Pathological Observations on Six Cases of Diabetic Neuropathy

Greenbaum, David S.; Richardson, P. M.; Salmon, M; Urich, H.

doi:10.1093/brain/87.2.201

Cited by 120 publications

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“…Using the spontaneously type 1 diabetic BB/Wor rat we demonstrate here 1) increased stainability and upregulation of active caspase-3 and proapoptotic Bax in diabetic DRGs, 2) that these apoptotic stresses are accompanied by the induction of antiapoptotic Bcl-xl and survival promoting HSP27 and HSP70, 3) that NGF content in sciatic nerve and high-affinity NGF receptor TrkA expression in diabetic DRGs are decreased, 4) that morphometric analyses of sural nerve reveal myelinated and unmyelinated fiber loss and axonal atrophy in diabetic rats, and 5) that morphometric and morphologic examinations of DRGs show no neuronal loss or qualitative changes indicative of apoptosis. Instead, DRG neurons show progressive hydropic damage similar to that described in human DPN (22).…”

Section: Discussionsupporting

confidence: 56%

“…Human DPN shows progressive loss of myelinated and unmyelinated sensory fibers in peripheral nerves, accompanied by degeneration and loss of parent DRG neurons, and is classified as a peripheral axonopathy of dying-back type (1,7,(22)(23)(24). Hyperglycemia with consequent perturbations of the polyol pathway, nerve hypoxemia, and oxidative stress have been suggested as the main culprits (1).…”

Section: Discussionmentioning

confidence: 99%

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Apoptotic Stress Is Counterbalanced by Survival Elements Preventing Programmed Cell Death of Dorsal Root Ganglions in Subacute Type 1 Diabetic BB/Wor Rats

2005

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Several groups have reported apoptosis of dorsal root ganglion (DRG) cells as a prominent feature of diabetic polyneuropathy (DPN), although this has been controversial. Here, we examined subacute (4-month) type 1 diabetic BB/Wor rats with respect to sensory nerve functions, DRG and sural nerve morphometry, pro-and antiapoptotic proteins, and the expression of neurotrophic factors and their receptors. Sensory nerve conduction velocity was reduced by 13% and was accompanied by significant hyperalgesia. The numbers of DRG neurons including substance P-and calcitonin gene-related peptide-positive neurons were not altered, although they showed significant atrophy. Sural nerve morphometry showed decreased numbers of myelinated and unmyelinated fibers. Active caspase-3 and Bax expressions were increased, whereas antiapoptotic Bcl-xl and heat shock protein (HSP) 27 expressions in DRGs were increased. Nerve growth factor (NGF) contents in sciatic nerves and the expression of NGF receptor TrkA in DRGs were decreased. Immunohistochemistry showed increased numbers of active caspase-3-, HSP70-, and HSP27-positive neurons. Examinations of DRGs revealed no structural evidence of apoptosis but rather progressive hydropic degenerative changes. We conclude that apoptotic stress is induced in DRGs but is counterbalanced by survival elements in subacute type 1 diabetic BB/Wor rats and that distal nerve fiber loss reflects a dying-back phenomenon caused by impaired neurotrophic support. Diabetes 54: 3288 -3295, 2005 D iabetic polyneuropathy (DPN) is the most common late complication of diabetes and shows an increasing prevalence. Like other diabetes complications, DPN has been ascribed to hyperglycemia and subsequent metabolic abnormalities, particularly oxidative stress. Although other factors contribute to its development, such as insulin and C-peptide deficiencies and consequent deprivation of neurotrophic support (1), these have received less attention. Several investigators have reported neuronal apoptosis in relatively acute (2-to 3-month) streptozotocin-induced diabetes (STZ-D) in rats, sometimes exceeding 30% of dorsal root ganglion (DRG) cells as a contributing factor to DPN (2-4), while others have reported no significant neuronal loss in DRGs even after 12 months of STZ-D (5,6). The validity of major programmed cell death can be disputed, since the magnitude of reported apoptotic neuronal death does not correlate with a corresponding loss of axonal extensions in the peripheral nerve of the STZ-D rat. In contrast to the STZ-D rat, the spontaneously type 1 diabetic BB/Wor rat develops progressive sensory nerve fiber loss (7), as in humans, which therefore could reflect loss of parent DRG cells.Apoptotic phenomena occur in pancreatic ␤-cells in type 1 diabetes (8), in diabetic retinopathy (9), and in hippocampal neurons in primary diabetic encephalopathy (10,11). Programmed cell death is believed to result from hyperglycemia-induced mitochondrial dysfunction (4,12) and depletion of antiapoptotic trophic factors like IGFs, i...

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Apoptotic Stress Is Counterbalanced by Survival Elements Preventing Programmed Cell Death of Dorsal Root Ganglions in Subacute Type 1 Diabetic BB/Wor Rats

2005

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“…It may also be explained, however, by a diminution of the fibre calibre. A loss of large myelinated fibres was observed by Greenbaum (1964) in short-term diabetics [ 11]. Since the number of fibres was not counted in that study, fibre diminution, without loss of fibres, may have occurred.…”

Section: Discussionmentioning

confidence: 64%

Axonal dwindling in early experimental diabetes. I. A study of cross sectioned nerves

Jakobsen

1976

Diabetologia

172

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Summary. A diminution of the cross sectional area of myelinated fibres in the common peroneal nerve was observed in rats four weeks after the induction of diabetes with streptozotocin. Small fibres were affected more than larger ones and the axon reduction was twice that of the myelin sheath. The fibre diminution and the decreased axon/myelin ratio may explain the slowing of nerve conduction in experimental diabetes.Key words: Streptozotocin diabetes, axons, myelin sheath, nerve degeneration, neural conduction.Peripheral nerves are involved early in juvenile diabetes. Thus Gregersen (1967) demonstrated decreased motor nerve conduction velocity within the first year after the clinical onset of the disease [1]. At this time there were no clinical symptoms of neuropathy. The structural alteration underlying this functional abnormality is still unknown.Also in experimental diabetes, whether induced by streptozotocin, aUoxan or pancreatectomy, slowing of nerve conduction occurs from the very beginning. The morphological lesion has not been identified here either.A few histological studies have reported Schwann cell abnormalities several months after the induction of diabetes [2,3]. However, a recent extensive morphometric study failed to define any pathological alterations at all in diabetic animals [4].In this report of early experimental diabetes quantitative morphological changes, mainly affecting the axon, are demonstrated. The pathological lesion observed in the present study may well explain the functional abnormalitiy of nerve conduction in diabetic animals. Materials and MethodsMale Wistar rats raised on a standard rat chow diet with water ad libitum were used for the experiments. Animals 18 to 20 weeks old weighing between 330 and 380 g were selected at random for the different groups of the experiment. Diabetes was induced in ten rats by intravenous injection of 40 to 45 mg streptozotocin per kg body weight. The animals were maintained for four weeks without insulin treatment.Ten other rats were selected as a control group (control group 1). Both groups of animals were killed four weeks later.For the purpose of imitating the weight loss of the diabetic rats another group of five normal animals was deprived of food for four days and subsequently fed on a restricted daily diet of nearly 50% of the standard diet for 24 days (control group 2). With this diet it was intended to induce a weight loss somewhat greater than that observed to occur in the group of diabetic rats, to compensate for the increase in gastrointestinal filling known to occur in diabetic rats.Body weight was determined weekly in all animals. Blood glucose and 24 h urine output were measured at ten day intervals in the diabetic rats, and at the end of the experiment in the rats of the control groups. Blood samples were taken in the morning as duplicates from non-fasting animals. Blood glucose was determined by a glucose oxidase method [5] and urine glucose by a p-toluidine method. Tissue PreparationPeripheral nerves were initially fixed by vas...

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“…These results indicated that the peripheral nerve lesions in human diabetics were mainly due to metabolic impairment of nerve fibers, accompanying dysmetabolism of Schwann cells and diabetic microangiopathy, and that these changes proceeded independently diabetic neuropathy; ultrastructure; axonal degeneration; demyelination; microangiopathy Although peripheral neuropathy is a very common complication in the diabetic patients, the adequate clarification for the morphological alterations of nerve tissues in the human diabetics has not yet been presented. In an autopsy study on the diabetic patients, Greenbaum et al (1964) observed degeneration and loss of myelinated nerve fibers and nerve cells in both spinal cord and ganglions and they considered that a neuronal disorder was mainly responsible for the diabetic neuropathy.…”

mentioning

confidence: 99%

Ultrastructural Pathology of Peripheral Nerves in Patients with Diabetic Neuropathy

Yagihashi

Matsunaga

1979

Tohoku J. Exp. Med.

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Pathological Observations on Six Cases of Diabetic Neuropathy

Cited by 120 publications

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Apoptotic Stress Is Counterbalanced by Survival Elements Preventing Programmed Cell Death of Dorsal Root Ganglions in Subacute Type 1 Diabetic BB/Wor Rats

Apoptotic Stress Is Counterbalanced by Survival Elements Preventing Programmed Cell Death of Dorsal Root Ganglions in Subacute Type 1 Diabetic BB/Wor Rats

Axonal dwindling in early experimental diabetes. I. A study of cross sectioned nerves

Ultrastructural Pathology of Peripheral Nerves in Patients with Diabetic Neuropathy

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