References

Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycemic damage. Nature 2000 404 787-790. 2. Smith AG, Ramachandran P, Tripp S, Singleton JR. Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy. Neurology 2001 13 1701-1704. 3. Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003 60 108-111. 4....

Erectile Dysfunction

Erectile dysfunction (ED), defined as the consistent or recurrent inability of a man to attain and or maintain a penile erection sufficient for sexual activity (15), is one of the most common sexual dysfunctions in men. ED is more common with advancing age, and since the aged population will increase, its prevalence will continue to rise (16). Diabetes mellitus is the most frequent organic cause for ED, the onset of which starts about 15 years earlier in the diabetic than in the nondiabetic...

Diabetesinduced Neuropathology

While there are earlier reports of spinal cord lesions associated with diabetes mellitus (refs. 5-7), the publication of a series of key (8-12) and other (13-16) neuropathologi-cal studies in the latter half of the 20th century established the histological nature of this injury. These reports helped promote the concept that myelopathy is a part of the diabetic process and remain the definitive neuropathological studies. Unlike myelopathy, the existence of peripheral neuropathy and radiculopathy...

Treatment Of Painful Diabetic Neuropathy

Under this section the many different approaches to the management of symptoms in those with distal sensory neuropathy will be considered. First, the role of blood glucose control in the prevention and management of painful neuropathy will be discussed followed by a description of the various pharmacological treatments that have been proposed. This section will be divided into those purely symptomatic treatments and those symptoms that target the underlying pathogenesis of neuropathy and might...

Studies In Animals

Outside the field of diabetes research, animal models are widely used to explore the mechanisms of learning and memory. Although many questions remain unanswered, much progress has been made in identifying the cellular and molecular events that underlie the storage of information in specific brain areas. In this respect, the hippocampus, a structure in the medial temporal lobe, has attracted particular attention. Within the hippocampus, activity-dependent plastic changes in the strength of...

Clinical Approach To Complaints Of Cognitive Dysfunction In Diabetic Patients

The data that are reviewed in this chapter clearly show that diabetes is associated with changes in cerebral function and structure. However, it should be noted that the diagnosis diabetic encephalopathy cannot be readily established in individual patients. This is because of the fact that the changes in cognition and in brain structure, as observed on computed tomography or MRI, are not specific to diabetes. There is, for example, considerable overlap with functional and structural changes in...

Studies In Man Therapies

To date the only published studies that have evaluated the effects of different treatment modalities on cognition in type 1 diabetes, are the intensive insulin treatment trials (48,95). In these trials cognition was monitored primarily in order to detect possible unwanted side effects of an increased incidence of hypoglycemic episodes. Neither study detected a deterioration of cognitive function in relation to the occurrence of hypo-glycemic episodes, but they also failed to show an improvement...

Studies In Man Neuropathology And Brain Imaging

Up till two decades ago, studies on the structural basis of impaired cognition in man largely depended on neuropathology. Much has changed since the introduction of powerful neuroimaging techniques, such as computed tomography, and even more so Magnetic resonance imaging (MRI). Neuroimaging now plays a key role both in daily clinical practice and in cognition and dementia research. In patients suspected of dementia, MR in particular not only serves to exclude (rare) treatable causes of...

Studies In Man Cognition And Dementia

Studies into the effects of diabetes on cognitive functioning in man can be broadly divided in two categories case-control studies, which are mostly cross-sectional, and population-based surveys, which are often longitudinal. The case-control studies usually involved selected populations of patients and matched nondiabetic controls, using performance on a battery of neuropsychological tests as an outcome measure. Population-based surveys mostly involved elderly subjects, and used either...

Acute Nerve Ischemia

It is important when considering some types of neuropathy in diabetes to ask whether ischemia plays a role. Peripheral nerve trunks are resistant to acute ischemia in part because of their rich anastamotic vascular supply and their limited metabolic demands. Several models of experimental ischemic neuropathy have been developed ranging from multiple arterial ligation, embolization by microspheres or other agents, and the topical application of the potent vasoconstrictor endothelin (3,41-50)....

Patterns Of Anhidrosis In Diabetic Neuropathy

There are a number of patterns of anhidrosis in diabetic neuropathy. A full appreciation of these patterns requires the administration of the thermoregulatory sweat test, a method that is not under widespread clinical use. Several well characterized patterns are described. Perhaps, the most common pattern of anhidrosis is distal anhidrosis. The burning feet syndrome is perhaps the most common presentation of diabetic neuropathy. These patients have distal involvement with burning, prickling,...

Microangiopathy Diabetes And The Peripheral Nervous System Experimental Studies

Tuck and colleagues (22) initially reported that experimental diabetes of rats was associated with a decline of sciatic nerve blood flow and endoneurial hypoxia. Several other laboratories have reported similar findings and a variety of interventions have been reported to both correct nerve blood flow and diabetic electrophysiological abnormalities in tandem (see review 2 ). A large number of such studies through their findings have consequently implied that reductions in nerve blood flow...

Role For Vascular Vs Nonvascular Mechanisms

Over past several years, the importance of vascular vs nonvascular mechanisms in the pathogenesis of PDN remained a subject of debate. The key role of reduced NBF and resulting endoneurial hypoxia in diabetes-associated nerve conduction deficit appears to be supported by the findings with a variety of vasodilators for example, the -adrenoceptor antagonist prazosin (20), the K(ATP) channel openers, celikalim and WAY135201 (21), the AT-converting enzyme (ACE) inhibitor enalapril, and the AT II...

Epidemiological Principles Relevant To The Study Of Diabetic Neuropathy

In order to understand published research on the epidemiology of diabetic neuropathy, certain principles of epidemiological study design must be taken into consideration. These principles guided these authors in the selection of relevant citations and data presentation. Cross-sectional or case-control studies conducted in a population-based sample (such as a defined community or health plan enrollment) were considered for this chapter based on review of Medline citations using the keywords...

Autonomic Regulation Of Cardiovascular Function

The best known manifestation of early dysautonomia in human diabetic neuropathy is a loss of cardiovagal function (7). Similar abnormalities have been described after several months of diabetes in experimental diabetic neuropathy (EDN). In a study of Yucatan miniature pigs, blood pressure (BP) and heart rate where recorded telemetrically (8). After 3 months of diabetes induced with streptozotocin (STZ), there was a marked reduction in respiratory sinus arrhythmia. Beyond 3 months, the...

Clinical Classification Of Diabetic Polyneuropathy

Although clinical classification of the various syndromes of diabetic peripheral neuropathy are often difficult because of the very considerable overlap in the mixture of clinical features, attempts at classification stimulate thought as to the etiology of the various syndromes and also assist in the planning of management strategy for the patient. Watkins and Edmonds (9) have suggested a classification for diabetic polyneuropathy based on the natural history of the various syndromes, which...

Summary

Neuropathy is one of the major complications of long-term diabetes. Despite many years of intense research by a number of laboratories, the pathogenetic mechanisms of this disease are still not completely understood. Likely contributing factors of this disease include the polyol pathway, nonenzymatic glycation, protein kinase-C activation, hexosamine pathway, and overproduction of superoxide by the mitochondrial respiratory chain. Their roles in the pathogenesis of diabetic neuropathy are...

Epidermal Innervation In Clinical Trials

Skin biopsy with determination of epidermal nerve fiber density lends itself to application as an outcome measure in regenerative and longitudinal studies. The technique offers the advantage over NCVs that it focuses on a larger subset of nerve fibers than nerve conduction testing and unmyelinated nerve fibers appear to be a more sensitive measure of neuropathy than large myelinated nerve fibers. Several small studies have used serial skin biopsies as an outcome measure. In a trial of...

Lower Extremity Arterial Disease And Diabetes

The concomitant occurrence of atherosclerotic peripheral vascular disease and peripheral neuropathy in patients with diabetes is the main factor in the development of diabetic foot pathology. Although neuropathy has proven the main risk factor for foot ulceration, peripheral arterial disease of the lower extremities is considered the major risk factor for lower-extremity amputation and it is also accompanied by a high likelihood for cardiovascular and cerebrovascular diseases (45). The rate of...

Gastroduodenal Dysfunction The Gastroparesis Syndrome

Diabetic gastroparesis is an electromechanical motility disorder that in many instances involves not only the stomach, but also the upper small bowel. The molecular pathophysiology of diabetic gastroparesis is unknown. In fact, a variety of pathogenetic factors may be implicated in most patients. Animal studies point to a defect in the enteric nervous system characterized by a loss of nitric oxide signals from nerves to gut smooth muscle (18,19). Interstitial cells of Cajal might also be...

Gustatory Sweating

Gustatory sweating was first linked to diabetes mellitus by Watkins (75), and is now known to occur quite commonly in patients with either diabetic nephropathy or neuropathy (76). The syndrome consists of localized hyperhidrosis of the face during meals. The mechanism of gustatory sweating is not proven, but is considered to be because of sympathetic postganglionic denervation followed by aberrant reinnervation by parasympathetic fibers. It is suggested that sympathetic cholinergic fibers to...

Treatment Of Nocturnal Hypertension

Normal subjects have a diurnal variation in BP, with lower nocturnal BP. Patients with neurogenic OH have nocturnal hypertension. To minimize the problems of nocturnal hypertension, pressor medications should not be taken after 6 pm. The head of the bed should be elevated, resulting in lower intracranial BP. A nighttime snack with a glass of fluids (not coffee or tea) results in some postprandial hypotension, and can be used to increase fluid intake and decrease nocturnal hypertension. Patients...

Therapies For Microvascular Insufficiency

Although it is clear that there are significant alterations of blood vessels in diabetes, data thus far has been conflicting whether neuropathy promotes the changes in the microvasculature or whether it is the changes in the microvessels of the nerves that lead to neuropathy. Whatever the case, evidence is growing that re-establishing more normal patterns of blood flow to the nerves results in improved neurological function. Protein kinase C PKC and diacylglycerol DAG are intracellular...