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Combined PTEN knockdown and local insulin in chronic experimental diabetic neuropathy
Diabetes ( IF 6.2 ) Pub Date : 2023-03-17 , DOI: 10.2337/db22-0743
Vuong M Pham 1, 2 , Prashanth Komirishetty 3 , Aparna Areti 3 , Trevor Poitras 3 , Nitish Thakor 4 , Douglas W Zochodne 3
Affiliation  

Diabetic polyneuropathy (DPN) renders progressive sensory neurodegeneration linked to hyperglycemia and its associated metabolopathy. Here we hypothesized that there may be additive impacts of direct insulin signaling, independent of glycemia and PTEN (phosphatase and tensin homolog deleted on chromosome 10) knockdown on neuropathy. Our targets for combined interventions were neurons and Schwann cells in vitro and chronic Type 1 DPN in mice. IR (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 long term mouse model of experimental DPN unilateral intra-hindpaw 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, thermal and mechanical sensory loss. Moreover, combined interventions improved sural and tibial nerve myelin thickness, hindpaw epidermal innervation and pAkt expression in dorsal root ganglia sensory neurons. We conclude that local PTEN inhibition or knockdown and insulin provide additive trophic support for sensory neurons and SCs whilst reversing key abnormalities of experimental DPN but without requiring metabolic correction.

中文翻译:

联合 PTEN 敲低和局部胰岛素治疗慢性实验性糖尿病神经病变

糖尿病性多发性神经病 (DPN) 呈现与高血糖及其相关代谢病相关的进行性感觉神经变性。在这里,我们假设可能存在直接胰岛素信号传导的附加影响,与血糖和 PTEN(磷酸酶和张力蛋白同源物在 10 号染色体上删除)敲低对神经病变无关。我们联合干预的目标是体外神经元和雪旺细胞以及小鼠慢性 1 型 DPN。神经元或 SC 中的高葡萄糖条件不会改变 IR(胰岛素受体)的表达,胰岛素促进神经元的存活和 SC 的体外增殖。在感觉神经元的生长和 SC 的轴突髓鞘形成中,胰岛素信号传导和 PTEN 敲低之间存在累加影响。在实验性 DPN 的慢性长期小鼠模型中,单侧后爪内注射 PTEN siRNA 和局部胰岛素对纠正独立于血糖的慢性实验性 DPN 的关键特征具有附加影响,包括运动轴突传导、热和机械感觉丧失。此外,联合干预改善了腓肠和胫神经髓鞘厚度、后爪表皮神经支配和背根神经节感觉神经元中的 pAkt 表达。我们得出结论,局部 PTEN 抑制或敲低和胰岛素为感觉神经元和 SC 提供额外的营养支持,同时逆转实验性 DPN 的关键异常,但不需要代​​谢校正。热和机械感觉丧失。此外,联合干预改善了腓肠和胫神经髓鞘厚度、后爪表皮神经支配和背根神经节感觉神经元中的 pAkt 表达。我们得出结论,局部 PTEN 抑制或敲低和胰岛素为感觉神经元和 SC 提供额外的营养支持,同时逆转实验性 DPN 的关键异常,但不需要代​​谢校正。热和机械感觉丧失。此外,联合干预改善了腓肠和胫神经髓鞘厚度、后爪表皮神经支配和背根神经节感觉神经元中的 pAkt 表达。我们得出结论,局部 PTEN 抑制或敲低和胰岛素为感觉神经元和 SC 提供额外的营养支持,同时逆转实验性 DPN 的关键异常,但不需要代​​谢校正。
更新日期:2023-03-17
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