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Treatment-Induced Neuropathy in Diabetes (TIND)—Developing a Disease Model in Type 1 Diabetic Rats

Treatment-induced neuropathy in diabetes (TIND) is defined by the occurrence of an acute neuropathy within 8 weeks of an abrupt decrease in glycated hemoglobin-A1c (HbA1c). The underlying pathogenic mechanisms are still incompletely understood with only one mouse model being explored to date. The ai...

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Autores principales: Baum, Petra, Koj, Severin, Klöting, Nora, Blüher, Matthias, Classen, Joseph, Paeschke, Sabine, Gericke, Martin, Toyka, Klaus V., Nowicki, Marcin, Kosacka, Joanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913916/
https://www.ncbi.nlm.nih.gov/pubmed/33557206
http://dx.doi.org/10.3390/ijms22041571
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author Baum, Petra
Koj, Severin
Klöting, Nora
Blüher, Matthias
Classen, Joseph
Paeschke, Sabine
Gericke, Martin
Toyka, Klaus V.
Nowicki, Marcin
Kosacka, Joanna
author_facet Baum, Petra
Koj, Severin
Klöting, Nora
Blüher, Matthias
Classen, Joseph
Paeschke, Sabine
Gericke, Martin
Toyka, Klaus V.
Nowicki, Marcin
Kosacka, Joanna
author_sort Baum, Petra
collection PubMed
description Treatment-induced neuropathy in diabetes (TIND) is defined by the occurrence of an acute neuropathy within 8 weeks of an abrupt decrease in glycated hemoglobin-A1c (HbA1c). The underlying pathogenic mechanisms are still incompletely understood with only one mouse model being explored to date. The aim of this study was to further explore the hypothesis that an abrupt insulin-induced fall in HbA1c may be the prime causal factor of developing TIND. BB/OKL (bio breeding/OKL, Ottawa Karlsburg Leipzig) diabetic rats were randomized in three groups, receiving insulin treatment by implanted subcutaneous osmotic insulin pumps for 3 months, as follows: Group one received 2 units per day; group two 1 unit per day: and group three 1 unit per day in the first month, followed by 2 units per day in the last two months. We serially examined blood glucose and HbA1c levels, motor- and sensory/mixed afferent conduction velocities (mNCV and csNCV) and peripheral nerve morphology, including intraepidermal nerve fiber density and numbers of Iba-1 (ionized calcium binding adaptor molecule 1) positive macrophages in the sciatic nerve. Only in BB/OKL rats of group three, with a rapid decrease in HbA1c of more than 2%, did we find a significant decrease in mNCV in sciatic nerves (81% of initial values) after three months of treatment as compared to those group three rats with a less marked decrease in HbA1c <2% (mNCV 106% of initial values, p ≤ 0.01). A similar trend was observed for sensory/mixed afferent nerve conduction velocities: csNCV were reduced in BB/OKL rats with a rapid decrease in HbA1c >2% (csNCV 90% of initial values), compared to those rats with a mild decrease <2% (csNCV 112% of initial values, p ≤ 0.01). Moreover, BB/OKL rats of group three with a decrease in HbA1c >2% showed significantly greater infiltration of macrophages by about 50% (p ≤ 0.01) and a decreased amount of calcitonin gene related peptide (CGRP) positive nerve fibers as compared to the animals with a milder decrease in HbA1c. We conclude that a mild acute neuropathy with inflammatory components was induced in BB/OKL rats as a consequence of an abrupt decrease in HbA1c caused by high-dose insulin treatment. This experimentally induced neuropathy shares some features with TIND in humans and may be further explored in studies into the pathogenesis and treatment of TIND.
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spelling pubmed-79139162021-02-28 Treatment-Induced Neuropathy in Diabetes (TIND)—Developing a Disease Model in Type 1 Diabetic Rats Baum, Petra Koj, Severin Klöting, Nora Blüher, Matthias Classen, Joseph Paeschke, Sabine Gericke, Martin Toyka, Klaus V. Nowicki, Marcin Kosacka, Joanna Int J Mol Sci Article Treatment-induced neuropathy in diabetes (TIND) is defined by the occurrence of an acute neuropathy within 8 weeks of an abrupt decrease in glycated hemoglobin-A1c (HbA1c). The underlying pathogenic mechanisms are still incompletely understood with only one mouse model being explored to date. The aim of this study was to further explore the hypothesis that an abrupt insulin-induced fall in HbA1c may be the prime causal factor of developing TIND. BB/OKL (bio breeding/OKL, Ottawa Karlsburg Leipzig) diabetic rats were randomized in three groups, receiving insulin treatment by implanted subcutaneous osmotic insulin pumps for 3 months, as follows: Group one received 2 units per day; group two 1 unit per day: and group three 1 unit per day in the first month, followed by 2 units per day in the last two months. We serially examined blood glucose and HbA1c levels, motor- and sensory/mixed afferent conduction velocities (mNCV and csNCV) and peripheral nerve morphology, including intraepidermal nerve fiber density and numbers of Iba-1 (ionized calcium binding adaptor molecule 1) positive macrophages in the sciatic nerve. Only in BB/OKL rats of group three, with a rapid decrease in HbA1c of more than 2%, did we find a significant decrease in mNCV in sciatic nerves (81% of initial values) after three months of treatment as compared to those group three rats with a less marked decrease in HbA1c <2% (mNCV 106% of initial values, p ≤ 0.01). A similar trend was observed for sensory/mixed afferent nerve conduction velocities: csNCV were reduced in BB/OKL rats with a rapid decrease in HbA1c >2% (csNCV 90% of initial values), compared to those rats with a mild decrease <2% (csNCV 112% of initial values, p ≤ 0.01). Moreover, BB/OKL rats of group three with a decrease in HbA1c >2% showed significantly greater infiltration of macrophages by about 50% (p ≤ 0.01) and a decreased amount of calcitonin gene related peptide (CGRP) positive nerve fibers as compared to the animals with a milder decrease in HbA1c. We conclude that a mild acute neuropathy with inflammatory components was induced in BB/OKL rats as a consequence of an abrupt decrease in HbA1c caused by high-dose insulin treatment. This experimentally induced neuropathy shares some features with TIND in humans and may be further explored in studies into the pathogenesis and treatment of TIND. MDPI 2021-02-04 /pmc/articles/PMC7913916/ /pubmed/33557206 http://dx.doi.org/10.3390/ijms22041571 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Baum, Petra
Koj, Severin
Klöting, Nora
Blüher, Matthias
Classen, Joseph
Paeschke, Sabine
Gericke, Martin
Toyka, Klaus V.
Nowicki, Marcin
Kosacka, Joanna
Treatment-Induced Neuropathy in Diabetes (TIND)—Developing a Disease Model in Type 1 Diabetic Rats
title Treatment-Induced Neuropathy in Diabetes (TIND)—Developing a Disease Model in Type 1 Diabetic Rats
title_full Treatment-Induced Neuropathy in Diabetes (TIND)—Developing a Disease Model in Type 1 Diabetic Rats
title_fullStr Treatment-Induced Neuropathy in Diabetes (TIND)—Developing a Disease Model in Type 1 Diabetic Rats
title_full_unstemmed Treatment-Induced Neuropathy in Diabetes (TIND)—Developing a Disease Model in Type 1 Diabetic Rats
title_short Treatment-Induced Neuropathy in Diabetes (TIND)—Developing a Disease Model in Type 1 Diabetic Rats
title_sort treatment-induced neuropathy in diabetes (tind)—developing a disease model in type 1 diabetic rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913916/
https://www.ncbi.nlm.nih.gov/pubmed/33557206
http://dx.doi.org/10.3390/ijms22041571
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