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Autophagy in the posterior interosseous nerve of patients with type 1 and type 2 diabetes mellitus: an ultrastructural study
Lund University, Sweden; Skåne University Hospital Malmö, Sweden.
Lund University, Sweden; Skåne University Hospital Malmö, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-1342-369X
2015 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 3, 625-632 p.Article in journal (Refereed) Published
Abstract [en]

We addressed the question of whether the autophagy pathway occurs in human peripheral nerves and whether this pathway is associated with peripheral neuropathy in diabetes mellitus. By using electron microscopy, we evaluated the presence of autophagy-related structures and neuropathy in the posterior interosseous nerve of patients who had undergone carpal tunnel release and had type 1 or type 2 diabetes mellitus, and in patients with no diabetes (controls). Autophagy-related ultrastructures were observed in the samples taken from all patients of the three groups. The number of autophagy-associated structures was significantly higher (p less than 0.05) in the nerves of patients with type 1 than type 2 diabetes. Qualitative and quantitative evaluations of fascicle area, diameter of myelinated and unmyelinated nerve fibres, the density of myelinated and unmyelinated fibres and the g-ratio of myelinated fibres were performed. We found degeneration and regeneration of a few myelinated axons in controls, and a well-developed neuropathy with the loss of large myelinated axons and the presence of many small ones in patients with diabetes. The pathology in type 1 diabetes was more extensive than in type 2 diabetes. The results of this study show that the human peripheral nerves have access to the autophagy machinery, and this pathway may be regulated differently in type 1 and type 2 diabetes; insulin, presence of extensive neuropathy, and/or other factors such as duration of diabetes and HbA(1c) level may underlie this differential regulation.

Place, publisher, year, edition, pages
Springer Verlag (Germany) , 2015. Vol. 58, no 3, 625-632 p.
Keyword [en]
Autophagy; Diabetes; Electron microscopy; Human; Neuropathy; Peripheral nerve
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-115314DOI: 10.1007/s00125-014-3477-4ISI: 000349244100024PubMedID: 25523623OAI: oai:DiVA.org:liu-115314DiVA: diva2:795099
Available from: 2015-03-13 Created: 2015-03-13 Last updated: 2017-12-04
In thesis
1. Autophagy in Peripheral Neuropathy
Open this publication in new window or tab >>Autophagy in Peripheral Neuropathy
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Peripheral neuropathy includes a wide range of diseases affecting millions around the world, and many of these diseases have unknown etiology. Peripheral neuropathy in diabetes represents a large proportion of peripheral neuropathies. Nerve damage can also be caused by trauma. Peripheral neuropathies are a significant clinical problem and efficient treatments are largely lacking. In the case of a transected nerve, different methods have been used to repair or reconstruct the nerve, including the use of nerve conduits, but functional recovery is usually poor.

Autophagy, a cellular mechanism that recycles damaged proteins, is impaired in the brain in many neurodegenerative diseases affecting animals and humans. No research, however, has investigated the presence of autophagy in the human peripheral nervous system. In this study, I present the first structural evidence of autophagy in human peripheral nerves. I also show that the density of autophagy structures is higher in peripheral nerves of patients with chronic idiopathic axonal polyneuropathy (CIAP) and inflammatory neuropathy than in controls. The density of these structures increases with the severity of the neuropathy.

In animal model, using Goto-Kakizaki (GK) rats with diabetes resembling human type 2 diabetes, activation of autophagy by local administration of rapamycin incorporated in collagen conduits that were used for reconnection of the transected sciatic nerve led to an increase in autophagy proteins LC3 and a decrease in p62 suggesting that the autophagic flux was activated. In addition, immunoreactivity of neurofilaments, which are parts of the cytoskeleton of axons, was increased indicating increased axonal regeneration. I also show that many proteins involved in axonal regeneration and cell survival were up-regulated by rapamycin in the injured sciatic nerve of GK rats four weeks after injury.

Taken together, these findings provide new knowledge about the involvement of autophagy in neuropathy and after peripheral nerve injury and reconstruction using collagen conduits.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. 54 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1582
National Category
Neurosciences Cell and Molecular Biology Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-142125 (URN)10.3384/diss.diva-142125 (DOI)9789176854723 (ISBN)
Public defence
2017-10-31, Berzeliussalen, Campus US, Linköping, 12:09 (English)
Opponent
Supervisors
Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2017-11-14Bibliographically approved

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