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Peripheral Hypoglycaemic Neuropathy in Type 1 Diabetic Rats: Morphologic and Metabolic Studies
Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hyperglycaemia caused by insulin deficiency is believed to play a major role in the de-velopment of neuropathy in diabetic patients. The clinical and pathological features of diabetic neuropathy vary considerably, although sensory and autonomic dysfunctions are the most common characteristics. Normalisation of the blood glucose level by ef-fective insulin treatment decreases the incidence of diabetic neuropathy in patients. However, intensive insulin therapy may result in more frequent hypoglycaemic epi-sodes than are provoked by less ambitious diabetes control. Neuropathy might also be induced by severe hypoglycaemia in diabetes or insulinoma. Accordingly, it seems that the diversity in clinical symptoms of diabetic neuropathy may be due to the combined effects of hyperglycaemia and hypoglycaemia. Based on that assumption, the general aim of this project was to study the relationship between severe hypoglycaemia and pe-ripheral neuropathy in diabetic rats. To understand how the development of neuropathy is related to glycaemic control, we needed to be aware of the glucose dynamics in the animal model that we used. The aim was to ascertain whether the diabetic rats were similar to type 1 diabetic patients with regard to such dynamics. To achieve that goal, we used a MiniMed continuous glucose monitoring system (CGMS®) to measure sub-cutaneous glucose in freely moving rats over a period of 72 hours. The glucose monitor worked well, and it showed that the insulin-treated diabetic BB/Wor rats with a hyper-glycaemic insulin regimen have a glycaemic status similar to that of type 1 diabetic patients with poor glycaemic control. The diabetic rats with a hypoglycaemic regimen generally had low blood glucose levels.

Prolonged hypoglycaemia led to axonal de- and regeneration of large myelinated fibres in vagus nerve destined to the laryngeal muscle. Axonal de- and regeneration was also observed in the gastrocnemius and sural nerves, although the frequency of degeneration was much lower in the sural nerve. Small myelinated and unmyelinated nerve fibres were normal in these nerves. These results suggest that hypoglycaemia preferentially damages muscle-related nerve fibres. In contrast, in the diabetic rats exposed to pro-longed hyperglycaemia, only the sural nerve exhibited decreased myelinated fibre diameter in the absence of obvious axonal degeneration.

In situ glucose measurements by microdialysis showed that the glucose concentrations in blood and subcutaneous tissue were similar in healthy, diabetic hyperglycaemic, and diabetic hypoglycaemic rats. In the healthy and hyperglycaemic animals, the lowest glucose level was found in the peripheral nerve. Moreover, in controls, the glucose level was lower in muscle than in blood. In hypoglycaemic rats, there were no signifi-cant differences in glucose concentrations between different tissues.

Place, publisher, year, edition, pages
2006.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 973
Keyword [en]
Diabetes Mellitu, Hypoglycaemia, Neuropathy, Morphology, Microdialysis, Glucose level
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-7978ISBN: 91-85643-20-3 (print)OAI: oai:DiVA.org:liu-7978DiVA: diva2:22867
Public defence
2006-12-15, Eken, Cell Biology, 581 85 Linköping, Camups US, 09:00 (English)
Opponent
Supervisors
Available from: 2007-01-09 Created: 2007-01-09 Last updated: 2016-02-29
List of papers
1. Continuous monitoring of the subcutaneous glucose level in freely moving normal and diabetic rats and in humans with Type I diabetes
Open this publication in new window or tab >>Continuous monitoring of the subcutaneous glucose level in freely moving normal and diabetic rats and in humans with Type I diabetes
2002 (English)In: Diabetes Technology and Therapeutics, ISSN 1520-9156, Vol. 4, no 3, 305-312 p.Article in journal (Refereed) Published
Abstract [en]

Laboratory animals are extensively used in diabetic research. However, it is not known whether the glucose dynamics in laboratory animals are similar to the dynamics in humans. The aim of the present study is to see whether the Medtronic MiniMed continuous subcutaneous glucose monitoring system can be used to record fluctuations of the glucose level in freely moving normal and insulin-treated diabetic rats. The monitoring system was applied during 3 days to normal and diabetic hyperglycemic and hypoglycemic rats treated with insulin implants. Corresponding data from type 1 diabetic patients with poor glycemic control were selected retrospectively in order to note the similarities and differences. In normal rats the subcutaneous glucose level varied slightly (median = 111 mg/dL). In hyperglycemic rats the subcutaneous glucose values fluctuated markedly around a median of 226 mg/dL. The fluctuations formed a short-wave pattern with a low amplitude, superimposed on a long-wave pattern with a high amplitude. The subcutaneous glucose profile seen in type 1 diabetic patients (median = 180 mg/dL) was similar to that observed in hyperglycemic rats. In hypoglycemic rats, the subcutaneous glucose level fluctuated moderately around a median of 55 mg/dL. In these rats the fluctuations formed a short-wave pattern with low amplitude, without any obvious long-wave pattern. The subcutaneous glucose values conformed to corresponding blood glucose measurements. We conclude that the Medtronic MiniMed continuous glucose monitoring system can be used to record the subcutaneous glucose level over time in freely moving rats.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14187 (URN)10.1089/152091502760098447 (DOI)
Available from: 2007-01-09 Created: 2007-01-09 Last updated: 2016-02-29
2. Hypoglycaemia causes degeneration of large myelinated nerve fibres in the vagus nerve of insulin-treated diabetic ΒB/Wor rats
Open this publication in new window or tab >>Hypoglycaemia causes degeneration of large myelinated nerve fibres in the vagus nerve of insulin-treated diabetic ΒB/Wor rats
2005 (English)In: Acta Neuropathologica, ISSN 0001-6322, Vol. 109, no 2, 198-206 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to find out whether dysglycaemia causes neuropathy in the vagus nerve of insulin-treated diabetic BB/Wor rats. Specimens were collected from the left vagus nerve proximal and distal to the level of recurrent laryngeal branch and from the recurrent branch itself in control rats and diabetic BB/Wor rats subjected to hyper- or hypoglycaemia. Myelinated and unmyelinated axons were counted and myelinated axon diameters were measured by electron microscopy. In controls, the vagus nerve proximal to the recurrent branch exhibited three regions in terms of fibre composition: part A was mainly composed of large myelinated axons, part B contained small myelinated and unmyelinated axons, and part C contained mainly unmyelinated axons. The distal level resembled part C at the proximal level and the recurrent branch resembled parts A and B. In hyperglycaemic rats, a normal picture was found at the proximal and distal levels of the vagus nerve and in the recurrent branch. In hypoglycaemic rats, signs of past and ongoing degeneration and regeneration of large myelinated axons were found at the proximal and distal levels and in the recurrent branch. We conclude that hypoglycaemia elicits degenerative alterations in large myelinated axons in the vagus and recurrent laryngeal nerves in diabetic BB/Wor rats. The absence of signs of neuropathy in unmyelinated and small myelinated axons suggests that the sensory and autonomic components of the nerve are less affected. In contrast, the hyperglycaemic rats examined here did not show obvious degenerative alterations.

Keyword
Diabetes mellitus, Hypoglycaemia, Neuropathy, Vagus nerve, BB/Wor rat
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14188 (URN)10.1007/s00401-004-0932-1 (DOI)
Available from: 2007-01-09 Created: 2007-01-09 Last updated: 2016-02-29
3. Differential neuropathies in hyperglycemic and hypoglycemic diabetic rats
Open this publication in new window or tab >>Differential neuropathies in hyperglycemic and hypoglycemic diabetic rats
2006 (English)In: Journal of Neuropathology & Experimental Neurology, ISSN 0022-3069, Vol. 65, no 12, 1118-1125 p.Article in journal (Refereed) Published
Abstract [en]

We investigated the effects of hyperglycemia and hypoglycemia on development of peripheral neuropathy in somatic motor and sensory nerves in type 1 diabetic BB/Wor rats. The animals were maintained in a hyper- or hypoglycemic state by treatment with insulin for 3 months. Nondiabetic siblings served as controls. Qualitative analysis of the gastrocnemius and sural nerves by light and electron microscopy revealed signs of Wallerian-type axonal degeneration and regeneration of large myelinated fibers in the hypoglycemic but not the hyperglycemic animals. Degeneration was more common in the gastrocnemius nerve than in the sural nerve. In hypoglycemic rats, myelinated fibers in both the gastrocnemius and sural nerves had significantly shorter internodes and smaller diameters. The decreased fiber diameter was related (r = -0.9) to the duration of severe hypoglycemia (≤2.5 mmol/L). Myelinated fiber occupancy was also decreased without any significant changes in fiber counts in both the gastrocnemius and sural nerves. In hyperglycemic rats, myelinated fibers in the sural nerve but not the gastrocnemius nerve had smaller diameters compared with controls. We conclude that hypoglycemia has a more severe impact on somatic motor nerves than on somatic sensory nerves, whereas hyperglycemia affects only somatic sensory nerves.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14189 (URN)10.1097/01.jnen.0000248546.13176.d4 (DOI)
Available from: 2007-01-09 Created: 2007-01-09 Last updated: 2016-02-29
4. Simultaneous glucose measurement in blood, peripheral nerve, muscle and skin in control and diabetic rats
Open this publication in new window or tab >>Simultaneous glucose measurement in blood, peripheral nerve, muscle and skin in control and diabetic rats
Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-14190 (URN)
Available from: 2007-01-09 Created: 2007-01-09 Last updated: 2010-01-13

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