GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/Akt pathway
GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/Akt pathway
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DOI：
10.1172/jci26295
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发表时间：
2006-02-01
影响因子：
15.9
通讯作者：
Srinivasan, S
中科院分区：
文献类型：
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作者：
Anitha, M;Gondha, C;Srinivasan, S
糖尿病可导致肠神经元的丧失和随后的胃肠道并发症。糖尿病中肠神经元丢失的机制尚不清楚。我们研究了高血糖对肠神经元存活的影响，以及胶质细胞源性神经营养因子（GDNF）对调节这种存活的影响。原代肠神经元暴露于20 mM葡萄糖（高血糖症）24小时导致细胞凋亡的显着增加相比，5 mM葡萄糖（正常）。暴露于20 mM葡萄糖导致Akt磷酸化降低和叉头盒O3 a（FOXO 3a）核转位增强。用GDNF治疗肠神经元可改善这些变化。在链脲佐菌素诱导的糖尿病小鼠中，有证据表明肌间神经元凋亡和Akt磷酸化减少。糖尿病小鼠的NADPH黄递酶染色的肌间神经元丢失，胃排空延迟，肠道通过时间增加。在糖尿病胶质细胞酸性蛋白-GDNF（GFAP-GDNF）Tg小鼠中，高血糖的病理生理学效应（细胞凋亡、Akt磷酸化减少、抑制性神经元损失、运动性改变）被逆转。总之，我们证明，高血糖症通过减少Akt介导的生存信号诱导神经元损失，这些影响被GDNF逆转。GDNF可能是糖尿病相关胃肠动力障碍的潜在治疗靶点。
Diabetes can result in loss of enteric neurons and subsequent gastrointestinal complications. The mechanism of enteric neuronal loss in diabetes is not known. We examined the effects of hyperglycemia on enteric neuronal survival and the effects of glial cell line-derived neurotrophic factor (GDNF) on modulating this survival. Exposure of primary enteric neurons to 20 mM glucose (hyperglycemia) for 24 hours resulted in a significant increase in apoptosis compared with 5 mM glucose (normoglycemia). Exposure to 20 mM glucose resulted in decreased Akt phosphorylation and enhanced nuclear translocation of forkhead box O3a (FOXO3a). Treatment of enteric neurons with GDNF ameliorated these changes. In streptozotocin-induced diabetic mice, there was evidence of myenteric neuronal apoptosis and reduced Akt phosphorylation. Diabetic mice had loss of NADPH diaphorase-stained myenteric neurons, delayed gastric emptying, and increased intestinal transit time. The pathophysiological effects of hyperglycemia (apoptosis, reduced Akt phosphorylation, loss of inhibitory neurons, motility changes) were reversed in diabetic glial fibrillary acidic protein-GDNF (GFAP-GDNF) Tg mice. In conclusion, we demonstrate that hyperglycemia induces neuronal loss through a reduction in Akt-mediated survival signaling and that these effects are reversed by GDNF. GDNF may be a potential therapeutic target for the gastrointestinal motility disorders related to diabetes.