Singapore Institute for Neurotechnology, National University of Singapore, Singapore.
Department of Biotechnology, Ho Chi Minh City University of Food Industry, Ho Chi Minh City, Vietnam.
Diabetes. 2023 Jun 1;72(6):795-811. doi: 10.2337/db22-0743.
Diabetic polyneuropathy (DPN) renders progressive sensory neurodegeneration linked to hyperglycemia and its associated metabolopathy. We hypothesized that there may be additive impacts of direct insulin signaling, independent of glycemia and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) knockdown on neuropathy. Our targets for combined interventions were neurons and Schwann cells (SCs) in vitro and chronic type 1 DPN in mice. Insulin receptor expression was not altered by high-glucose conditions in neurons or SCs, and insulin promoted survival of neurons and proliferation of SCs in vitro. There were additive impacts between insulin signaling and PTEN knockdown in sensory neuron outgrowth and in axon myelination by SCs. In a chronic mouse model of experimental DPN, unilateral intra-hind paw injections of a PTEN siRNA and local insulin had additive impacts on correcting key features of chronic experimental DPN independent of glycemia, including motor axon conduction and thermal and mechanical sensory loss. Moreover, combined interventions improved sural and tibial nerve myelin thickness, hind paw epidermal innervation, and pAkt expression in dorsal root ganglion sensory neurons. We conclude that local PTEN inhibition or knockdown and insulin provide additive trophic support for sensory neurons and SCs while reversing key abnormalities of experimental DPN but without requiring metabolic correction.
Impaired growth and plasticity of neurons may contribute to chronic diabetic polyneuropathy. Both direct insulin signaling of neurons and neuron knockdown of the protein phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a roadblock to neuronal regenerative growth, offer direct support of neurons. Direct insulin and PTEN knockdown using siRNA had additive impacts on neuron survival, Schwann cell proliferation, neuron outgrowth, and myelination in vitro. Combined local insulin and PTEN siRNA hind paw injections improved abnormalities in chronic experimental diabetic polyneuropathy, including sensory axon loss, independently of glycemia.
糖尿病性多发性神经病（DPN）导致与高血糖及其相关代谢病相关的进行性感觉神经退行性变。我们假设，直接胰岛素信号可能会产生附加影响，而与血糖和磷酸酶和张力蛋白同源物缺失 10 号染色体（PTEN）敲低无关，对神经病有影响。我们联合干预的目标是神经元和施万细胞（SCs）在体外和慢性 1 型糖尿病周围神经病小鼠。高葡萄糖条件下神经元或 SCs 的胰岛素受体表达未改变，胰岛素促进神经元存活和 SCs 的增殖。在感觉神经元生长和 SCs 轴突髓鞘形成中，胰岛素信号和 PTEN 敲低之间存在附加影响。在慢性实验性糖尿病周围神经病小鼠模型中，单侧后爪内注射 PTEN siRNA 和局部胰岛素对纠正慢性实验性糖尿病周围神经病的关键特征具有附加作用，包括运动轴突传导和热和机械感觉丧失，而与血糖无关。此外，联合干预改善了后爪和胫骨神经髓鞘厚度、后爪表皮神经支配和背根神经节感觉神经元中的 pAkt 表达。我们的结论是，局部 PTEN 抑制或敲低和胰岛素为感觉神经元和 SCs 提供了附加的营养支持，同时逆转了实验性糖尿病周围神经病的关键异常，但不需要代谢纠正。
神经元生长和可塑性受损可能导致慢性糖尿病性多发性神经病。神经元的直接胰岛素信号和蛋白磷酸酶和张力蛋白同源物缺失 10 号染色体（PTEN）的神经元敲低，是神经元再生生长的障碍，都为神经元提供了直接支持。使用 siRNA 的直接胰岛素和 PTEN 敲低对神经元存活、施万细胞增殖、神经元生长和体外髓鞘形成具有附加影响。局部胰岛素和 PTEN siRNA 后爪注射联合改善了慢性实验性糖尿病周围神经病的异常，包括感觉轴突丧失，与血糖无关。
