Increased nerve polyol levels in experimental diabetes and their reversal by Sorbinil.

Sciatic nerve glucose, sorbitol, fructose and myo-inositol levels were measured over a 24-week period in rats made diabetic using a single intraperitoneal injection of streptozotocin at 45 mg kg-1 body weight. In addition, the effect of the aldose reductase inhibitor Sorbinil (Pfizer Ltd) at 25 mg kg-1 day-1 in reversing the accumulation of nerve polyols following 8 weeks of diabetes was investigated. Following induction of diabetes 47, 471 and 456% increases and a 43% decrease in sciatic nerve glucose, sorbitol, fructose and myo-inositol concentrations (mumol g-1 wet weight) respectively, were observed by day 14. Over the remainder of the experimental course untreated diabetic control animals demonstrated relatively consistent elevations in sciatic nerve glucose, sorbitol and fructose. Although a significant, progressive reduction in sciatic nerve myo-inositol to 30% of onset values was observed over the first 84 days of the study, this was followed by a spontaneous partial recovery (31%) over the remainder of the experimental course. However, sciatic nerve myo-inositol levels at the end of the study were still significantly lower than onset values (P less than 0.01). Sorbinil treatment, initiated after 8 weeks of diabetes, and without effect on sciatic nerve glucose levels, normalized sorbitol concentrations following 4, 8, or 12 weeks of treatment but only partially reversed the accumulation of fructose by 368, 161 and 199%, compared to age-matched non-diabetic control values, at the above times, respectively. Mean myo-inositol levels were progressively increased following Sorbinil treatment over the experimental period, although the increase was only significant, compared to results from untreated diabetic animals, at weeks 4 and 16.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myo-inositol normalizes decreased sodium permeability of the blood-brain barrier in streptozotocin diabetes

The effect of a dietary supplement of an aldose reductase inhibitor (ponalrestat) or of myo-inositol on sodium transport into the rat brain and on concentrations of saccharide and polyols in cortical brain tissue and sciatic nerve was investigated in control rats and in streptozotocin-diabetic rats after a diabetes duration of 2 weeks. In untreated diabetes, the neocortical blood-brain barrier permeability for sodium decreased by 28% (3.4 +/- 0.4 vs 4.7 +/- 1.6 x 10(-5) ml/s g, mean +/- SD) as compared to controls. Levels of glucose, sorbitol and fructose increased in brain as well as in nerve tissues, whereas myo-inositol depletion was not demonstrable. Ponalrestat treatment of diabetic animals had no effect upon the decreased neocortical blood-brain barrier permeability to sodium (3.5 +/- 0.9 vs 4.7 +/- 1.1 x 10(-5) ml/s g) despite normalization of brain and nerve content of sorbitol and fructose. Myo-inositol supplementation of diabetic rats normalized sodium passage into the brain (4.2 +/- 1.1 vs 4.4 +/- 0.5 x 10(-5) ml/s g). Brain concentrations of monosaccharides and polyols were normalized as compared to the myo-inositol treated control group and nerve concentrations of glucose, sorbitol, and fructose were significantly increased. Myo-inositol treatment leads to a normalization of blood-brain barrier permeability; it is suggested that myo-inositol exerts a restituting effect upon Na+/K+-ATPase activity of the cerebral endothelial cells.     

The role of endoneural edema in the pathogenesis of diabetic neuropathy

Average endoneurial area was correlated with measurements of myelinated fiber density in sural nerves from diabetics and controls. Although, in general, myelinated fiber density decreased with increasing endoneurial area, this relationship was not significant for diabetic nerves. The increase in endoneurial area was attributed to expansion of the endoneurial space as a result of endoneurial edema. A possible role for such edema in the pathogenesis of diabetic neuropathy is considered.     

Endoneurial Microangiopathy of Sural Nerve in Experimental Vacor-Induced Diabetes

The pathogenic mechanism of diabetic peripheral neuropathy is multifactorial. This study investigated microangiopathic changes of endoneurial vessels of sural nerve in Vacor-induced diabetic rats. Experimental rats were divided into 3 groups: acute (80 mg/kg, once), chronic diabetic (8 mg/kg, 14 times), and control. Ultrastructural morphometric parameters of endoneurial microvessels, blood glucose, and body weight changes were statistically analyzed, and correlations among the variables were evaluated. The body weight and blood glucose levels were significantly different between the control and diabetic rats. The blood glucose was more significantly elevated in the acute diabetic rats than the chronic diabetic rats. Inner and outer vascular circumference, vascular area, luminal area, basement membrane area, and basement membrane thickness were significantly increased in the acute diabetic rats compared to the control group, but not between the chronic diabetic rats and the control group. The thickness of basement membrane was positively correlated with hyperglycemia and body weight loss ( P <. 01). These results suggest that the microangiopathy of the peripheral nerve could be developed in acute Vacor-induced diabetes. The decreased perfusion through microangiopathic endoneurial vessels appears to have a pathogenic role causing diabetic peripheral neuropathy.     

Endoneurial microangiopathy of sural nerve in experimental vacor-induced diabetes

The pathogenic mechanism of diabetic peripheral neuropathy is multifactorial. This study investigated microangiopathic changes of endoneurial vessels of sural nerve in Vacor-induced diabetic rats. Experimental rats were divided into 3 groups: acute (80 mg/kg, once), chronic diabetic (8 mg/kg, 14 times), and control. Ultrastructural morphometric parameters of endoneurial microvessels, blood glucose, and body weight changes were statistically analyzed, and correlations among the variables were evaluated. The body weight and blood glucose levels were significantly different between the control and diabetic rats. The blood glucose was more significantly elevated in the acute diabetic rats than the chronic diabetic rats. Inner and outer vascular circumference, vascular area, luminal area, basement membrane area, and basement membrane thickness were significantly increased in the acute diabetic rats compared to the control group, but not between the chronic diabetic rats and the control group. The thickness of basement membrane was positively correlated with hyperglycemia and body weight loss (P < .01). These results suggest that the microangiopathy of the peripheral nerve could be developed in acute Vacor-induced diabetes. The decreased perfusion through microangiopathic endoneurial vessels appears to have a pathogenic role causing diabetic peripheral neuropathy.     

Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil

There is reason to believe that diabetic neuropathy may be related to the accumulation of sorbitol in nerve tissue through an aldose reductase pathway from glucose. Short-term treatment with aldose reductase inhibitors improves nerve conduction in subjects with diabetes, but the effects of long-term treatment on the neuropathologic changes of diabetic neuropathy are unknown. To determine whether more prolonged aldose reductase inhibition reverses the underlying lesions that accompany symptomatic diabetic peripheral polyneuropathy, we performed a randomized, placebo-controlled, double-blind trial of the investigational aldose reductase inhibitor sorbinil (250 mg per day). Sural-nerve biopsy specimens obtained at base line and after one year from 16 diabetic patients with neuropathy were analyzed morphometrically in detail and compared with selected electrophysiologic and clinical indexes. In contrast to patients who received placebo, the 10 sorbinil-treated patients had a decrease of 41.8 +/- 8.0 percent in nerve sorbitol content (P less than 0.01) and a 3.8-fold increase in the percentage of regenerating myelinated nerve fibers (P less than 0.001), reflected by a 33 percent increase in the number of myelinated fibers per unit of cross-sectional area of nerve (P = 0.04). They also had quantitative improvement in terms of the degree of paranodal demyelination, segmental demyelination, and myelin wrinkling. The increase in the number of fibers was accompanied by electrophysiologic and clinical evidence of improved nerve function. We conclude that sorbinil, as a metabolic intervention targeted against a specific biochemical consequence of hyperglycemia, can improve the neuropathologic lesions of diabetic neuropathy.     

Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis

One important complication of diabetes is damage to the peripheral nervous system. However, in spite of the number of studies on human and experimental diabetic neuropathy, the current therapeutic arsenal is meagre. Consequently, the search for substances to protect the nervous system from the degenerative effects of diabetes has high priority in biomedical research. Neuroactive steroids might be interesting since they have been recently identified as promising neuroprotective agents in several models of neurodegeneration. We have assessed whether chronic treatment with progesterone (P), dihydroprogesterone (DHP) or tetrahydroprogesterone (THP) had neuroprotective effects against streptozotocin (STZ)-induced diabetic neuropathy at the neurophysiological, functional, biochemical and neuropathological levels. Using gas chromatography coupled to mass-spectrometry, we found that three months of diabetes markedly lowered P plasma levels in male rats, and chronic treatment with P restored them, with protective effects on peripheral nerves. In the model of STZ-induced of diabetic neuropathy, chronic treatment for 1 month with P, or with its derivatives, DHP and THP, counteracted the impairment of nerve conduction velocity (NCV) and thermal threshold, restored skin innervation density, and improved Na(+),K(+)-ATPase activity and mRNA levels of myelin proteins, such as glycoprotein zero and peripheral myelin protein 22, suggesting that these neuroactive steroids, might be useful protective agents in diabetic neuropathy. Interestingly, different receptors seem to be involved in these effects. Thus, while the expression of myelin proteins and Na(+),K(+)-ATPase activity are only stimulated by P and DHP (i.e. two neuroactive steroids interacting with P receptor, PR), NCV, thermal nociceptive threshold and intra-epidermal nerve fiber (IENF) density are also affected by THP, which interacts with GABA-A receptor. Because, a therapeutic approach with specific synthetic receptor ligands could avoid the typical side effects of steroids, future experiments will be devoted to evaluating the role of PR and GABA-A receptor in these protective effects.     

实验性糖尿病神经和微血管形态研究及黄腐酸钠早期干预

目的 :观察糖尿病大鼠神经和神经内膜毛细血管形态变化及黄腐酸钠早期干预效果。方法 :腹腔注射链脲佐菌素建立糖尿病大鼠模型。给予黄腐酸钠治疗 6个月。结果 :(1)糖尿病动物血糖明显增高。(2 )糖尿病组有髓神经纤维密度明显低于对照组。黄腐酸钠治疗组有髓神经纤维密度明显高于糖尿病组。(3)电镜下糖尿病组神经纤维、神经内膜毛细血管出现结构改变 ;黄腐酸钠治疗组上述改变较轻。结论 :提示糖尿病大鼠病程 6个月时出现早期糖尿病神经病变及神经内膜毛细血管结构改变 ,黄腐酸钠可一定程度地抑制其进展。     

Insulin-like Growth Factor I Reverses Experimental Diabetic Autonomic Neuropathy

Recent studies have suggested a role for neurotrophic substances in the pathogenesis and treatment of diabetic neuropathy. In this study, the effect of insulin-like growth factor I (IGF-I) on diabetic sympathetic autonomic neuropathy was examined in an experimental streptozotocin-induced diabetic rat model. Two months of IGF-I treatment of chronically diabetic rats with established neuroaxonal dystrophy (the neuropathological hallmark of the disease) involving the superior mesenteric ganglion and ileal mesenteric nerves resulted in nearly complete normalization of the frequency of neuroaxonal dystrophy in both sites without altering the severity of diabetes. Treatment with low-dose insulin (to control for the transient glucose-lowering effects of IGF-I) failed to affect the frequency of ganglionic or mesenteric nerve neuroaxonal dystrophy or the severity of diabetes. The striking improvement in the severity of diabetic autonomic neuropathy shown with IGF-I treatment in these studies and the fidelity of the rat model to findings in diabetic human sympathetic ganglia provide promise for the development of new clinical therapeutic strategies.     

Clinically diagnosed diabetic neuropathy: frequency, types and severity

OBJECTIVE: Studies of frequency of occurrence of diabetic neuropathy are few, and available studies were limited to the southern part of Nigeria. The objectives of the study were to determine the frequency of occurrence and grades of diabetes peripheral neuropathy using clinical measures. PATIENTS AND METHODS: Consecutive patients with diabetes mellitus attending the Jos University Teaching Hospital were recruited as the study population, including 120 diabetics and 60 age-matched, nondiabetic controls. A standard proforma based on the Michigan Neuropathy Screening Instrument (MNSI) was employed to screen for diabetic neuropathy. RESULTS: The frequency of occurrence of diabetic peripheral neuropathy was 75%. For the specific types of peripheral neuropathy, sensorimotor neuropathy was the commonest (40.4%, chi(2)=29.1; p<0.001). There was no significant difference, with severity of peripheral neuropathy among diabetics, when compared by gender. (Chi square=3.03, P value=0.081). CONCLUSION: The frequency of occurrence of peripheral neuropathy among diabetics in Jos University Teaching Hospital from this study is rather high.     

Peripheral neuropathy in patients with diabetes mellitus presenting as Bell's palsy

The aim of this study is to evaluate the peripheral nerves in diabetes mellitus with or without peripheral facial paralysis (PFP). A total of 49 diabetic patients with PFP within the last year (23 females, mean age 60.3 +/- 9.3), and 83 diabetic patients without PFP (41 females, mean age 59.5 +/- 9.9) were enrolled. The neurological examination, eye-blinking response, needle EMG and electrophysiological parameters of peripheral nerves were evaluated. The neuropathic pain, other positive and negative sensory symptoms were statistically more frequent in controls than the PFP group, while no difference was noted in total neuropathy score. Sural sensorial nerve action potential amplitudes were same in both groups, but median nerve amplitudes were significantly lower in the PFP group. It is suggested that PFP is not a part of multifocal neuropathy in diabetes mellitus. However, at least some parts of the nerve conduction studies were involved, focal neuropathies were more frequent while sensory neuropathies with small nerve fiber involvement were less frequent in diabetes patients with PFP.     

Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications

During the past decade, our appreciation of the original experiments with myo-inositol supplementation in diabetic rats has greatly expanded. The effects of myo-inositol on nerve conduction are now explained by concepts that were largely unappreciated in 1976, including the fundamental role of phosphoinositide metabolism in cell regulation and the importance of the activity of sodium-potassium-ATPase in nerve conduction. Aldose reductase inhibitors firmly link defects in myo-inositol metabolism to activation of the polyol pathway in diabetes; the resulting "sorbitol-myo-inositol hypothesis" has been extended from its application to the lenses and peripheral nerves to most of the tissues involved with diabetic complications. These biochemical mechanisms provide a new framework within which to explore the complex interactions between hyperglycemia and the vascular, genetic, and environmental variables in the pathogenesis of diabetic complications. It is anticipated that these endeavors will result in the appearance of new classes of therapeutic agents, the first of which--the aldose reductase inhibitors--has emerged from the laboratory and is now undergoing extensive clinical testing. These efforts are very likely to result in the appearance of new treatment methods that may dramatically lighten the burden of chronic complications in patients with diabetes.     

Pathogenesis of diabetic neuropathy: role of altered phosphoinositide metabolism

A unifying metabolic hypothesis completely accounting for the development of one or more of the chronic complications of diabetes on the basis of a single aspect of disturbed glucose metabolism resulting from insulin deficiency and/or hyperglycemia has been sought by clinical and basic scientists for decades. A growing body of loosely related but internally consistent scientific data obtained from cultured cells, incubated tissue preparations, animal models, and man implicate sorbitol- and glucose-induced myo-inositol depletion and altered phosphoinositide metabolism in a series of secondary biochemical, functional, and architectural abnormalities in the PNS in diabetes. These early metabolically based functional and structural changes simulate those that characterize human diabetic neuropathy. Can abnormal phosphoinositide metabolism in diabetic nerve thereby by itself explain the development of chronic diabetic neuropathy with all of its clinical complexity and heterogeneity? Almost certainly not. Even if the entire contribution of hyperglycemia to the development of diabetic neuropathy were mediated by secondary abnormalities in phosphoinositide metabolism, other factors must also play a role. Witness the differences in the histopathological picture of neuropathy in patients with IDDM and NIDDM despite similar durations and severity of diabetes, the apparent influence of age and gender on the appearance of early neuropathy in patients with IDDM, and the association of alcohol consumption with diabetic neuropathy. While early metabolic and functional disturbances in diabetic nerve such as impaired (Na,K)-ATPase function and paranodal swelling are empirically attributable to abnormal myo-inositol and phosphoinositide metabolism, more advanced abnormalities such as axo-glial dysjunction may reflect superimposed independent biochemical and/or hormonal defects (although, as mentioned previously, aldose reductase inhibition decreases axo-glial dysjunction in diabetic humans). The PNS has only a limited repertoire of responses to a variety of insults, so that Wallerian degeneration, axonal atrophy, impaired axonal transport, and dystrophic changes in diabetic neuropathy may represent multiple factors. On the other hand, the increasingly recognized importance of the phosphoinositide cascade in neuromodulation may attribute a progressively wider range of disturbances in the diabetic PNS to myo-inositol depletion and associated defects in phosphoinositide metabolism. Thus, while all effects of aldose reductase inhibitors in the PNS of diabetic rats have been reproduced by myo-inositol supplementation when this alternative intervention has been tested, the exact role of phosphoinositide metabolism in most of these responses is not well understood.(ABSTRACT TRUNCATED AT 400 WORDS)     

Ultrastructural evidence of peripheral neuropathy in spontaneous hyperglycemic Otsuka Long-Evans Tokushima Fatty rats: histopathological similarity to human diabetic neuropathy

The ultrastructure in the peripheral nerves of spontaneous hyperglycemic rats and of two cases of human diabetic neuropathy was compared using electron microscopy. Experimental animals were Otsuka Long-Evans Tokushima Fatty (OLETF) rats, bred to reveal spontaneous hyperglycemia and glucosuria after 20 weeks of age. The ultrastructural findings in the peripheral nerves of OLETF rats consisted of destructive changes of the myelin sheath, followed by axonal degeneration and basal laminal thickening of Schwann cells covering small-caliber axons. These alternations in the endoneurium were associated with the later onset of capillary vasculopathy, which revealed duplication of endothelial basal lamina and proliferation of microvilli at the luminal surface. It was characteristic that these histological alterations were apparently distinguished according to the duration of hyperglycemia between 10 and 30 weeks of age. The two human diabetic cases, who had suffered from non-insulin-dependent diabetes mellitus (NIDDM) for a considerable period, had undergone amputation of the leg following the onset of severe neuropathic ulcerative necrosis. Biopsied specimens from peripheral nerves revealed perineurial thickening, proliferation of endoneurial collagen tissue, loss of myelinated fibers, extension of Schwann cell processes with occasional onion-bulb formation, and endoneurial vascular basal laminal thickening. The results of these comparative histological studies suggested that the alterations occurring in peripheral nerve tissue of experimental diabetic OLETF rats may reflect the early pathological changes of human diabetic neuropathy.     

神经传导速度早期诊断糖尿病性周围神经病

本文对58例糖尿病人进行了神经传导速度(NCV)测定,其中有周围神经损害的症状和体征,临床诊断为糖尿病并发周围神经病者32例,临床无周围神经损害的糖尿病者26例。其结果表明,NCV测定为判断周围神经损害的一种客观指标,且感觉神经测定比运动神经敏感,下肢胫神经测定比上肢敏感,也可提示亚临床期的周围神经病变,有助于糖尿病性周围神经病的早期诊断。     

Structural abnormalities do not explain the early functional abnormalities in the peripheral nerves of the streptozotocin diabetic rat

The streptozotocin (STZ)-diabetic rat, the most commonly employed model of experimental diabetic neuropathy, is characterised by a reduction in nerve conduction velocity, pain threshold and blood flow. Whether or not structural abnormalities underlie these functional abnormalities is unclear. 10 adult male Sprague–Dawley STZ-diabetic rats (diabetes duration 27 d) and 10 age-matched (23 wk) control animals were studied. Motor nerve conduction velocity (m s⁻¹) was significantly reduced in diabetic (41.31±0.8) compared with control (46.15±1.5) animals ( P <0.001). The concentration of sciatic nerve glucose ( P <0.001), fructose ( P <0.001) and sorbitol ( P <0.001) was elevated, and myoinositol ( P <0.001) was reduced in diabetic compared with control animals. Detailed morphometric studies demonstrated no significant difference in fascicular area, myelinated fibre density, fibre and axon areas as well as unmyelinated fibre density and diameter. Endoneurial capillary density, basement membrane area and endothelial cell profile number did not differ between diabetic and control animals. However, luminal area ( P <0.03) was increased and endothelial cell area ( P <0.08) was decreased in the diabetic rats. We conclude there is no detectable structural basis for the reduction in nerve conduction velocity, pain threshold or blood flow, observed in the streptozotocin diabetic rat.     

The usefulness of the blink reflex in the early diagnosis of cranial nerve neuropathy associated with diabetes mellitus

BACKGROUND: Electrophysiological testing can be of value in early diagnosis of diabetic neuropathy. Limited data is available in the use of the blink reflex (BR) in diabetes mellitus (MD). AIM: is to evaluate the efficacy of BR in early diagnosis of cranial nerve neuropathy in DM. MATERIALS AND METHODS: 67 diabetes and 32 healthy controls-age and sex matched- were chosen. The diabetes were of type I and type II and of more than or less than 10 years duration. The BR was elicited by stimulation the supraorbital nerve using the Dantec Neuromatic 2000M machine. The latency of the components response recorded as R1, R2y (ipsilateral) and R2c (contralateral). A direct response was achieved by the stimulation of the facial nerve; a square wave of 200 msec. was used. RESULTS: No differences were noted when the two sides were compared in diabetic patients, while the difference was highly significant in the increased latency of R1, R2y and R2c each type of diabetes as compared to the control. Comparison of the types and duration of diabetes between each other showed no significant difference. Direct measurement of the latency response of the facial nerve gave a response in diabetics of both types and duration. CONCLUSION: the BR can be useful in the early diagnosis of diabetic neuropathy.     

All-trans retinoic acid induces nerve regeneration and increases serum and nerve contents of neural growth factor in experimental diabetic neuropathy

Local diminution of the neural growth factor (NGF) contributes to the apparition of diabetic neuropathy. All-trans retinoic acid (RA) increases the expression of neural growth factor and its receptor participating in translation pathways. This study evaluates RA as a treatment of diabetic neuropathy: 120 mice were assigned randomly to 4 groups. Group A (n = 30) was taken as control; group B (n = 30) received 50 mg/kg intraperitoneal streptozotocin (STZ); group C (n = 30) received STZ, and after diabetic neuropathy developed, they were treated with subcutaneous RA 20 mg/kg daily during 60 days; and group D (n = 30) only received RA. Plasma glucose, thermosensitive tests, serum, and the nerve contents of NGF were measured in all animals. Evaluation by electron microscopy was performed in search of morphologic changes secondary to neuropathy and nerve regeneration. Diabetic mice had an increased threshold to pain. Treatment with RA in diabetic mice reverted changes in sensitivity as compared with diabetic mice that received placebo (P < 0.001). No differences in pain threshold among controls, RA, and diabetes mellitus (DM) + RA groups were found. Glucose levels were not affected by the treatment with RA. NGF diminished significantly in the sciatic nerve in diabetic mice as compared with controls and with the RA group. Animals with DM + RA had a significant increase of NGF in nerves as compared with the other groups. RA also regressed the ultrastructural changes induced by diabetes that showed increased neural regeneration. RA can revert functional and ultrastructural changes and induce neural regeneration after the establishment of diabetic neuropathy, possibly because of the increased of NGF concentrations in nerve terminals.     

Skin biopsy as a beneficial procedure for morphological evaluation of diabetic neuropathy

In an attempt to evaluate the morphological abnormalities of dermal non-myelinated nerve fibers of diabetics and elucidate the pathogenesis of diabetic peripheral neuropathy, the terminal part of peripheral nerve in the upper dermis was observed on electron microscopy using skin samples biopsied in 10 diabetics with symptomatic neuropathy and 6 age-matched controls. In diabetics, the density of nerve fibers was significantly lower than in controls. In addition, swelling, lytic change and vacuolation in the axon, multiplication of basement membrane of the Schwann cell and Schwann cell cluster devoid of axon were more frequently observed in diabetics. The Schwann cell did not show significant structural alterations. These findings suggest that the axon is primarily involved, at least in the terminal region of nerve fiber, in diabetic peripheral neuropathy. It is also concluded that the skin biopsy technique is harmless, cosmetically not troublesome and might be beneficial for studying peripheral neuropathies including diabetic neuropathy.     

SKIN BIOPSY AS A BENEFICIAL PROCEDURE FOR MORPHOLOGICAL EVALUATION OF DIABETIC NEUROPATHY

In an attempt to evaluate the morphological abnormalities of dermal non-myelinated nerve fibers of diabetics and elucidate the pathogenesis of diabetic peripheral neuropathy, the terminal part of peripheral nerve in the upper dermis was observed on electron microscopy using skin samples biopsied in 10 diabetics with symptomatic neuropathy and 6 age-matched controls. In diabetics, the density of nerve fibers was significantly lower than in controls. In addition, swelling, lytic change and vacuolation in the axon, multiplication of basement membrane of the Schwann cell and Schwann cell cluster devoid of axon were more frequently observed in diabetics. The Schwann cell did not show significant structural alterations. These findings suggest that the axon is primarily involved, at least in the terminal region of nerve fiber, in diabetic peripheral neuropathy. It is also concluded that the skin biopsy technique is unharmful, cosmetically not troublesome and might be beneficial for studying peripheral neuropathies including diabetic neuropathy.