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Protective effects of polyamine depletion in mouse models of type 1 diabetes: implications for therapy

机译:多胺耗竭对1型糖尿病小鼠模型的保护作用:对治疗的意义

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摘要

The underlying pathophysiology of type 1 diabetes involves autoimmune-mediated islet inflammation, leading to dysfunction and death of insulin-secreting islet β cells. Recent studies have shown that polyamines, which are essential for mRNA translation, cellular replication, and the formation of the hypusine modification of eIF5A may play an important role in the progression of cellular inflammation. To test a role for polyamines in type 1 diabetes pathogenesis, we administered the ornithine decarboxylase inhibitor difluoromethylornithine to two mouse models--the low-dose streptozotocin model and the NOD model--to deplete intracellular polyamines, and administered streptozotocin to a third model, which was haploinsufficient for the gene encoding the hypusination enzyme deoxyhypusine synthase. Subsequent development of diabetes and/or glucose intolerance was monitored. In the low-dose streptozotocin mouse model, continuous difluoromethylornithine administration dose-dependently reduced the incidence of hyperglycemia and led to the preservation of β cell area, whereas in the NOD mouse model of autoimmune diabetes difluoromethylornithine reduced diabetes incidence by 50%, preserved β cell area and insulin secretion, led to reductions in both islet inflammation and potentially diabetogenic Th17 cells in pancreatic lymph nodes. Difluoromethylornithine treatment reduced hypusinated eIF5A levels in both immune cells and islets. Animals haploinsufficient for the gene encoding deoxyhypusine synthase were partially protected from hyperglycemia induced by streptozotocin. Collectively, these studies suggest that interventions that interfere with polyamine biosynthesis and/or eIF5A hypusination may represent viable approaches in the treatment of diabetes.
机译:1型糖尿病的潜在病理生理学涉及自身免疫介导的胰岛炎症,导致胰岛素分泌胰岛β细胞功能障碍和死亡。最近的研究表明,多胺对mRNA的翻译,细胞复制以及eIF5A的酪氨酸修饰的形成是必不可少的,可能在细胞炎症的进展中起重要作用。为了测试多胺在1型糖尿病发病机制中的作用,我们向两种小鼠模型(低剂量链脲佐菌素模型和NOD模型)施用了鸟氨酸脱羧酶抑制剂二氟甲基鸟氨酸,以耗尽细胞内多胺,对第三种模型施用了链脲佐菌素,其单倍不足以编码编码羟化酶deoxyhypusine合酶的基因。监测糖尿病和/或葡萄糖不耐症的随后发展。在低剂量链脲佐菌素小鼠模型中,连续二氟甲基鸟氨酸给药可剂量依赖性地降低高血糖的发生率并导致β细胞面积的保留,而在自身免疫性糖尿病的NOD小鼠模型中,二氟甲基鸟氨酸将糖尿病的发病率降低50%,β细胞得以保留面积和胰岛素分泌,导致胰岛炎症和胰腺淋巴结中可能致糖尿病的Th17细胞减少。二氟甲基鸟氨酸治疗可降低免疫细胞和胰岛中的养分蛋白eIF5A水平。对编码脱氧hysupsine合酶的基因单倍不足的动物被部分保护免受链脲佐菌素诱导的高血糖症的影响。总体而言,这些研究表明,干扰多胺生物合成和/或eIF5A促性素化的干预措施可能是治疗糖尿病的可行方法。

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