Baum Petra, Koj Severin, Klöting Nora, Blüher Matthias, Classen Joseph, Paeschke Sabine, Gericke Martin, Toyka Klaus V, Nowicki Marcin, Kosacka Joanna
Department of Neurology, University of Leipzig, Liebigstraße 20, D-04103 Leipzig, Germany.
Department of Medicine, University of Leipzig, Liebigstraße 21, D-04103 Leipzig, Germany.
Int J Mol Sci. 2021 Feb 4;22(4):1571. doi: 10.3390/ijms22041571.
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. (bio breeding/, 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 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, ≤ 0.01). A similar trend was observed for sensory/mixed afferent nerve conduction velocities: csNCV were reduced in 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, ≤ 0.01). Moreover, rats of group three with a decrease in HbA1c >2% showed significantly greater infiltration of macrophages by about 50% ( ≤ 0.01) and a decreased amount of calcitonin gene related peptide () 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.
糖尿病治疗诱导性神经病变（TIND）的定义为糖化血红蛋白A1c（HbA1c）急剧下降后8周内出现急性神经病变。其潜在致病机制仍未完全明确，迄今为止仅探索了一种小鼠模型。本研究的目的是进一步探究以下假说：胰岛素诱导的HbA1c急剧下降可能是TIND发生的主要因果因素。将（生物繁殖/，渥太华卡尔斯堡莱比锡）糖尿病大鼠随机分为三组，通过植入皮下渗透胰岛素泵接受胰岛素治疗3个月，具体如下：第一组每天接受2单位；第二组每天1单位；第三组在第一个月每天1单位，后两个月每天2单位。我们连续检测血糖和HbA1c水平、运动及感觉/混合传入神经传导速度（mNCV和csNCV）以及周围神经形态，包括表皮内神经纤维密度和坐骨神经中Iba-1（离子钙结合衔接分子1）阳性巨噬细胞数量。仅在第三组大鼠中，HbA1c快速下降超过2%，与HbA1c下降不明显<2%的第三组大鼠相比，治疗3个月后坐骨神经mNCV显著下降（降至初始值的81%）（P≤0.01）。感觉/混合传入神经传导速度也观察到类似趋势：HbA1c快速下降>2%的大鼠csNCV降低（csNCV为初始值的90%），而HbA1c轻度下降<2%的大鼠csNCV为初始值的112%（P≤0.01）。此外，与HbA1c下降较轻微的动物相比，HbA1c下降>2%的第三组大鼠巨噬细胞浸润显著增加约50%（P≤0.01），降钙素基因相关肽（）阳性神经纤维数量减少。我们得出结论，高剂量胰岛素治疗导致HbA1c急剧下降，从而在BB/OKL大鼠中诱发了伴有炎症成分的轻度急性神经病变。这种实验诱导的神经病变与人类TIND有一些共同特征，可在TIND发病机制和治疗研究中进一步探索。
