GK大鼠的糖耐量受损和胰岛素减少会导致周围神经病变。

Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy.

作者信息

Murakawa Yuichi, Zhang Weixian, Pierson Christopher R, Brismar Tom, Ostenson Claes-Göran, Efendic Suad, Sima Anders A F

机构信息

Department of Pathology, Wayne State University, School of Medicine, Detroit, MI, USA.

出版信息

Diabetes Metab Res Rev. 2002 Nov-Dec;18(6):473-83. doi: 10.1002/dmrr.326.

DOI:10.1002/dmrr.326

PMID:12469361

Abstract

BACKGROUND

Recent studies indicate that impaired glucose tolerance (IGT) in man is a causative factor in idiopathic sensory neuropathy, and that insulinopenia may contribute substantially to the severity of diabetic peripheral neuropathy. The effect of sustained IGT and progressive insulinopenia in the absence of overt hyperglycemia on peripheral nerve abnormalities was examined in the Goto-Kakizaki (GK)-rat.

METHODS

Two and eighteen-month-old GK rats with decreased glucose tolerance and overt insulinopenia, respectively, were examined with respect to nerve function, structure, morphometry and molecular integrity, and were compared to age-matched control rats.

RESULTS

Both 2-(p < 0.001) and 18-month-old (p < 0.001) GK rats showed reduced body weight. Blood glucose levels following glucose tolerance tests were elevated in both the 2-month and the 18-month-old GK rats. Fasting plasma insulin levels in the 2-month GK rats were increased threefold (p < 0.05) but decreased by 71% (p < 0.001) in the 18-month GK rats. The two-month GK rats showed a normal nerve conduction velocity, whereas in the 18-month GK rats it was reduced to 76% (p < 0.001) of control values. No morphometric abnormalities were found in the 2-month GK rats, whereas the 18-month GK rats showed loss of small myelinated fibers (p < 0.001), atrophy and loss of unmyelinated axons (p < 0.05) and an increased (p < 0.01) frequency of regenerating fibers. In the older GK rats, both mRNA and protein expression of nerve growth factor (NGF) in the sciatic nerve were significantly reduced (p < 0.001 and p < 0.05), and NGFR TrkA (high affinity NGF receptor) and NGFRp75 (low affinity NGF-receptor) protein expression was reduced in dorsal root ganglia (DRG) (both p < 0.05). These changes were accompanied by significantly reduced protein expressions of substance P (SP) and calcitonin gene-related protein (CGRP) in DRG's (both p < 0.001) as well as a 40% (p < 0.001) decrease in SP and a 62% (p < 0.001) decrease in CGRP-positive DRG neurons. In the sciatic nerve, SP and CGRP protein expression was decreased by 71% (p < 0.01) and 79% (p < 0.01), respectively.

CONCLUSION

IGT combined with hyperinsulinemia for 2 months have no detectable effect on peripheral nerve function or structure. In contrast, IGT and subsequent insulinopenia result in a functional and structural neuropathy associated with impaired NGF support and neuropeptide synthesis. We suggest that these abnormalities are mainly due to insulinopenia rather than hyperglycemia.

摘要

背景

最近的研究表明，人类糖耐量受损（IGT）是特发性感觉神经病变的一个致病因素，并且胰岛素缺乏可能在很大程度上导致糖尿病性周围神经病变的严重程度。在Goto-Kakizaki（GK）大鼠中研究了持续IGT和渐进性胰岛素缺乏在无明显高血糖情况下对周围神经异常的影响。

方法

分别对葡萄糖耐量降低和明显胰岛素缺乏的2月龄和18月龄GK大鼠进行神经功能、结构、形态测量和分子完整性检查，并与年龄匹配的对照大鼠进行比较。

结果

2月龄（p<0.001）和18月龄（p<0.001）GK大鼠体重均减轻。葡萄糖耐量试验后的血糖水平在2月龄和18月龄GK大鼠中均升高。2月龄GK大鼠空腹血浆胰岛素水平增加了两倍（p<0.05），但18月龄GK大鼠中降低了71%（p<0.001）。2月龄GK大鼠神经传导速度正常，而18月龄GK大鼠中降至对照值的76%（p<0.001）。2月龄GK大鼠未发现形态测量异常，而18月龄GK大鼠显示有小的有髓纤维丢失（p<0.001）、无髓轴突萎缩和丢失（p<0.05）以及再生纤维频率增加（p<0.01）。在老年GK大鼠中，坐骨神经中神经生长因子（NGF）的mRNA和蛋白表达均显著降低（p<0.001和p<0.05），背根神经节（DRG）中NGF高亲和力受体（NGFR TrkA）和低亲和力受体（NGFRp75）蛋白表达降低（均p<0.05）。这些变化伴随着DRG中P物质（SP）和降钙素基因相关肽（CGRP）蛋白表达显著降低（均p<0.001）以及SP阳性DRG神经元减少40%（p<0.001）和CGRP阳性DRG神经元减少62%（p<0.001）。在坐骨神经中，SP和CGRP蛋白表达分别降低了71%（p<0.01）和79%（p<0.01）。