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Open AccessArticle

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

Department of Neurology, University of Leipzig, Liebigstraße 20, D-04103 Leipzig, Germany
Department of Medicine, University of Leipzig, Liebigstraße 21, D-04103 Leipzig, Germany
Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), Helmholtz Zentrum München, University of Leipzig, Philipp-Rosenthal-Straße 27, D-04103 Leipzig, Germany
Institute of Anatomy, University of Leipzig, Liebigstraße 13, D-04103 Leipzig, Germany
Institute of Anatomy and Cell Biology, University of Halle, Große Steinstraße 52, D-06108 Halle, Germany
Department of Neurology, University of Würzburg, Josef-Schneider-Straße 11, D-97080 Würzburg, Germany
Author to whom correspondence should be addressed.
P.B. and S.K.—equal contribution as the first authors.
M.N. and J.K.—equal contribution as the senior authors.
Academic Editor: Anna Solini
Int. J. Mol. Sci. 2021, 22(4), 1571;
Received: 23 December 2020 / Revised: 27 January 2021 / Accepted: 2 February 2021 / Published: 4 February 2021
(This article belongs to the Section Molecular Neurobiology)
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. View Full-Text
Keywords: BB/OKL rats; peripheral neuropathy; sciatic nerve; TIND; Type 1 diabetes BB/OKL rats; peripheral neuropathy; sciatic nerve; TIND; Type 1 diabetes
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MDPI and ACS Style

Baum, P.; Koj, S.; Klöting, N.; Blüher, M.; Classen, J.; Paeschke, S.; Gericke, M.; Toyka, K.V.; Nowicki, M.; Kosacka, J. Treatment-Induced Neuropathy in Diabetes (TIND)—Developing a Disease Model in Type 1 Diabetic Rats. Int. J. Mol. Sci. 2021, 22, 1571.

AMA Style

Baum P, Koj S, Klöting N, Blüher M, Classen J, Paeschke S, Gericke M, Toyka KV, Nowicki M, Kosacka J. Treatment-Induced Neuropathy in Diabetes (TIND)—Developing a Disease Model in Type 1 Diabetic Rats. International Journal of Molecular Sciences. 2021; 22(4):1571.

Chicago/Turabian Style

Baum, Petra; Koj, Severin; Klöting, Nora; Blüher, Matthias; Classen, Joseph; Paeschke, Sabine; Gericke, Martin; Toyka, Klaus V.; Nowicki, Marcin; Kosacka, Joanna. 2021. "Treatment-Induced Neuropathy in Diabetes (TIND)—Developing a Disease Model in Type 1 Diabetic Rats" Int. J. Mol. Sci. 22, no. 4: 1571.

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