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Hypoglycaemic neuropathy: Experimental studies in diabetic rats treated witn insulin implants
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-1342-369X
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Insulin dependent diabetes mellitus is a metabolic disease that causes secondary complications such as peripheral neuropathy. it is generally believed that diabetic neuropathy is due to chronic hyperglycaemia. In order to understand the pathophysiology of diabetic neuropathy many workers have examined nerves from diabetic rats. While most workers say that animals with high blood glucose levels develop neuropathy, some investigators report that the peripheral nerves are normal in hyperglycaemic rats. Hypoglycaemia may also cause neuropathy. The general aim of the present study is to examine the long-term relation between glycaemia and peripheral neuropathy in diabetic BB/Wor rats. This necessitated establishment of a treatment regime allowing long-term survival of these sick animals.

We found that maintenance of diabetic BB/Wor rats on an eu/hyperglycaemic or an eu-/hypoglycaemic regime with insulin implants worked well for our purpose.

Unexpectedly, light and electron microscopic examination of plantar nerves in eu-/hyperglycaemic diabetic rats showed a normal picture. But, nerves from eu-/hypoglycemic rats showed severe qualitative changes, interpreted as axonal de- and regeneration. The total number of axons  was subnormal and the myelinated fibres were shifted towards smaller diameters. Hence, eu-/hypoglycaemic diabetic BB/Wor rats but not eu-/hyperglycaemic animals, develop a neuropathy in their plantar nerves.

The immunohistochemical occurrence of epidermal protein gene product 9.5 immunoreactive axon profiles was normal in heel skin biopsies from eu/hypoglycaemic rats, but many profiles were short and thin. The content of the neuropeptide calcitonin gene-related peptide in skin biopsies was subnormal. The occurrence of end plate axon terminals labeled with antibodies against the vesicular acetylcholine transporter protein was subnormal in sections from a plantar muscle of eu-/hypoglycaemic rats. Moreover, the end plate axon terminals were abnormally small. Hence, the hypoglycaemic neuropathy seen in plantar nerve trunks of diabetic BB/Wor rats treated with insulin implants is accompanied by mild alterations in the epidermal innervation of plantar skin and a more obviously abnormal nerve terminal pattern in plantar muscle.

Electron microscopic examination of L5 dorsal roots from eu/hypoglycaemic rats showed a normal morphology and normal numbers of axons. In L5 ventral roots the picture varied: in 2 rats it was normal and 3 rats showed signs of axonal degeneration. The L5 dorsal root ganglion and the L5 ventral horn showed a normal picture. Hence, eu-/hypoglycaemia affects ventral root axons but not dorsal root axons. Moreover, the degree of ventral root pathology is variable and sensory and motor neuron perikarya are not affected.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2000. , 73 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 618
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25692Local ID: 10068ISBN: 91-7219-575-4 (print)OAI: oai:DiVA.org:liu-25692DiVA: diva2:246240
Public defence
2000-03-10, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2016-02-29Bibliographically approved
List of papers
1. Neuropathy in diabetic BB/Wor rats treated with insulin implants
Open this publication in new window or tab >>Neuropathy in diabetic BB/Wor rats treated with insulin implants
1998 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 96, no 2, 144-150 p.Article in journal (Refereed) Published
Abstract [en]

To elucidate the pathophysiology of diabetic neuropathy many workers have examined nerve specimens from diabetic rats. While most workers found that animals with high blood glucose levels develop neuropathy, some researchers report that the peripheral nerves are normal in hyperglycaemic rats. Hypoglycaemia may also cause neuropathy. Some workers suggest that neuropathy is linked to fluctuations of the blood glucose level. In the present study we examine plantar nerves of diabetic BB/ Wor rats maintained on an eu-/hyperglycaemic or an eu-/ hypoglycaemic regime with insulin implants. Treatment with implants worked well. Light microscopic examination of nerve fibres in non-diabetic control rats and in eu-/ hyperglycaemic diabetic rats showed a normal picture. Preparations from eu-/hypoglycemic rats showed irregular myelin sheaths and signs of Wallerian degeneration. The lengths and diameters of the largest internodes were significantly subnormal. We conclude, that periodic moderate hypoglycaemia, but not periodic moderate hyperglycaemia, elicits neuropathy in diabetic BB/Wor rats treated with insulin implants.

Keyword
Neuropathy, Hypoglycaemia, Hyperglycaemia, Insulin, BB/Wor rat
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79476 (URN)10.1007/s004010050874 (DOI)
Available from: 2012-08-03 Created: 2012-08-03 Last updated: 2017-12-07Bibliographically approved
2. Hypoglycaemic neuropathy in BB/Wor rats treated with insulin implants: Electron microscopic observations
Open this publication in new window or tab >>Hypoglycaemic neuropathy in BB/Wor rats treated with insulin implants: Electron microscopic observations
1998 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 96, no 2, 151-156 p.Article in journal (Refereed) Published
Abstract [en]

Insulin-dependent diabetes mellitus is a chronic metabolic disease that causes long-term secondary complications such as neuropathy. The occurrence of diabetic neuropathy has generally been thought of as being associated with hyperglycaemia. However, in a previous light microscopic examination of plantar nerves in diabetic BB/Wor rats treated with insulin implants we found that eu-/hyperglycaemic rats present a normal picture, whereas eu-/hypoglycaemic rats show severe changes. The aim of the present work is to supplement our previous light microscopic report with electron microsocpic data from the lateral plantar nerve of normal, eu-/hyperglycaemic and eu-/hypoglycaemic BB/Wor rats. Under the electron microscope lateral plantar nerves collected from eu-/hyperglycaemic rats presented a qualitatively normal picture. In addition, the fibre numbers and the size distribution of the myelinated fibres were normal. In contrast, specimens from eu-/hypoglycaemic BB/Wor rats showed severe qualitative changes, interpreted as signs of axonal de- and regeneration. The total number of axons was somewhat subnormal and the sizes of the myelinated fibres were strongly shifted towards smaller diameters. These data confirm our previous light microscopic observations. We conclude that eu-/hypoglycaemic BB/Wor rats treated with insulin implants, but not similarly treated eu-/hyperglycaemic animals, develop a neuropathy in their plantar nerves.

Keyword
Neuropathy, Hypoglycemia, Insulin, implant, Rat, Electron microscopy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79477 (URN)10.1007/s004010050875 (DOI)
Available from: 2012-08-03 Created: 2012-08-03 Last updated: 2017-12-07Bibliographically approved
3. Hypoglycaemic neuropathy: Occurrence of axon terminals in plantar skin and plantar muscle of diabetic BB/Wor rats treated with insulin implants
Open this publication in new window or tab >>Hypoglycaemic neuropathy: Occurrence of axon terminals in plantar skin and plantar muscle of diabetic BB/Wor rats treated with insulin implants
2000 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 99, no 3, 257-262 p.Article in journal (Refereed) Published
Abstract [en]

It is generally believed that diabetic neuropathy is due to chronic hyperglycaemia. However, experience from insulinoma patients and experimental studies show that hypoglycaemia may also cause neuropathy. Accordingly, the plantar nerves of diabetic eu-/hypoglycaemic BB/Wor rats treated with insulin implants exhibit a distinct neuropathy. To what extent hypoglycaemic neuropathy affects axon terminals in skin and muscle is unknown. In the present study we examine the occurrence of epidermal axon profiles and the neuropeptide calcitonin gene-related peptide (CGRP) in plantar skin, and of end plate axon terminals in a plantar muscle of diabetic BB/Wor rats subjected to long periods of hypoglycaemia. The number of protein gene product-immunoreactive axon profiles was found to be normal in heel skin biopsy specimens from eu-/hypoglycaemic rats, but many profiles were short and thin. The content of CGRP in the skin biopsy samples was significantly below normal. After staining with antibodies against the vesicular acetylcholine transporter protein, the occurrence of end plate axon terminals was significantly reduced in sections from the flexor hallucis brevis muscle of eu-/hypoglycaemic rats. Moreover, the end plate axon terminals tended to be abnormally small in these rats. We conclude that the hypoglycaemic neuropathy seen in plantar nerve trunks of diabetic BB/Wor rats treated with insulin implants is accompanied by mild alterations in the epidermal innervation of plantar skin and a more obviously abnormal nerve terminal pattern in plantar muscle.

Keyword
Hypoglycaemia, Glabrous skin, Nerve fibre, Plantar muscle, Motor end plate
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25083 (URN)10.1007/PL00007435 (DOI)9513 (Local ID)9513 (Archive number)9513 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
4. Hypoglycaemic neuropathy in diabetic BB/Wor rats treated with insulin implants affects ventral root axons but not dorsal root axons
Open this publication in new window or tab >>Hypoglycaemic neuropathy in diabetic BB/Wor rats treated with insulin implants affects ventral root axons but not dorsal root axons
2000 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 100, no 4, 415-420 p.Article in journal (Refereed) Published
Abstract [en]

It is believed that hyperglycaemia underlies diabetic neuropathy. However, low blood glucose values may also cause pathological changes in peripheral nerves and in neuronal perikarya. This study examined spinal roots, dorsal root ganglia and the ventral horn at the segmental level L5 in long-term insulin-treated eu-/hypoglycaemic diabetic rats with an obvious plantar nerve pathology. The purpose was to determine whether hypoglycaemic neuropathy affects sensory and/or motor neurons at root and/or perikaryal levels. Electron microscopic examination of dorsal roots from eu-/hypoglycaemic rats showed a normal qualitative morphology and normal numbers of unmyelinated and myelinated axons. In ventral roots the picture varied. Whereas two rats exhibited an essentially normal morphology, three rats presented moderate or marked signs of pathology such as clusters of small and medium-sized myelinated axons, medium-sized myelinated axons with abnormally thin sheaths, large unmyelinated axons and signs of past or ongoing axonal degeneration. Light microscopic examination of the L5 dorsal root ganglion and ventral horn showed a qualitatively normal picture in eu-/hypoglycaemic rats and the mean number of large ventral horn neurons per section was normal. These results suggest that the type of eu-/hypoglycaemia examined here affects ventral root axons but not dorsal root axons, that the degree of ventral root pathology is variable and that sensory and motor neuron perikarya do not appear to be affected.

Keyword
Hypoglycaemia, Neuropathy, Spinal roots, Dorsal root ganglion, Ventral horn
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25276 (URN)10.1007/s004010000204 (DOI)9716 (Local ID)9716 (Archive number)9716 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved

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