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PubMed1993

Relationship between myoinositol influx and lipids in diabetic neuropathy.

Diabetic neuropathy is associated with abnormalities in lipid metabolism and has been postulated to be associated with abnormal myoinositol metabolism. Leucocyte myoinositol influx was measured using a triple isotope method in long-standing type 1 (insulin-dependent) diabetic patients with and without diabetic neuropathy and in a group of matched controls. No differences in fasting lipid, glucose concentrations or glycated haemoglobin were found in the diabetic groups. Myoinositol influx was significantly but negatively correlated with the serum very low density lipoprotein (VLDL) cholesterol concentration in patients with and without neuropathy but not in the controls. The VLDL cholesterol concentration also correlated negatively with the transporter Km (Rs = -0.87, P < 0.005, neuropathic group only) and Vmax (Rs = -0.93, P < 0.001, neuropathic group; Rs = -0.59, P < 0.05, non-neuropathic group). Myoinositol influx correlated with the glycated haemoglobin only in the diabetic patients without neuropathy. The lipid relationships in diabetic subjects were independent of glucose control, which suggests that myoinositol influx mechanisms represent another transporter affected by intracellular lipid metabolism. The control of VLDL metabolism by fibrates could offer a method for reducing the progression of diabetic neuropathy.

Blood Glucose↗
PubMed1988

Peripheral diabetic neuropathy.

Diabetic neuropathy is a common complication of diabetes mellitus with significant morbidity and mortality. Hyperglycemia with its secondary metabolic, vascular, and enzymatic consequences is most likely to be the predominant cause. The clinical manifestations includes a wide range of somatic and autonomic syndromes. Painful diabetic neuropathy may require symptomatic treatment. The precise role of therapies such as continuous subcutaneous insulin therapy and aldose reductase inhibitors remains to be clarified.

Autonomic Nervous System Diseases↗
PubMed2004

Diabetic neuropathies.

Diabetic neuropathy (DN) is a common complication of diabetes that often is associated with considerable morbidity and mortality. The epidemiology and natural history of DN is clouded with uncertainty because of confusion regarding the definition and measurement of this disorder. The recent resurgence of interest in the vascular hypothesis, oxidative stress, the neurotrophic hypothesis,and the possibility of the role of autoimmunity has opened up new avenues of investigation for therapeutic intervention. The ability to manage successfully the many different manifestations of diabetic neuropathy depends ultimately on success in uncovering the pathogenic processes underlying this disorder.

Aldehyde Reductase↗
PubMed1996

Diabetic neuropathy.

Diabetic neuropathy affects up to 60 percent of the estimated 13 million Americans who have diabetes mellitus. Foot and ankle complications are responsible for more hospital admissions than all other complications of diabetes mellitus combined. Neuropathy is more likely to affect patients who have higher degrees of hyperglycemia and a longer history of diabetes, and those who are older, taller and male. Diabetic neuropathy is usually diagnosed by the loss of ankle reflexes and distal vibratory sensation, but these signs may not always be present. Electromyography is useful in establishing a diagnosis. Treatment is directed toward alleviating the symptoms and correcting the underlying pathogenesis. Strict glycemic control is key in the ultimate prevention of diabetic neuropathy. The family physician can play a significant role in preventing this complication by emphasizing the importance of strict glycemic control.

Diabetic Neuropathies↗
PubMed2003

New insights into the metabolic and molecular basis for diabetic neuropathy.

Diabetic polyneuropathy is the most common complication of diabetes mellitus. Several interactive pathogenetic mechanisms have been identified mainly in streptozotocin-induced diabetes in rats and have been ascribed to hyperglycemia. Over the last number of years it is becoming increasingly clear that diabetic neuropathy differs in type 1 and type 2 diabetes in humans and in murine models that more accurately mimic the human disorders. Beside hyperglycemia, attention is increasingly being paid to the pathogenetic roles of insulin and C-peptide deficiencies, particularly in type 1 diabetic neuropathy. There is now evidence to suggest that insulin and C-peptide deficiencies are mainly responsible for perturbations of neurotrophic factors and contribute to oxidative stress in diabetic nerve. This may also be true for apoptotic phenomena afflicting both the peripheral and central nervous systems in diabetes. The new data have lead to re-evaluations of pathogenetic components in this complex disorder, and their further exploration is likely to form a more refined basis for future therapeutic and preventive measures.

Animals↗
PubMedDate not supplied

The outpatient management of peripheral diabetic neuropathy.

Diabetic neuropathy is a common complication of diabetes. Its commonest form is the bilateral, distal sensorimotor neuropathy and this has been associated with increased risk of disability from foot ulceration, inadvertent injury leading to gangrene as well as to amputation. The economic implications of the treatment of diabetic neuropathy and its consequences are enormous. In spite of this, there is no universally accepted method of treating it and efforts are still underway to find an adequate form of therapy. The following is a review of the outpatient management of peripheral diabetic neuropathy.

Ambulatory Care↗
PubMed2005

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 Neuropathies↗
PubMed1992

Clinical observations and experiments in diabetic neuropathy.

Diabetic neuropathies form a group of diverse conditions, which can be distinguished between those which recover (acute painful neuropathies, radiculopathies, mononeuropathies) and those which progress (sensory and autonomic neuropathies). These two main groups can be distinguished in several ways: sensory and autonomic neuropathies are classic diabetic complications progressing gradually in patients with long-standing diabetes who often have other specific complications, while the reversible neuropathies do not have these features. The latter are characterised by their occurrence at any stage of diabetes, often at diagnosis, they may be precipitated on starting insulin treatment, and they are more common in men; they can occur at any age, though more often in older patients, and are unrelated to other diabetic complications. The two groups of neuropathies also show differences in nerve structural abnormalities and with regard to distinctive blood flow responses. The underlying mechanisms responsible for these very different forms of neuropathy remain speculative, but evidence for an immunological basis for the development of severe symptomatic autonomic neuropathy is presented.

Diabetic Neuropathies↗
PubMed2005

The fusion of bone-marrow-derived proinsulin-expressing cells with nerve cells underlies diabetic neuropathy.

Diabetic neuropathy is the most common microvascular complication of diabetes. Here we show that, in streptozotocin-induced diabetic rodents with neuropathy, a subpopulation of bone-marrow-derived cells marked by proinsulin expression migrates to and fuses with neurons in the sciatic nerve and dorsal root ganglion (DRG), resulting in neuronal dysfunction and accelerated apoptosis. The absence or presence of proinsulin expression, which identifies the fusion cells, and not the disease state (nondiabetic vs. diabetic) of the rats from which the DRG neurons are isolated determines whether the DRG neurons show normal or abnormal calcium homeostasis and apoptosis. These results suggest that bone-marrow-derived cells may play an important role in the pathogenesis of diabetic complications.

Animals↗
PubMed2004

Direct insulin signaling of neurons reverses diabetic neuropathy.

Diabetic polyneuropathy is the most common acquired diffuse disorder of the peripheral nervous system. It is generally assumed that insulin benefits human and experimental diabetic neuropathy indirectly by lowering glucose levels. Insulin also provides potent direct support of neurons and axons, and there is a possibility that abnormalities in direct insulin signaling on peripheral neurons relate to the development of this disorder. Here we report that direct neuronal (intrathecal) delivery of low doses of insulin (0.1-0.2 IU daily), insufficient to reduce glycemia or equimolar IGF-I but not intrathecal saline or subcutaneous insulin, improved and reversed slowing of motor and sensory conduction velocity in rats rendered diabetic using streptozotocin. Moreover, insulin and IGF-I similarly reversed atrophy in myelinated sensory axons in the sural nerve. That intrathecal insulin had the capability of signaling sensory neurons was confirmed by observing that fluorescein isothiocyanate-labeled insulin given intrathecally accessed and labeled individual lumbar dorsal root ganglion neurons. Moreover, we confirmed that such neurons express the insulin receptor, as previously suggested by Sugimoto et al. Finally, we sequestered intrathecal insulin in nondiabetic rats using an anti-insulin antibody. Conduction slowing and axonal atrophy resembling the changes in diabetes were generated by anti-insulin but not by an anti-rat albumin antibody infusion. Defective direct signaling of insulin on peripheral neurons through routes that include the cerebrospinal fluid may relate to the development of diabetic peripheral neuropathy.

Animals↗
PubMed1997

Pathogenesis of diabetic neuropathy.

Diabetes mellitus affects over 14 million people in the United States and the number of diabetics is increasing by 5% per year. Diabetic neuropathy (DN) is a common complication of diabetes and occurs in approximately 50% of diabetic patients over time. Clinical trials have proven that hyperglycemia almost certainly conditions the development of DN. Despite this fact, we still do not understand the mechanism(s) underlying DN. Several possible etiologies have been proposed including altered metabolism of polyol, lipids, or amino acids, vascular insufficiency, increased superoxide-induced free radical formation, impaired axonal transport or reduced neurotrophism. Accumulating evidence suggests that these defects are likely interrelated and that their interaction(s) within the diabetic milieu are responsible for the development and progression of DN. In this review we will discuss these theories, their interrelationships and how, collectively, these ideas may begin to explain the etiology of DN.

Diabetic Neuropathies↗
PubMed1996

[Clinical aspects, diagnosis and therapy of diabetic neuropathy].

Diabetic neuropathy is regarded as the most common form of neuropathy in the Western industrial countries. At least one third of the diabetic patients is affected by a clinically manifest peripheral neuropathy, which can be diagnosed by the clinical neurological examination without a great deal of effort. The involvement of the autonomic nervous system may be associated with an increased mortality. It may result in erectile impotence as well as severe physical disability from orthostatic hypotension, fecal incontinence or bladder dysfunction and life-threatening complications such as silent myocardial infarction or sudden death. Diabetic cardiovascular autonomic neuropathy is detected in more than 20% of the patients. The best possible glycaemic control including patient education is regarded as the most important therapeutic measure. However, additional drug treatment is frequently needed to maintain the patient's quality of life. It is usually effective in reducing symptoms of diabetic peripheral neuropathy. The therapeutic prospects depend not only on the treatment approach but also on the stage of the neuropathic process. Favourable effects can be expected particularly in terms of prevention and in the early stages of the disease. Treatment options based on the current pathogenetic concepts are restricted to clinical trials, except for the antioxidant mode of action. The efficacy of symptomatic treatment is limited for some drugs, and significant adverse reactions are common. Therefore, before any symptomatic drug treatment is initiated, its potential risk should be thoroughly weighed against its possible benefit.

Autonomic Nervous System Diseases↗
PubMed2004

Advances in diabetes for the millennium: new treatments for diabetic neuropathies.

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.

Diabetic Neuropathies↗
PubMed2006

Mechanisms of disease: mitochondria as new therapeutic targets in diabetic neuropathy.

Diabetic neuropathy (DN) is the most common complication of diabetes mellitus, and it imposes a considerable burden on a patient's quality of life and the health-care system. Despite the prevalence and severity of DN, there are no effective treatments. Pathogenetic evidence suggests that DN is marked by degeneration of dorsal root ganglion (DRG) neurons in peripheral nerves, and that DRG mitochondria are particularly affected. DRG mitochondria are especially vulnerable because they are the origin of reactive oxygen species production in the hyperglycemic neuron. Accumulating evidence indicates that neuronal mitochondria are subject to damage at the level of their DNA, and their outer and inner membranes, and also via deregulation of mitochondrial fission and fusion proteins that control mitochondrial shape and number. This Review will survey the mechanisms of mitochondrial degeneration in the pathogenesis of DN, highlighting potential mitochondrial sites for therapeutic intervention.

Animals↗
PubMed1986

Current aspects of research on the pathogenesis of diabetic neuropathy.

Diabetic neuropathy contributes to the long-term complications of diabetes mellitus. Its pathogenesis is still unknown although a host of abnormalities in peripheral nerves in human diabetics and animal models has been discovered. This article emphasizes the current metabolic hypotheses: increased polyol pathway, decreased myoinositol nerve content; altered phospholipid metabolism, decreased Na+/K+ ATPase activity and non-enzymatic glycosylation of proteins. Future perspectives relevant to animal and clinical research and new therapeutic aspects are also discussed.

Animals↗
PubMed2002

Inhibition of p38 MAP kinase corrects biochemical and neurological deficits in experimental diabetic neuropathy.

Diabetes is known to activate MAP kinase p38 in sensory neurons in both rats and patients. In vitro, activation of p38 in sensory neurons by combined glucose and oxidant stress causes cell damage or death. Consequently we tested the hypothesis that inhibition of MAP kinase p38 might prevent neuronal dysfunction in rats with experimental diabetes, such as the classical defect of slowed nerve conduction. Thus, treatment of streptozotocin-diabetic rats with the p38 inhibitor SB239063 for the second half of a 12-week diabetes protocol selectively prevented the nerve conduction deficit in sensory neurons. This implicates activation of MAP kinase p38 as an early step in the signal pathway to dysfunction in experimental diabetic neuropathy.

Animals↗
PubMed2002

[Systematic aspects and therapy of diabetic neuropathy].

Diabetic neuropathy (DN) is an important complication contributing to high morbidity and morbidity of diabetic subjects. Primarily, interventional strategies aim at normalization hyperglycemia (to prevent development and progression of DN), at early diagnosis and at prevention of ulcers and amputations. In addition, an increasing number of pharmaceutical agents is used to symptomatically treat dysesthesia and pain associated with DN. During recent years attempts have been made to pharmacologically treat DN by acting on underlying patho-physiological mechanisms (e.g. sorbitol pathway, non-enzymatic glycation, microvascular abnormalities). So far, these strategies have not changed clinical praxis. This review will give a systematic overview of DN and summarize current pharmacological options to symptomatically treat dysesthesia and pain associated with DN.

Combined Modality Therapy↗
PubMedDate not supplied

Can the BB-rat help to unravel diabetic neuropathy?

Diabetic neuropathy is probably the most common and one of the most disabling complications of diabetes mellitus. Although several possible pathogenetic mechanisms for this complication have been suggested, they cannot easily be tested in man. Therefore animal models with induced or spontaneous onset of diabetes mellitus have been used. The spontaneously diabetic BB-rat may provide a valuable model, since it displays both metabolic, functional and structural abnormalities of peripheral nerve similar to those present in humans. Based on systematic studies of these abnormalities in peripheral nerve in this model, inter-relationships between diabetic dysmetabolism, dysfunction and structural changes are starting to emerge. These findings are reviewed and a scheme of proven and proposed correlations which now can be tested in this animal model is presented.

Animals↗