any agent or maneuver that improved the measure would be accepted as beneficial (15).

Vibration perception threshold
This measure assess larger myelinated fibers and have been shown to relate to a risk of foot ulceration (16). Such a measure is useful as a screening tool for the at-risk foot, requiring removal of the shoes and socks, which in itself is a primary and effective maneuver to allow careful inspection of the feet.

Temperature discrimination threshold
Such a measure assesses small fiber function and is very difficult to carry out in a repeatable and accurate fashion (17). However, every attempt should be made to develop more reliable methods, for this is an attempt to measure fibers related to sympathetic function, which is so vital for the maintenance and integrity of the microvasculature.

Sural nerve biopsy
It was hoped that this invasive investigation would be the gold standard by which to measure all aspects of nerve structure and possibly relate this to function. Using this technique, accurate counts of fiber density and number can be made, along with an assessment of fiber regeneration and demyelination. However, in studies reported so far, the standard deviation of fiber density in biopsy specimens is very wide indeed, denying the ability of any clinical trial to establish efficacy of a specific agent (18). Such a wide scatter of results probably represents our very poor clinical classification, which results in very heterogeneous groups of patients and the common mixture of subjects with type 2 and type 1 diabetes. The case is therefore further made to have an agreed scoring and staging system in diabetic neuropathy studies.

The hope for the future will be that imaging techniques will allow noninvasive assessment of peripheral nerve—even sural nerve. Appropriate manipulation with biochemical or radioactive markers could allow assessment of change within nerves without invasive technique.

PATHOGENETIC THEORIES FROM ANIMAL WORK— A major problem exists in extrapolating from animal studies in neuropathy to the human situation. The age of the animal and the age at which diabetes is induced, coupled with the variation in the degree of maturation of nerve at particular ages, have a profound effect on the results obtained. Most studies in rodents have been carried out early in the life of the animal and with diabetes induced at a very early stage. Diabetic neuropathy is a disease of long-living human subjects with multiple causative factors. Moreover, these diabetic rodents do not seem to develop microvascular disease and do not stand upright. Assuming the upright posture brings into action a complex series of humoral and neurogenic responses to protect the microvasculature from excess process-reflex vasoconstriction. Small fiber dysfunction, known to be defective in many diabetic subjects, results in failure to vasoconstrict in standing, allowing back pressure within the microvasculature (19).

It is not the purpose of this article to review in detail the various pathogenetic theories from animal work but simply to outline the individual theories, placing them in the context of findings in the human situation (20).

Aldose reductase
The polyol hypothesis has been intensively studied over the past 20 years, and yet no drug is generally available for prescription. Work on the hypothesis has dominated neuropathic research so as to block out thought to other possible mechanisms. Administration of aldose reductase inhibitors to diabetic rodents produces a wonderful picture of improved function (CVs) and structure (21), but sadly these benefits have not been apparent in human clinical trials. No improvement in symptoms has been reported, and improvements of CV are somewhat less than 2 m/s, with some protection against the known deterioration of CV in diabetes. Admittedly, many trials have been of a relatively short duration, and maybe some of the agents have not been sufficiently powerful. However, at this stage in the natural history of diabetic neuropathy research, it seems reasonable to now abandon this hypothesis.

Advanced glycation end products
Advanced glycation end products (AGEs) have been localized in endoneurial and perineurial vessels, axons, and Schwann cells of peripheral nerve in diabetic rodents. These changes result in significant alteration in nerve function, and as a source of free radicals, they could well lead to extensive neural damage (22). Inhibition of advanced glycation by aminoguanidine prevents CV defects in rodents, but no human studies are yet available to encourage optimism. Moreover, given that these products are by definition aging compounds and are laid down over very long periods of time, it seems unlikely that changes will be reversible in long-standing human diabetic subjects.

Oxidative stress
Early after diagnosis of diabetes in rodents, there is an increase in sciatic nerve lipid peroxidation and a decrease in supraoxide dismutase, changes that are prevented by insulin (23). Such damage by oxygen free radicals is known to be related to deficits of CV and impairment of nerve blood flow (24). The fact that such changes and the metabolic associations with them can be reversed by administration of antioxidants to these animals gives some encouragement that these pathways may well be reversible in the human situation. Antioxidants such as -tocopherol ascorbic acid and -lipoic acid have been shown to have beneficial effects on neural blood flow and CVs in animals (25). -Lipoic acid, a potent antioxidant, is under trial in the human situation.

With regard to other pathways leading to nerve damage, it is interesting that there is now good evidence that oxidative stress, exacerbated by increase flux through the polyol pathway and advanced glycated end product formation, results in pathology within the vasa nervorum (26).

Essential fatty acids
Deficiency of -linolenic acid has been demonstrated in rodent diabetic nerve. This deficiency allows an imbalance between lipo-oxygenase and cyclo-oxygenase products, resulting in a marked tendency toward vasoconstriction (27). Again, as with oxidative stress, impairment of nerve blood flow and CV has been related to these abnormalities, with improvement of both measures of blood flow and conduction after administration of -linolenic acid (28).

The agent -linolenic acid has been studied in clinical trials resulting in rather similar findings to those with aldose reductase inhibitors—small increments in CV and other neurophysiological measures without any symptomatic improvement (29).

Perhaps the most encouraging feature of the animal work at the moment is the demonstration of a significant synergistic effect when antioxidants and -linolenic acid are administered together (30). Moreover, treatment with -linolenic acid and an aldose reductase inhibitor likewise produces very significant improvements in CV and nerve blood flow compared with treatment with individual agents. Apart from the encouragement for eventual future therapy in human subjects, this observation underlines the extreme complexity of pathways leading to nerve dysfunction and deny the likelihood that one simple mechanism will be corrected to ameliorate the many problems of diabetic nerve disease.

Neurotrophic growth factors
IGF gene expression is reduced in rodents with diabetes. Administration of IGF reverses the impaired nerve regeneration and has some effect on pain assessment (31,32). Circulating IGFs are reduced in human subjects with type 1 diabetes (and type 2 diabetes), and the reduction is significantly more pronounced in patients with diabetic neuropathy. Normally, it is assumed that IGFs provide support for the nervous system and that neurotrophins allow specific support for specialized tissues. It seems reasonable to suggest that administration of growth factors in human subjects will help the process of regeneration and repair. One clinical trial of recombinant nerve growth factor is now underway (33).

MAJOR PATHOGENETIC THEORIES FROM HUMAN STUDIES

Morphology
Biopsy of nerve gives detailed electron-microscopic pictures of myelin and Schwann cells, and many abnormalities of structure and function have been described with great precision. Rather like the detailed descriptive studies of clinical neurology in diabetes, these studies are elegant but do not give a clear understanding as to why the nerves have been damaged in the first place.

Microvasculature of human peripheral nerve
A major area of interest is the demonstration of structural and functional changes in the microvasculature of human sural nerve in subjects with diabetic neuropathy (34). Electron-microscopic pictures of sural nerve capillaries show massive basal lamina thickening, with a picture of endothelial reduplication and proliferation (35). The degree of thickening of these capillaries is far greater than that seen in any other diabetic tissue, and the degree of damage relates to the severity of the neuropathy. Subsequent to these studies, direct needling of sural nerve demonstrated a state of hypoxia, confirming that the nerve was ischemic (36). Photography of epineurial vessels of sural nerve have shown arterial sclerosis with venous distension and tortuosity and the presence of arteriovenous shunts (37). In the interesting condition of insulin neuritis, there is not only extensive destruction of normal vasculature with numerous arteriovenous shunts but also the presence of proliferation of "neural new vessels" (38)—presumably a response to ischemia very similar to that found in the retina. Injection of intravenous fluorescein in subjects with diabetic neuropathy shows a very distinct poverty of flow within the nerve.

These microvasculature changes are undoubted and profound. Exactly when in the natural history these changes occur and what triggers them will be very important to establish. Moreover, it will be important to develop noninvasive methods of assessing nerve ischemia and blood flow.

CONTROL OF PAIN IN DIABETIC NEUROPATHY— The exact mechanism of pain is not understood. Peripheral mechanisms involve nonmyelinated C-fibers and may be assessed by temperature stimulation or pain production (39). However, spinal cord and central mechanisms cannot be excluded. Because it seems unlikely that effective therapy for symptoms or prevention of nerve damage based on an understanding of pathogenesis will be available for many years, more research is required into mechanisms of pain and its control while a more fundamental therapy is developed.

SUMMARY— Progress in the understanding of why the diabetic nerve is so badly damaged will depend on studies in human subjects, because the detailed understanding of mechanisms has not been usefully advanced by animal studies. This will require the development of more sophisticated techniques for the assessment of nerve fibers (particularly small nerve fibers) and the noninvasive imaging of peripheral nerve.

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From the Department of Diabetic Medicine, Royal Hallamshire Hospital, Sheffield, U.K.

Address correspondence and reprint requests to John Dale Ward, MD, FRCP, Department of Diabetic Medicine, Floor P, Royal Hallamshire Hospital, Sheffield S10 2JF, U.K.

Received for publication 23 June 1998 and accepted in revised form 20 August 1998.

Abbreviations: CV, conduction velocity.

This article is based on a presentation at a satellite symposium of the 16th International Diabetes Federation Congress. The symposium and the publication of this article were made possible by educational grants from Hoechst Marion Roussel AG.

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