Pathology and pathogenetic mechanisms of diabetic neuropathy: Correlation with clinical signs and symptoms

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Abstract

Drastic increase in diabetic patients poses serious problems in the care of neuropathy so that there needs to explore the pathogenesis and to establish the effective treatment. Recent clinical and basic studies revealed characteristic pathophysiology of diabetic neuropathy and some clue to the direction of the treatment. The pathology of diabetic neuropathy is characterized by progressive nerve fiber loss that gives rise to positive and negative clinical signs and symptoms such as pain, paresthesia and loss of sensation. The nerve fiber loss takes the form of pan-modal pattern with proximo-distal gradient. Endoneurial microangiopathic change is also a constant feature of peripheral nerve pathology and negatively correlates with nerve fiber density. The vascular change and distal nerve fiber loss of small caliber, in particular, at the site of epidermis, commence even in subjects with impaired glucose tolerance and precede loss of nerve fibers in the nerve trunk of lower extremities. Pathogenetic mechanisms underlying the progressive nerve fiber loss seem to be multifactorial, including polyol pathway, glycation, reactive oxygen species, and altered protein kinase C activity. Clinical trials based on this background confirmed that fundamental treatment is in fact beneficial for the prevention and halting of this intractable disorder.

Introduction

Functional and structural impairments of peripheral nervous system are generally defined as diabetic neuropathy and its diagnosis is based on the exclusion of other diseases that may involve nervous system [1]. In fact, diabetic neuropathy is the most common complication of diabetes reaching 45–50% prevalence compared to 25–30% of retinopathy and 20% of nephropathy [2]. Recent advances in clinical evaluation and pathological studies on diabetic neuropathy revealed systematic changes of peripheral nervous systems. Signs and clinical symptoms can mostly be attributed to functional and structural alterations detected in peripheral nerves and many studies on experimental diabetic animal models have explored the pathogenetic mechanisms of this disorder [3], [4], [5]. In this communication, pathological background of diabetic neuropathy and underlying mechanisms at the molecular levels are briefly summarized. Recent results of clinical trials targeted for the pathogenetic factors are also introduced.

Section snippets

Pathological background and its clinical relevance

Most pathological studies to date on diabetic neuropathy were conducted on autopsy materials or biopsied samples of sural nerve obtained from diabetic patients with established neuropathy. From these systematic studies, it is well established that peripheral nerve pathology in diabetic patients is characterized by progressive nerve fiber loss with pan-modal fiber size pattern [3], [6] (Fig. 1). In particular, the nerve fiber degeneration is length-dependent and conspicuous in distal portion. It

Neuropathy in IGT

There are several lines of evidence that showed the presence of neurological involvement at the stage of IGT. The symptoms are the type of small fiber neuropathy pathologically characterized by loss of intradermal nerve fibers [8], [9]. The suggestion of an early presence of neuropathy in IGT is also supported by the Japanese epidemiological survey of IGT patients that showed high prevalence of subjects with loss of Achilles tendon reflex, reduced vibration perception threshold, or even reduced

Pathogenesis of neuropathy

As alluded earlier, it is essential to prevent or halt the development of diabetic neuropathy based on the information about the pathogenesis. Long term hyperglycemia elicits enhanced polyol pathway, increased nonenzymatic glycation of structural proteins, increased oxidative stress as well as altered protein kinase C activity and polyADP-ribose polymerase (PARP) activation that are all interrelated for the cause and development of neuropathy [3], [4], [5] (Fig. 3). These in turn activate or

Role of polyol pathway

Polyol pathway is a simple metabolic pathway converting glucose to sorbitol by enzyme of aldose reductase (AR), then converting sorbitol to fructose by sorbitol dehydrogenase (SDH). Under normoglycemic condition, glucose is metabolized to oxidative glycolytic pathway with phosphorylated oxidation through mitochondria. They produce ATP energy by citric acid cycle. Under hyperglycemia, excessive glucose is converted to sorbitol by AR. During this process, NADPH is consumed as a coenzyme.

Results from studies on AR-transgenic animals

To explore detailed mechanisms how polyol pathway is involved in diabetic neuropathy and to develop specific inhibitors for human AR, transgenic mouse model overexpressing human AR is now available. Under galactose load, this model exhibits significant delay of motor nerve conduction velocity and nerve fiber atrophy with tissue accumulation of polyol (galactitol). In this setting, neither blood glucose levels nor insulin levels are altered. Hyperactivity of polyol pathway indeed causes

Results from clinical trials

For the treatment of diabetic neuropathy, two basic directions may be raised; one for the symptomatic treatment for signs and symptoms that the patients complain, another for the fundamental treatment based on the pathogenetic mechanisms. Symptomatic treatment may not be effective for the prevention or halting of the disease but should be good for pain or to alleviate other subjective symptoms, while fundamental treatment may not be effective to relieve the symptoms but able to halt or inhibit

Concluding remarks

Recent studies demonstrated that neuropathy is treatable and preventable disease and early diagnosis is essential for this condition. To this end, exploration of pathogenesis of diabetic complications is most important, and such efforts will eventually lead to better outcome in diabetic patients in long-run.

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