Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
J Neuropathol Exp Neurol. 2011 May;70(5):323-39. doi: 10.1097/NEN.0b013e318215669a.
Retraction of distal sensory axons is a prominent feature in diabetic peripheral neuropathy (DPN), a process amenable to insulin therapy. Nevertheless, diabetic patients and long-term diabetic mice develop motor deficits after longer durations of DPN, a process that may be related to insulin deficiency. To compare the efficacy of intranasal delivery of insulin (IN-I) and subcutaneous insulin (Subc-I) in preventing motor deficits in a long-term mouse model of DPN, IN-I or Subc-I, 0.87 IU daily or placebo was delivered in separate cohorts of diabetic and nondiabetic CD1 mice for 8 months. Radiolabeled detection was used to assess insulin delivery and biodistribution. Biweekly behavioral tests and monthly electrophysiological and multipoint quantitative studies assessed motor function deficits. Morphometric analysis of spinal cord, peripheral nerve, muscle innervation, and specific molecular markers were evaluated at and before the end point. Despite progressive distal axonal terminal loss, numbers and caliber of motor neurons were preserved. There were no differences in glycemia between IN-I and Subc-I-treated mice. Intranasal delivery of insulin and, to a lesser extent, Subc-I, protected against electrophysiological decline, loss of neuromuscular junctions, and loss of motor behavioral skills. Intranasal delivery of insulin was associated with greater preservation of the phosphatidylinositol 3-kinase signaling pathway involving Akt, cyclic AMP response element binding protein,and glycogen synthase kinase 3β but did not alter extracellular signal-regulated kinase, mitogen-activated protein kinase/extracellular signal-regulated kinase, or c-Jun amino-terminal kinase. Thus, direct delivery of insulin to the nervous system might prevent motor deficit in human type 1 diabetes by preservation of the phosphatidylinositol 3-kinase-Akt pathway rather than only affecting glycemic levels; the effects of insulin on other signaling pathways may, however, play additional roles.
远端感觉轴突的回缩是糖尿病周围神经病变（DPN）的一个显著特征，这一过程对胰岛素治疗有效。然而，糖尿病患者和长期糖尿病小鼠在 DPN 更长时间后会出现运动功能障碍，这一过程可能与胰岛素缺乏有关。为了比较经鼻给予胰岛素（IN-I）和皮下给予胰岛素（Subc-I）在预防长期 DPN 小鼠模型运动功能障碍中的疗效，分别在糖尿病和非糖尿病 CD1 小鼠的两个亚组中给予 0.87 IU 的 IN-I 或 Subc-I 或安慰剂，持续 8 个月。放射性标记检测用于评估胰岛素的递送和生物分布。双周行为测试和每月电生理及多点定量研究评估运动功能障碍。在终点前评估脊髓、周围神经、肌肉神经支配和特定分子标志物的形态计量学分析。尽管远端轴突末端逐渐丧失，但运动神经元的数量和口径仍保持不变。IN-I 和 Subc-I 治疗的小鼠血糖无差异。经鼻给予胰岛素和（在一定程度上）Subc-I 可防止电生理下降、神经肌肉接头丧失和运动行为技能丧失。经鼻给予胰岛素与胰岛素信号通路中磷酸肌醇 3-激酶（PI3K）途径的更大保留有关，该途径涉及 Akt、环磷酸腺苷反应元件结合蛋白和糖原合酶激酶 3β，但不改变细胞外信号调节激酶、丝裂原活化蛋白激酶/细胞外信号调节激酶或 c-Jun 氨基末端激酶。因此，直接将胰岛素递送至神经系统可能通过保留 PI3K-Akt 途径来预防人类 1 型糖尿病的运动功能障碍，而不仅仅是影响血糖水平；然而，胰岛素对其他信号通路的作用可能发挥额外的作用。
