Diabetic painful and insensate neuropathy: Pathogenesis and potential treatments

Advanced peripheral diabetic neuropathy (PDN) is associated with elevated vibration and thermal perception thresholds that progress to sensory loss and degeneration of all fiber types in peripheral nerve. A considerable proportion of diabetic patients also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain. One or several manifestations of abnormal sensation and pain are described in all the diabetic rat and mouse models studied so far (i.e., streptozotocin-diabetic rats and mice, type 1 insulinopenic BB/Wor and type 2 hyperinsulinemic diabetic BBZDR/Wor rats, Zucker diabetic fatty rats, and nonobese diabetic, Akita, leptin- and leptin-receptor-deficient, and high-fat diet—fed mice). Such manifestations are 1) thermal hyperalgesia, an equivalent of a clinical phenomenon described in early PDN; 2) thermal hypoalgesia, typically present in advanced PDN; 3) mechanical hyperalgesia, an equivalent of pain on pressure in early PDN; 4) mechanical hypoalgesia, an equivalent to the loss of sensitivity to mechanical noxious stimuli in advanced PDN; 5) tactile allodynia, a painful perception of a light touch; and 5) formalin-induced hyperalgesia. Rats with short-term diabetes develop painful neuropathy, whereas those with longer-term diabetes and diabetic mice typically display manifestations of both painful and insensate neuropathy, or insensate neuropathy only. Animal studies using pharmacological and genetic approaches revealed important roles of increased aldose reductase, protein kinase C, and poly(ADP-ribose) polymerase activities, advanced glycation end-products and their receptors, oxidative-nitrosative stress, growth factor imbalances, and C-peptide deficiency in both painful and insensate neuropathy. This review describes recent achievements in studying the pathogenesis of diabetic neuropathic pain and sensory disorders in diabetic animal models and developing potential pathogenetic treatments.     

Diabetic neuropathy

Diabetic neuropathy is not a single entity but manifests as several different clinical syndromes. It is likely that different pathophysiological mechanisms contribute to the development of the neuropathy, including metabolic alterations, microvascular changes, and inflammatory changes. A summary of the underlying pathophysiological mechanisms and clinical aspects of different diabetic neuropathies are outlined in this article.     

Diabetic neuropathy

Peripheral nerve disorders are important late complications of diabetes mellitus. Polyneuropathy, which may involve varying proportions of sensory, motor, and autonomic fibers, is considered the consequence of metabolic derangements that result from chronic hyperglycemia. Symmetrical proximal motor neuropathy ("diabetic amyotrophy") also may have a metabolic basis. Mononeuropathies in diabetes may have an ischemic or compressive cause. Advances have been made in understanding the biochemical basis for diabetic polyneuropathy. The treatment of symptomatic diabetic neuropathy should be directed toward long-term normalization of blood glucose until more specific therapies become available.     

Diabetic neuropathy: An update

Diabetic neuropathy is the most common neuropathy in industrialized countries, with a remarkable range of clinical manifestations. The usual pattern is a distal symmetrical sensory polyneuropathy, associated with autonomic disturbances. Less often, diabetes is responsible for a focal or multifocal neuropathy affecting cranial nerves, especially oculomotor nerves, and roots and nerves innervating proximal muscles of the lower limbs. Metabolic abnormalities due to hyperglycaemia, lack of insulin and their consequences and ischaemic phenomena secondary to diabetic microangiopathy account for nerve lesions.     

Diabetic autonomic neuropathy

Diabetic autonomic neuropathy is the most frequent autonomic neuropathy in western countries. Diabetic autonomic neuropathy affects almost every organ. Among the most common symptoms are cardiovascular disturbances such as reduced heart rate variability and pathologic orthostatic reaction. The diagnosis of diabetic autonomic neuropathy is mainly based on the analysis of cardiovascular challenge maneuvers. The following article describes epidemiology, clinical findings, diagnosis, pathogenesis, therapeutic options and prognosis in diabetic autonomic neuropathy.     

Diabetic autonomic neuropathy

Diabetic autonomic neuropathy is the most common and troublesome complication of diabetes mellitus. Although involvement of the autonomic nervous system is generally diffuse, symptoms may be confined to a single target organ or organ system. Complications of diabetic autonomic neuropathy contribute greatly to the morbidity, mortality, and reduced quality of life of the person with diabetes and are the major source of increased costs of caring for the diabetic patient. Factors in the pathogenesis of these complications are altered metabolism, vascular insufficiency, loss of growth factor trophism, and autoimmune destruction of nerves in a visceral and cutaneous distribution. The clinical manifestations and the complications of diabetic autonomic neuropathy are reviewed. Future therapeutic strategies that are developed from a better understanding of the pathogenetic processes underlying this disorder can be directed at the cause rather than the manifestations. There are studies in progress that suggest that autonomic nerves can be induced to regenerate, and the future for patients with diabetic autonomic neuropathy is brighter.     

糖尿病周围神经病的研究进展

糖尿病（DM）是累及全身多系统和器官的最常见的慢性疾病之一，全世界有l亿多DM患者。“DM如果没有并发症，将不再是重大的健康问题”，这一观点已是不同学科医生的共识。DM神经病通常指伴有DM的各种周围神经病，其中远端对称性感觉运动性多发性周围神经病最常见，几乎占47％～91％，大多数报道在60％左右。近年来随着对DM并发症的重视和诊断技术的发展，人们除了对DM痛性神经病和自主神经病越来越重视以外，还提出了DM前或糖耐量异常周围神经病和胰岛素介导的周围神经病。     

Diabetic somatic polyneuropathy. Pathogenesis, clinical manifestations and therapeutic concepts

Diabetic polyneuropathy is the most frequent neuropathy in western countries. In Germany, there are 3.5 to 4 million diabetic patients. Diagnosis should rule out other polyneuropathies and assess two out of the five diagnostic criteria: neuropathic symptoms, neuropathic deficits, pathological nerve conduction studies, pathological quantitative sensory testing and pathological quantitative autonomic testing. So far, the pathophysiology of diabetic neuropathy remains to be fully understood. Among the various pathophysiological concepts are the Sorbitol-Myo-Inositol hypothesis attributing Myo-Inositol depletion to the accumulation of Sorbitol and Fructose, the concept of deficiency of essential fatty acids with reduced availability of gamma-linolenic-acid and prostanoids, the pseudohypoxia- and hypoxia-hypothesis attributing endothelial and axonal dysfunction and structural lesions to increased oxidative stress and free radical production. Obviously, the hyperglycemia induced generation of advanced glycation end products (AGEs) also contributes to structural dysfunctions and lesions. Elevated levels of circulating immune complexes and activated T-lymphocytes as well the identification of autoantibodies against vagus nerve or sympathetic ganglia support the concept of an immune mediated neuropathy. The reduction of neurotrophic factors such as nerve growth factor, neurotrophin-3 or insulin-like growth factors also seems to further diabetic neuropathy. The symmetrical, distally pronounced and predominantly sensory neuropathy is far more frequent than the symmetrical neuropathy with predominant motor weakness or the asymmetrical neuropathy. The painless neuropathy manifests with impaired light touch sensation, position sense, vibratory perception and diminished or absent ankle deep tendon reflexes. The painful sensory diabetic neuropathy primarily affects small nerve fibers and accounts for decreased temperature perception and paresthesias. The proximal, diabetic amyotrophy evolves subacutely or acutely, induces motor weakness of the proximal thigh and buttock muscles and is painful. Cranial nerve III-neuropathy is also painful and has an acute onset. Truncal radiculopathy follows the distribution of truncal roots and frequently causes intense pain. Autonomic neuropathy occurs with and without somatic neuropathy. The most important therapy is to attempt optimal blood glucose control, to reduce body weight and hyperlipidemia. Symptomatic therapy includes alpha-lipoic acid treatment, as the antioxidant seems to improve neuropathic symptoms. Aldose reductase inhibitors might reduce sorbitol and fructose production and normalize myo-inositol levels. However, there are no aldose reductase inhibitors available in Europe as yet. Evening primrose oil, containing gamma-linolenic acid, might improve nerve conduction velocities, temperature perception, muscle strength, tendon reflexes and sensory function. Substitution of nerve growth factor showed promising results in pilot studies but failed in a large-scale multicenter study. Symptomatic pain treatment can be achieved with tricyclic antidepressants, selective serotonin reuptake inhibitors, anticonvulsants such as carbamazepine, gabapentin or lamotrigine, or anti-arrhythmic drugs such as mexiletine. Topical capsaicin application should reduce neuropathic pain but also induces local discomfort in the beginning of therapy. Vasoactive substances, so far have not proven to be of major benefit in diabetic neuropathy. Physical therapy and thorough footcare are of primary importance and allow prevention of secondary complications such as foot amputations.     

Diabetic neuropathy and braille ability

Thirty-five individuals with visual impairment due to diabetic retinopathy underwent neurologic examination with special emphasis on two-point discrimination and nerve conduction studies to determine whether concomitant peripheral neuropathy would interfere with their ability to read braille. Twenty-two individuals with insulin-dependent diabetes mellitus (9 men and 13 women) and 13 with noninsulin-dependent diabetes mellitus (4 men and 9 women) were evaluated. All had peripheral neuropathy; there were 4 with stage 1, 29 with stage 2, and 2 with stage 3 neuropathy. Two-point discriminatory ability appeared to be relatively well-preserved and at least 25 of the 35 individuals were able to learn to read standard or jumbo braille. Individuals with abnormalities in two-point discrimination (greater than 5 mm) were found to have abnormalities in braille reading. Individuals with visual impairment due to diabetes should not be discouraged from undertaking braille on the basis of apparent polyneuropathy.     

Diabetic proximal neuropathy: Clinical and electromyographic studies

Clinical and electromyographic findings in 27 diabetics with proximal lower extremity weakness were analyzed. Two groups could be distinguished: patients in whom electromyographic findings were restricted to the clinically involved parts of the lower extremity (group A) and those in whom an associated distal symmetric, peripheral neuropathy could be proved on clinical and electromyographic grounds (group B). Patients in group B had significantly greater incidence of the following features: gradual onset of symptoms, bilateral proximal lower extremity weakness, insulin dependency, recent weight loss, EMG evidence of bilateral disease and paraspinal fibrillations. These findings concur with recent reports describing heterogeneity in the syndrome of “diabetic proximal neuropathy”.     

Diabetic thoracoabdominal neuropathy: Clinical and electrodiagnostic features

Five diabetic patients developed upper back or abdominal pain associated with substantial weight loss in three. Electrophysiological evidence of associated thoracoabdominal somatic neuropathy was found in all cases. Signs of a generalized neuropathy were present in two patients, and four had asymmetrical proximal leg weakness. At least two have improved spontaneously. The syndrome is closely related to diabetic amyotrophy; it is probably more common than is recognized.     

Diabetic neuropathy: models, mechanisms and mayhem.

Rational treatment of diabetic polyneuropathy depends upon establishing its cause, which is at present unknown. A number of animal models of diabetes have been examined and although abnormalities are detectable in the peripheral nervous system they do not duplicate the degenerative neuropathy encountered in the human. The relevance of these abnormalities is therefore uncertain, although they may reflect the earlier changes in man. For human neuropathy, it is likely that vascular lesions or an abnormal susceptibility to mechanical injury are responsible for focal neuropathies. The evidence that ischaemia and hypoxia are responsible for the diffuse sensory neuropathy and autonomic polyneuropathy is still equivocal and it is often difficult to establish whether the vascular changes are primary or secondary. Metabolic explanations, such as sorbitol accumulation in nerve, have not so far been adequately validated by responses to treatment. The manifestations of diabetic neuropathy are complex and a single explanation should not be sought.     

Diabetic neuropathy: cellular mechanisms as therapeutic targets

In patients with diabetes, nerve injury is a common complication that leads to chronic pain, numbness and substantial loss of quality of life. Good glycemic control can decrease the incidence of diabetic neuropathy, but more than half of all patients with diabetes still develop this complication. There is no approved treatment to prevent or halt diabetic neuropathy, and only symptomatic pain therapies, with variable efficacy, are available. New insights into the mechanisms leading to the development of diabetic neuropathy continue to point to systemic and cellular imbalances in metabolites of glucose and lipids. In the PNS, sensory neurons, Schwann cells and the microvascular endothelium are vulnerable to oxidative and inflammatory stress in the presence of these altered metabolic substrates. This Review discusses the emerging cellular mechanisms that are activated in the diabetic milieu of hyperglycemia, dyslipidemia and impaired insulin signaling. We highlight the pathways to cellular injury, thereby identifying promising therapeutic targets, including mitochondrial function and inflammation.     

Multifocal motor neuropathy: current concepts and controversies

Multifocal motor neuropathy (MMN) is now a well-defined purely motor multineuropathy characterized by the presence of multifocal partial motor conduction blocks (CB), frequent association with anti-GM1 IgM antibodies, and usually a good response to high-dose intravenous immunoglobulin (IVIg) therapy. However, several issues remain to be clarified in the diagnosis, pathogenesis, and therapy of this condition including its nosological position and its relation to other chronic dysimmune neuropathies; the degree of CB necessary for the diagnosis of MMN; the existence of an axonal form of MMN; the pathophysiological basis of CB; the pathogenetic role of antiganglioside antibodies; the mechanism of action of IVIg treatments in MMN and the most effective regimen; and the treatment to be used in unresponsive patients. These issues are addressed in this review of the main clinical, electrophysiological, immunological, and therapeutic features of this neuropathy.     

Diabetic peripheral neuropathy: An update on pathogenesis and management

Conclusions Diabetic peripheral neuropathy remains a major source of morbidity and mortality in patients with diabetes. It is foreseeable that an increasing understanding of the pathogenetic mechanisms will lead to effective treatment in the future. Currently, early detection of DPN is the only means of slowing the progression of this complication.     

Diabetic peripheral neuropathy: An update on pathogenesis and management

Conclusions  Diabetic peripheral neuropathy remains a major source of morbidity and mortality in patients with diabetes. It is foreseeable that an increasing understanding of the pathogenetic mechanisms will lead to effective treatment in the future. Currently, early detection of DPN is the only means of slowing the progression of this complication.