Hepatic insulin gene therapy prevents diabetic enteropathy in STZ-treated CD-1 mice.
Hepatic insulin gene therapy prevents diabetic enteropathy in STZ-treated CD-1 mice.
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DOI：
10.1038/mtm.2015.28
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Thulé PM
中科院分区：
文献类型：
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作者：
You S;Anitha M;deSouza SM;Jia D;Lu X;Kozlowski M;Olson DE;Srinivasan S;Thulé PM
根据受检人群的不同，6%至83%的糖尿病患者表现出肠道动力改变的症状，表现为吞咽困难、反流、早饱、恶心、腹痛、腹泻或便秘。在糖尿病啮齿动物和糖尿病患者中，已证实高血糖导致肠道神经系统内的细胞丢失。建议控制血糖以预防糖尿病胃肠病变，但目前的治疗方式往往难以实现。我们询问肝脏胰岛素基因治疗(HIGT)是否能抑制糖尿病小鼠胃肠病变的发展。比较糖尿病小鼠(DM)、对照组非糖尿病小鼠(CON)和HIGT治疗的糖尿病小鼠(HIGT)的肠长、肠道转运、结肠肌肉松弛以及结肠肌间神经丛中刺激神经元和抑制神经元的数量。用腺相关病毒8型血清(AAV8)将代谢响应性胰岛素转基因转移到STZ糖尿病小鼠的肝脏，可在一个多月内产生接近正常的血糖，并防止糖尿病小鼠观察到的解剖、功能和神经组织学变化。我们的结论是，除了使糖尿病啮齿动物的氧化代谢正常化外，HIGT还足以预防糖尿病胃肠病变的发展。
Depending on the population examined, from 6 to 83% of people with diabetes mellitus exhibit symptoms of altered gut motility, manifesting as dysphagia, reflux, early satiety, nausea, abdominal pain, diarrhea, or constipation. Hyperglycemia-induced cell loss within the enteric nervous system has been demonstrated in both diabetic rodents and patients with diabetes. Glycemic control is recommended to prevent diabetic gastroenteropathy but is often difficult to achieve with current treatment modalities. We asked if hepatic insulin gene therapy (HIGT) could inhibit the development of diabetic gastroenteropathy in mice. Bowel length, bowel transit, colonic muscle relaxation, and the numbers of both stimulatory and inhibitory neurons in the colonic myenteric plexus were compared in groups of diabetic mice (DM), control nondiabetic mice (Con), and diabetic mice treated with HIGT (HIGT). Delivery of a metabolically responsive insulin transgene to the liver of STZ-diabetic mice with an adeno-associated virus, sero-type 8 (AAV8) produced near-normal blood sugars for over 1 month and prevented anatomic, functional, and neurohistologic changes observed in diabetic mice. We conclude that in addition to normalizing oxidative metabolism in diabetic rodents, HIGT is sufficient to prevent the development of diabetic gastroenteropathy.