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PubMedDate not supplied

The epidemiology of diabetic neuropathy. Diabetic Cardiovascular Autonomic Neuropathy Multicenter Study Group.

Although neuropathy has long been recognized as a complication of diabetes, the impact of this condition has not been adequately established. The prevalence of diabetic neuropathy is virtually unknown because the published studies differ considerably with regard to definition, method of assessment, and patient selection. Furthermore, the determination of prevalence has been hampered by the fact that there is no generally accepted classification of the variety of manifestations of diabetic neuropathy. The introduction of new sensitive diagnostic methods aids in the detection of less severe stages of neuropathy, as compared with clinically based assessment, and renders the disease more prevalent. The prevalence of diabetic neuropathy in the few reported population-based studies was approximately 30%. We have evaluated the prevalence of cardiovascular autonomic neuropathy in a group of approximately 1000 diabetic patients randomly included from 21 hospitals in Germany, Austria, and Switzerland. The results of this study and those of a prospective study on the natural history of neural dysfunction during the first 5 years after diagnosis of type 1 diabetes will be presented.

Adolescent↗
PubMed2000

Distinctive pathologic findings in proximal diabetic neuropathy (diabetic amyotrophy).

OBJECTIVE: To investigate the pathogenesis of proximal diabetic neuropathy (PDN) with nerve and muscle biopsies. BACKGROUND: Recent evidence suggests that nerve ischemia secondary to immune-mediated vasculopathy rather than diabetic microangiopathy may be responsible for PDN. METHOD: - Fifteen patients with PDN and two diabetic controls underwent nerve and muscle biopsy and clinical, electrophysiologic, and laboratory evaluation. There were eight men and seven women between 49 and 79 years of age with type II diabetes. All had progressive, painful, asymmetric, proximal weakness with duration of 5 weeks to 12 months. None had evidence of systemic autoimmune disorder. RESULTS: Four patients showed the distinctive findings of polymorphonuclear small-vessel vasculitis affecting epineurial vessels with transmural infiltration of postcapillary venules with polymorphonuclear leukocytes. Immunoglobulin M (IgM) deposits were found along the endothelium and intramurally in affected vessels. IgM staining was seen in the subperineurial space and in the endoneurium. Activated complement deposition was seen along endothelium of small vessels. Three of these four patients were evaluated within 6 seeks of onset of PDN, and the fourth patient during acute flare of PDN 6 months after the initial onset. Six patients showed "perivasculitis" with mononuclear cell infiltrates around small epineurial vessels without vasculitis (fibrinoid necrosis or transmural inflammation). One patient showed recanalized vessels with transmural lymphocytes without fibrinoid necrosis, possibly suggesting healed vasculitis. CONCLUSION: These distinctive pathologic findings support that proximal diabetic neuropathy has an immune-mediated inflammatory basis and suggest that polymorphonuclear vasculitis with immune complex and complement deposition may be the primary event in the acute phase of proximal diabetic neuropathy.

Aged↗
PubMed2005

Evaluation and prevention of diabetic neuropathy.

Diabetic neuropathy is a debilitating disorder that occurs in nearly 50 percent of patients with diabetes. It is a late finding in type 1 diabetes but can be an early finding in type 2 diabetes. The primary types of diabetic neuropathy are sensorimotor and autonomic. Patients may present with only one type of diabetic neuropathy or may develop combinations of neuropathies (e.g., distal symmetric polyneuropathy and autonomic neuropathy). Distal symmetric polyneuropathy is the most common form of diabetic neuropathy. Diabetic neuropathy also can cause motor deficits, silent cardiac ischemia, orthostatic hypotension, vasomotor instability, hyperhidrosis, gastroparesis, bladder dysfunction, and sexual dysfunction. Strict glycemic control and good daily foot care are key to preventing complications of diabetic neuropathy.

Diabetic Neuropathies↗
PubMed2000

Diabetic neuropathies.

Diabetic neuropathy is a common complication of diabetes that is often associated both with considerable morbidity and mortality. The epidemiology and natural course of diabetic neuropathy is clouded with uncertainty, largely due to 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 have opened up new avenues of investigation for therapeutic intervention. Paralleling our increased understanding of the pathogenesis of diabetic neuropathy, there must be refinements in our ability to measure quantitatively the different types of defects that occur in this disorder, so that appropriate therapies can be targeted to specific fibre types. These tests must be validated and standardised to allow comparability between studies and a more meaningful interpretation of study results. Our ability to manage successfully the many different manifestations of diabetic neuropathy depends ultimately on our success in uncovering the pathogenic processes underlying this disorder.

Aldehyde Reductase↗
PubMed1988

Pathogenesis and prevention of diabetic neuropathy.

Diabetic neuropathy, long-recognized as an important but complex and poorly understood clinical complication of diabetes, is finally yielding to more than a decade of intense clinical and laboratory investigation. At least one basic biochemical mechanism involving sorbitol and MI metabolism, phosphoinositides, protein kinase C, and the (Na,K)-ATPase has been identified that can rationally account for the neurotoxicity of glucose. This biochemical sequence has been examined in some detail in vitro, but some of its elements, such as the link between abnormal sorbitol and MI metabolism, and between protein kinase C and the (Na,K)-ATPase, remain the subject of ongoing investigation. Through its effect on the (Na,K)-ATPase, this metabolic sequence can explain both the rapidly-reversible functional impairment and the early structural lesions of nerve fibers, such as paranodal swelling in acute diabetes. Extrapolation of early paranodal swelling to the more advanced stages of nerve fiber damage remains somewhat speculative, although axo-glial dysjunction is a likely intermediate step. Impaired axonal transport or microvascular dysfunction may be additional contributing factors, possibly also related to abnormal sorbitol and MI metabolism. Blunted phosphoinositide-mediated signal transduction could potentially explain a putative insensitivity to neurotrophic factors and a diminished regenerative response in diabetic neuropathy. Human morphometric studies and ARI trials support the relevance of these pathogenetic processes to human diabetic neuropathy, and suggest that specific metabolic therapy with agents such as ARIs hold promise as important new elements in the treatment and possibly prevention of diabetic neuropathy.

Diabetic Neuropathies↗
PubMed1999

Treatment options in painful diabetic neuropathy.

Diabetic neuropathy is common in patients with diabetes mellitus, and 7.5% of diabetics experience pain from diabetic neuropathy. Complications of diabetes mellitus are more common where control of the disease is not optimal. By improving the control of the disease, both the neuropathy and the pain it can produce may be improved. The pain of diabetic neuropathy can frequently be controlled using analgesics, antidepressants, anticonvulsants, topical capsaicin, and neuromodulation, either alone or in any combination.

Analgesics↗
PubMed2005

Therapeutic neovascularization using cord blood-derived endothelial progenitor cells for diabetic neuropathy.

Diabetic neuropathy is based on the impairment of nerve blood flow and the metabolic disorder. Although the vasodilating agents and anticoagulants improve nerve function and symptoms in diabetic neuropathy, more effective treatments are needed. Because endothelial progenitor cells (EPCs) have been identified in adult human peripheral blood, many studies have shown that transplantation of EPCs improves circulation to ischemic tissues. In this study, we have demonstrated that therapeutic neovascularization using human umbilical cord blood-derived EPCs reversed diabetic neuropathy. EPCs were isolated and expanded on day 7 of culture from cord blood mononuclear cells. Unilateral intramuscular injection of EPCs into hindlimb skeletal muscles significantly ameliorated impaired sciatic motor nerve conduction velocity and sciatic nerve blood flow in the EPC-injected side of streptozotocin-induced diabetic nude rats compared with the saline-injected side of diabetic nude rats. Histological study revealed an increased number of microvessels in hindlimb skeletal muscles in the EPC-injected side of diabetic rats. These findings suggest that transplantation of EPCs from cord blood may be a useful treatment for diabetic neuropathy.

Animals↗
PubMed2002

Preventing foot ulceration and amputation by decompressing peripheral nerves in patients with diabetic neuropathy.

Diabetic neuropathy occurs in a stocking and glove distribution, consistent with a systemic metabolic disease. As a result, it is commonly believed that no surgical options are available for this debilitating condition. The classic medical approach to the treatment of diabetic neuropathy consists of attempts to achieve a euglycemic state, obtain regular podiatric care of the feet, inspect the feet for the presence of deformities or ulcers, and help achieve pain control through the use of medication. Unfortunately, all too often this approach is not successful in relieving the patient's pain, and the loss of sensation provides the basis for deformity, ulceration, infection, and amputation. However, scientific and clinical research data support the statement that "today it is possible to restore sensation and relieve pain in 80% of patients with symptoms of diabetic neuropathy by decompression of multiple peripheral nerves." Furthermore, long-term follow-up has shown that no one who has had sensation restored with this procedure has developed an ulcer. These findings change the natural sequelae of diabetic neuropathy.

Carpal Tunnel Syndrome↗
PubMed2003

Current and future strategies for the management of diabetic neuropathy.

Diabetic neuropathy is common, related to increased morbidity and mortality, and has no effective treatment at present. Interventions based on putative pathways thought to contribute to damage and repair of nerve fibres have yielded little success to date. Pain is a potentially debilitating manifestation of diabetic neuropathy and has many potential sites of origin and, hence, modulation. Its cause is unclear and it does not respond well to traditional pain therapies, proposed to mediate their benefits via multiple peripheral and central mechanisms. A better understanding of the mechanisms leading to nerve fibre degeneration and regeneration as well as pain has recently resulted in the development of a more targeted approach to the treatment of diabetic neuropathy. Thus, specific NMDA receptor antagonists and more specific neuronal serotonin and norepinephrine (noradrenaline) uptake inhibitors offer promise in the treatment of painful diabetic neuropathy. A number of treatments which include the aldose reductase inhibitors and neurotrophins have failed to reach the clinical arena. However, the antioxidant alpha-lipoic acid, as well as compounds which correct vascular dysfunction and hence neuropathy, such as ACE inhibitors and protein kinase C-beta inhibitors, have demonstrated more success.

Diabetic Neuropathies↗
PubMed1988

Clinical aspects of diabetic neuropathies.

Diabetic neuropathy is a common complication of diabetes that may be associated both with considerable morbidity (painful polyneuropathy, neuropathic ulceration) and mortality (autonomic neuropathy). The epidemiology and natural history of diabetic neuropathy is clouded with uncertainty, largely due to confusion in the definition and measurement of this disorder. We have reviewed a variety of the clinical manifestations associated with somatic and autonomic neuropathy and discussed current views related to the management of the different abnormalities. Although unproven, the best evidence suggests that near normal control of blood glucose in the early years following onset of diabetes may help delay the development of clinically significant nerve impairment. Intensive therapy to achieve normalization of blood glucose may also lead to reversibility of early diabetic neuropathy, but again this is unproven. Our ability to manage successfully the many different manifestations of diabetic neuropathy depends ultimately on our success in uncovering the pathogenic processes underlying this disorder. The recent resurgence of interest in the vascular hypothesis, for example, has opened up new avenues of investigation for therapeutic intervention. Paralleling our increased understanding of the pathogenesis of diabetic neuropathy, there must be refinements in our ability to measure quantitatively the different types of defects that occur in this disorder. These tests must be validated and standardized to allow comparability between studies and more meaningful interpretation of study results.

Diabetes Mellitus, Type 1↗
PubMed1992

Diabetic neuropathies.

Diabetic neuropathy is a common complication of diabetes that may be associated both with considerable morbidity (painful polyneuropathy, neuropathic ulceration) and mortality (autonomic neuropathy). The epidemiology and natural history of diabetic neuropathy is clouded with uncertainty, largely caused by confusion in the definition and measurement of this disorder. We have reviewed various clinical manifestations associated with somatic and autonomic neuropathy, and we herein discuss current views related to the management of the various abnormalities. Although unproven, the best evidence suggests that near-normal control of blood glucose in the early years after diabetes onset may help delay the development of clinically significant nerve impairment. Intensive therapy to achieve normalization of blood glucose also may lead to reversibility of early diabetic neuropathy, but again, this is unproven. Our ability to manage successfully the many different manifestations of diabetic neuropathy depends ultimately on our success in uncovering the pathogenic processes underlying this disorder. The recent resurgence of interest in the vascular hypothesis, for example, has opened up new avenues of investigation for therapeutic intervention. Paralleling our increased understanding of the pathogenesis of diabetic neuropathy, refinements must be made in our ability to measure quantitatively the different types of defects that occur in this disorder. These tests must be validated and standardized to allow comparability between studies and more meaningful interpretation of study results.

Diabetes Mellitus↗
PubMed2001

Therapeutic potential of PKC inhibitors in painful diabetic neuropathy.

Diabetic neuropathy accompanied by anomalies in pain perception is one of the most frequent complications in insulin-dependent diabetes in humans. Many clinical and experimental studies have suggested that diabetes or hyperglycaemia alters pain sensitivity. In humans, diabetic neuropathy can be associated with burning, tactile hypersensitivity. Behavioural reactions of hyperalgesia in animal models of diabetes have been described. However, the aetiology of these disturbances is still unknown, although metabolic factors such as hyperglycaemia or neurotransmitter alteration may be involved. Activation of protein kinase C (PKC) has been implicated in changes in pain perception. Phorbol esters, which activate PKC, enhance the thermal hyperalgesia in diabetic mice and enhance nociceptive responses after tissue injury induced by formalin. Electrophysiological experiments have shown that activation of PKC leads to long-lasting enhancement of excitatory amino acid-mediated currents in dorsal horn neurones and trigeminal neurones. Thus, activation of PKC may underlie the neuronal sensitisation that produces hyperalgesia in diabetic neuropathy.

Animals↗
PubMed2006

Diabetic neuropathy.

Diabetic neuropathy (DN) refers to symptoms and signs of neuropathy in a patient with diabetes in whom other causes of neuropathy have been excluded. Distal symmetrical neuropathy is the commonest accounting for 75% DN. Asymmetrical neuropathies may involve cranial nerves, thoracic or limb nerves; are of acute onset resulting from ischaemic infarction of vasa nervosa. Asymmetric neuropathies in diabetic patients should be investigated for entrapment neuropathy. Diabetic amyotrophy, initially considered to result from metabolic changes, and later ischaemia, is now attributed to immunological changes. For diagnosis of DN, symptoms, signs, quantitative sensory testing, nerve conduction study, and autonomic testing are used; and two of these five are recommended for clinical diagnosis. Management of DN includes control of hyperglycaemia, other cardiovascular risk factors; alpha lipoic acid and L carnitine. For neuropathic pain, analgesics, non-steroidal anti-inflammatory drugs, antidepressants, and anticonvulsants are recommended. The treatment of autonomic neuropathy is symptomatic.

Aldehyde Reductase↗
PubMed2005

Role of advanced glycation end products and their receptors in development of diabetic neuropathy.

Diabetic neuropathy is a life-threatening complication involving both peripheral and autonomic nerves. The hyperglycemia-induced polyol pathway as well as enhanced oxidative stress are among the factors implicated in the pathogenesis of diabetic neuropathy. Their effects are possibly exerted by direct nerve tissue damage or mediated by endothelial injury or vascular dysfunction. Formation of advanced glycation end product (AGE) is another important candidate for the cause of peripheral neuropathy. Indeed, the levels of AGEs were increased in the serum and also in the peripheral nerves obtained from diabetic patients. Structural and functional proteins of those nerves are also glycated, resulting in impaired nerve function and characteristic pathologic alterations. In addition, interaction between AGEs and their receptors induce biological effects on the target tissues for diabetic complications. In the peripheral nerve, the receptor for AGE (RAGE) is expressed in endothelial and Schwann cells. It is thus anticipated that interactions between AGEs and RAGE facilitate endoneural vascular dysfunction, leading to microangiopathy in the peripheral nerve. The roles of these mechanisms, in particular on the molecular mechanisms of AGE-RAGE interactions in the development of diabetic neuropathy are largely still speculative and yet to be explored.

Animals↗
PubMed2004

Modulatory effect of the PDE-5 inhibitor sildenafil in diabetic neuropathy.

Diabetic neuropathy is one of the most frequent peripheral neuropathies associated with hyperalgesia and hyperesthesia. Besides alteration in the levels of neurotransmitter, alteration in the neuronal nitric oxide synthase (nNOS) is a key factor in the pathogenesis of diabetic neuropathy. The present study was aimed at evaluating the role of PDE-5 inhibitor on nociception in streptozotocin-induced diabetes in animal models of nociception (writhing assay in mice and paw hyperalgesia test in rats). Diabetic animals showed a significant decrease in pain threshold as compared to non-diabetic animals in both tests, indicating diabetes induced hyperalgesia in mice and rats. The PDE-5 inhibitor, sildenafil, significantly increased the pain threshold in both diabetic and non-diabetic animals. However, L-NAME, a non-specific NOS inhibitor and methylene blue (MB), a guanylate cyclase inhibitor blocked the antinociceptive effect. The per se administration of L-NAME or MB augmented the hyperalgesic response in diabetic animals with little or no effect in non-diabetic animals, indicating the alteration of NO-cGMP pathway in diabetes. The results in the present study demonstrate that the decreased nNOS-cGMP system may play a crucial role in the pathogenesis of diabetic neuropathy.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

Diabetic neuropathies.

Diabetes mellitus is a systemic disorder with a significant impact on the peripheral nervous system. Over half of the 15 million patients with diabetes mellitus in the United States have some form of diabetic neuropathy. Individuals with diabetes may develop acute or subacute painful polyneuropathy, proximal motor neuropathy, autonomic neuropathy, compression neuropathy, focal neuropathy, and chronic polyneuropathy. Studies have shown that optimizing diabetic control provides the greatest likelihood of either preventing or slowing the development of diabetic neuropathy.

Diabetic Neuropathies↗
PubMed2003

Hyperosmolar solutions selectively block action potentials in rat myelinated sensory fibers: implications for diabetic neuropathy.

Diabetic neuropathy is a common complication of diabetes mellitus patients. It is a wide range of abnormalities affecting proximal and distal peripheral sensory and motor nerves. Although plasma hyperosmolality is a common finding in diabetes mellitus, the effects of hyperosmolality on conduction of various sensory signal components have not been addressed in detail. Here we show that in rat dorsal root ganglion (DRG) preparations from normal rats, hyperosmolar solutions (360 mmol/kg, containing increased glucose, sucrose, NaCl, or mannitol) produce a selective block of signal propagation in myelinated sensory A-fibers. In compound action potential (CAP) recordings with suction electrodes, peak A-fiber CAP amplitude was selectively decreased (20%), while the C-fiber peak remained intact or was slightly increased. Hyperosmolar solutions had smaller effects on conduction velocity (CV) of both A- and C-fibers (approximately 5% decrease). Hyperosmolality-induced CAP changes could not be observed during recordings from isolated spinal nerves but were evident during recordings from desheathed spinal nerves. In intracellular recordings, hyperosmolar solutions produced a block of spinal nerve-evoked action potential invasion into the somata of some A-fiber neurons. Removal of extracellular calcium completely prevented the hyperosmolality-induced CAP decreases. Based on these data, we propose that the decreased CAP amplitudes recorded in human patients and in animal models of diabetes are in part due to the effects of hyperosmolality and would depend on the extracellular osmolality at the time of sensory testing. We also hypothesize that hyperosmolality may contribute to both the sensory abnormalities (paresthesias) and the chronic pain symptoms of diabetic neuropathy.

Action Potentials↗