Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, 168 HMRB, 3330 Hospital Dr. NW, Calgary, Canada.
Neurobiol Dis. 2011 Aug;43(2):414-21. doi: 10.1016/j.nbd.2011.04.012. Epub 2011 Apr 17.
Insulin deficiency may contribute toward the neurological deficits of diabetic polyneuropathy (DPN). In particular, the unique trophic properties of insulin, acting on sensory neuron and axon receptors offer an approach toward reversing loss of skin axons that develops during diabetes. Here we examined how local cutaneous insulin, acting on axon receptors, influences innervation of the epidermis. That cutaneous axons might be amenable to regrowth was suggested by confirming that a high proportion of epidermal axons expressed GAP43/B50, a growth associated protein. Also, IRβ (insulin receptor subunit β) mRNA was expressed and upregulated in the footpads of diabetic mice and protein expression was upregulated in their sensory dorsal root ganglia. Moreover, footpads expressed mRNAs of the downstream insulin transduction molecules, IRS-1 and IRS-2. IRβ protein was identified in dermal axons, some epidermal sensory axons, and in keratinocytes. In separate models of experimental diabetes, we identified a surprising and rapid local response of this axon population to insulin. C57BL/6J streptozotocin (STZ) injected mice, as a model of type 1 diabetes and dbdb mice, as a model of type 2 diabetes were both evaluated after 3 months of diabetes duration. Local hindpaw plantar injections of low dose subhypoglycemic insulin (that did not alter diabetic hyperglycemia) and carrier (into the opposite paw) were given over two days and innervation studied at 5 days. Insulin injections in both models were associated with an ipsilateral rise in the density of PGP 9.5 labeled diabetic epidermal axons at 5 days, compared to that of their contralateral carrier injected hindpaw. Nondiabetic controls did not have changes in innervation following insulin. In a separate cohort of STZ diabetic mice and controls evaluated for paw sensation, there was mild improvement in mechanical, but not thermal sensation at 2 weeks after insulin injection in diabetics but not controls. Fine unmyelinated epidermal axons have considerable plasticity. Here we identify a rapid improvement of skin innervation by doses of insulin insufficient to alter glycemia or innervation of the opposite paw. Local direct insulin signaling of receptors expressed on diabetic cutaneous axons may reverse retraction of their branches during experimental DPN.
胰岛素缺乏可能是导致糖尿病多发性神经病（DPN）神经功能缺损的原因之一。特别是，胰岛素的独特营养特性，作用于感觉神经元和轴突受体，为逆转糖尿病过程中皮肤轴突的丧失提供了一种方法。在这里，我们研究了局部皮肤胰岛素通过轴突受体作用如何影响表皮的神经支配。表皮轴突可能能够再生，这一点得到了证实，即高比例的表皮轴突表达了生长相关蛋白 GAP43/B50。此外，IRβ（胰岛素受体亚单位β）mRNA 在糖尿病小鼠的足垫中表达并上调，其感觉背根神经节中的蛋白表达上调。此外，足垫还表达了下游胰岛素转导分子 IRS-1 和 IRS-2 的 mRNA。IRβ 蛋白在真皮轴突、一些表皮感觉轴突和角质形成细胞中被鉴定出来。在实验性糖尿病的不同模型中，我们发现这种轴突群体对胰岛素的局部反应令人惊讶且迅速。C57BL/6J 链脲佐菌素（STZ）注射小鼠作为 1 型糖尿病模型和 dbdb 小鼠作为 2 型糖尿病模型，在糖尿病持续 3 个月后均进行了评估。在两天内，对低剂量亚低血糖胰岛素（不会改变糖尿病高血糖）和载体（对侧爪）进行局部后爪足底注射，并在第 5 天研究神经支配情况。在两种模型中，与对侧载体注射后爪相比，胰岛素注射均导致同侧 PGP 9.5 标记的糖尿病表皮轴突密度在第 5 天增加。非糖尿病对照组在接受胰岛素后神经支配没有变化。在另一组接受 STZ 糖尿病小鼠和对照者评估的爪感觉的队列中，在糖尿病患者中，在胰岛素注射后 2 周时，机械感觉有轻度改善，但热感觉没有改善，但在对照组中没有。无髓细表皮轴突具有相当大的可塑性。在这里，我们发现，即使胰岛素剂量不足以改变血糖或对侧爪的神经支配，也能快速改善皮肤神经支配。表达在糖尿病皮肤轴突上的受体的局部直接胰岛素信号可能会逆转实验性 DPN 中分支的回缩。
