Ultrastructural Pathology of Peripheral Nerves in Patients with Diabetic Neuropathy

Yagihashi, Soroku; Matsunaga, M

doi:10.1620/tjem.129.357

Cited by 74 publications

(36 citation statements)

References 16 publications

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“…A number of reports (21-.24) suggest that the neuropathy ofdiabetes mellitus may involve altered tubulin-microtubule function (25). Axonal shortening (26), decreased axonal flow (27), increased latency (28), and reduced conduction velocities (29) Tables 1 and 2 (in particular those for incubation with glucose 6-phosphate at 10 mg/ml) leads to the suggestion that colchicine may partially inhibit the formation of tubulin aggregates after glycosylation.…”

Section: Discussionmentioning

confidence: 99%

Structural and functional consequences of increased tubulin glycosylation in diabetes mellitus.

Williams¹,

Howarth²,

Devenny³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

110

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The extent ofin vitro nonenzymatic glycosylation of purified rat brain tubulin was dependent on time and glucose concentration. Tubulin glycosylation profoundly inhibited GTPdependent tubulin polymerization. Electron microscopy and NaDodSO4/polyacrylamide gel electrophoresis showed that glycosylated tubulin forms high molecular weight amorphous aggregates that are not disrupted by detergents or reducing agents. The amount of covalently bound NaB3H4-reducible sugars in tubulin recovered from brain of streptozotocin-induced diabetic rats was dramatically increased as compared with tubulin recovered from normal rat brain. Moreover, tubulin recovered from diabetic rat brain exhibited less GTP-induced polymerization than tubulin from nondiabetic controls. The possible implications of these data for diabetic neuropathy are discussed.Diabetes mellitus is often accompanied by the gradual development of diverse and multifocal pathology (1). Insulin and antibiotics have contributed substantially to the management of carbohydrate abnormalities and infection (2). However, deterioration in the microcirculation of retina and kidney and diabetic neuropathy continue to present serious clinical problems (3). It is still unclear whether these complications are uniquely the result of carbohydrate disturbances due to intermittent insulin deficiency or also reflect more subtle genetic or metabolic factors that are, at best, indirectly related to insulin levels (4).Recent data have supported the hypothesis that increased nonenzymatic as well as enzymatic glycosylation ofcellular components, as a result of the elevated glucose concentrations of diabetes, may play a contributory role in diabetic microangiopathy (5), and diabetic cataractogenesis (6). Modification, by the nonenzymatic addition of glucose, has now been reported for a variety of serum, cellular, and interstitial proteins and phospholipids (7-10), suggesting the possibility that unanticipated additional functional changes may yet be observed to result from nonenzymatic (or enzymatic) glycosylation.We present here evidence for in vitro and in vivo glycosylation of brain tubulin as a consequence of exposure to elevated glucose concentrations. The in vitro nonenzymatic glycosylation oftubulin results in the formation ofamorphous aggregates oftubulin and tubulin-associated proteins that remain insoluble in 8 M urea or NaDodSO4. The in vivo formation of glycosylation-induced tubulin aggregates was found to compete with ordered tubulin polymerization in diabetic rats. METHODS AND MATERIALSTubulin Isolation and Measurement. Tubulin was purified from male weanling Sprague-Dawley rat brain according to the procedure of Berkowitz et al. (11). Rats were sacrificed by occipital trauma and cervical dislocation. Brains were removed and weighed and 0.75 ml of purification buffer (11) [50 mM 4-morpholineethanesulfonic acid (Sigma)/2 mM EGTA/1 mM MgSO4/4.0 M glycerol, pH 6.9] was added per gram of brain.Brains were homogenized in a loose-fitting motor-driven Teflon/glass homogeniz...

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Section: Discussionmentioning

confidence: 99%

Structural and functional consequences of increased tubulin glycosylation in diabetes mellitus.

Williams¹,

Howarth²,

Devenny³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

110

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“…Since the sensitivity of measurement on sciatic nerve is higher than that on caudal nerve, nerve functional abnormalities in ZDF rats can be observed at an early age, about 12 weeks. In diabetic patients, pathological changes such as distal and sensory predominant nerve fiber degeneration, axonal loss, and endoneural microangiopathy, are observed in peripheral nervous system [90]. There are few reports in which histopathological analyses in obese diabetic rats were sufficiently performed.…”

Section: Neural Lesionsmentioning

confidence: 99%

Diabetic Complications in Obese Type 2 Diabetic Rat Models

et al. 2014

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We overviewed the pathophysiological features of diabetes and its complications in obese type 2 diabetic rat models: Otsuka Long-Evans Tokushima fatty (OLETF) rat, Wistar fatty rat, Zucker diabetic fatty (ZDF) rat and Spontaneously diabetic Torii (SDT) fatty rat. Pancreatic changes with progression of diabetes were classified into early changes, such as islet hypertrophy and degranulation of β cells, and degenerative changes, such as islet atrophy and fibrosis of islet with infiltration of inflammatory cells. Renal lesions in tubuli and glomeruli were observed, and nodular lesions in glomeruli were notable changes in OLETF and SDT fatty rats. Among retinal changes, folding and thickening were interesting findings in SDT fatty rats. A decrease of motor nerve conduction velocity with progression of diabetes was presented in obese diabetic rats. Other diabetic complications, osteoporosis and sexual dysfunction, were also observed. Observation of bone metabolic abnormalities, including decrease of osteogenesis and bone mineral density, and sexual dysfunction, including hypotestosteronemia and erectile dysfunction, in obese type 2 diabetic rats have been reported.

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“…The proximal-to-distal increase in morphometric abnormalities (1,20) and the topographic and temporal distribution of neurological signs and symptoms in diabetic distal symmetric polyneuropathy suggest a primary axonopathy preferentially involving longer myelinated axons (31)(32)(33). Nerve biopsies from young diabetic patients characteristically exhibit ultrastructural lesions most consistent with an early primary distal axonal atrophy and degeneration (28,29,35,37). Yet studies of sural nerve biopsies by Thomas and Lascelles (24,25) and others (27,30), and autopsy studies (26) have also emphasized segmental demyelination and remyelination in diabetic distal symmetric polyneuropathy, postulating a primary abnormality of Schwann cells.…”

Section: Introductionmentioning

confidence: 99%

Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin-dependent diabetes, and demonstration of axo-glial dysjunction in human diabetic neuropathy.

Sima¹,

Nathaniel²,

Bril³

et al. 1988

J. Clin. Invest.

205

145

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Altered sorbitol and myo-inositol metabolism, (Na,K)-ATPase function, electrochemical sodium gradients, axonal swelling, and distortion and disruption of the node of Ranvier ("axo-glial dysjunction") directly implicate hyperglycemia in the pathogenesis of neuropathy in diabetic rats, but the relevance of this sequence to clinical neuropathy in heterogeneous groups of diabetic patients remains to be established. Fascicular sural nerve morphometry in 11 patients with neuropathy complicating insulin-dependent diabetes revealed a pattern of interrelated structural changes strikingly similar to that of the diabetic rat when compared to age-matched controls. 17 older non-insulin-dependent diabetic patients with comparable duration and severity of hyperglycemia and severity of neuropathy, displayed similar nerve fiber loss, paranodal demyelination, paranodal remyelination and segmental demyelination compared to age-matched controls, but axo-glial dysjunction was replaced by Wallerian degeneration as the primary manifestation of fiber damage, and fiber loss occurred in a spatial pattern consistent with an ischemic component. The mechanistic model developed from the diabetic rat does indeed appear to apply to human diabetic neuropathy, but superimposed hormonal, metabolic, vascular, and/or age-related effects alter the morphologic expression of the neuropathy in non-insulin dependent diabetes.

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Ultrastructural Pathology of Peripheral Nerves in Patients with Diabetic Neuropathy

Cited by 74 publications

References 16 publications

Structural and functional consequences of increased tubulin glycosylation in diabetes mellitus.

Structural and functional consequences of increased tubulin glycosylation in diabetes mellitus.

Diabetic Complications in Obese Type 2 Diabetic Rat Models

Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin-dependent diabetes, and demonstration of axo-glial dysjunction in human diabetic neuropathy.

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