Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure.
Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure.
复制标题
DOI：
10.1007/s00125-010-1973-8
复制
发表时间：
2011-03
期刊：
影响因子：
8.2
通讯作者：
Schuermann, A.
中科院分区：
文献类型：
--
作者：
Kluth, O.;Mirhashemi, F.;Scherneck, S.;Kaiser, D.;Kluge, R.;Neschen, S.;Joost, H. -G.;Schuermann, A.
关键词：
无碳水化合物饮食可预防新西兰肥胖 (NZO) 小鼠模型中的高血糖和 β 细胞破坏。在这里，我们使用顺序饮食方案来分离肥胖和高血糖对 β 细胞功能和完整性的影响，并研究 16 天内葡萄糖诱导的关键转录因子的变化。通过连续 18 周喂食无碳水化合物饮食，小鼠变得肥胖。此后，给予含碳水化合物的饮食。测定血浆葡萄糖、血浆胰岛素和总胰腺胰岛素，并通过免疫组织化学监测叉头盒 O1 蛋白 (FOXO1) 磷酸化以及转录因子胰腺和十二指肠同源盒 1 (PDX1)、NK6 同源盒 1 蛋白 (NKX6.1) 和 v-maf 肌肉腱膜纤维肉瘤癌基因家族蛋白 A（禽类）(MAFA)，为期 16 天。在饮食挑战后的第 2 天到第 16 天之间，膳食碳水化合物导致 NZO 小鼠的血浆葡萄糖快速持续增加。高血糖在第 2 天导致 FOXO1 急剧去磷酸化，随后胰岛素储备逐渐耗尽。 β 细胞的损失是由细胞凋亡（在第 8 天可检测到）引发的，与关键转录因子（PDX1、NKX6.1 和 MAFA）的减少有关。将来自限制碳水化合物的 NZO 小鼠或 MIN6 细胞的分离胰岛与棕榈酸盐和葡萄糖一起孵育 48 小时，导致 FOXO1 和胸腺瘤病毒原癌基因 1 (AKT) 去磷酸化，而不改变两种蛋白质的蛋白质水平。饮食方案将 NZO 小鼠中肥胖（脂毒性）的影响与高血糖（糖毒性）的影响分开。肥胖的 NZO 小鼠无法通过增加胰岛素分泌或合成足够量的胰岛素来补偿碳水化合物的挑战。为了应对高血糖，FOXO1 被去磷酸化，导致 β 细胞特异性转录因子水平降低并导致细胞凋亡。本文的在线版本 (doi:10.1007/s00125-010-1973-8) 包含补充材料，可供授权用户使用。
Carbohydrate-free diet prevents hyperglycaemia and beta cell destruction in the New Zealand Obese (NZO) mouse model. Here we have used a sequential dietary regimen to dissociate the effects of obesity and hyperglycaemia on beta cell function and integrity, and to study glucose-induced alterations of key transcription factors over 16 days. Mice were rendered obese by feeding a carbohydrate-free diet for 18 weeks. Thereafter, a carbohydrate-containing diet was given. Plasma glucose, plasma insulin and total pancreatic insulin were determined, and forkhead box O1 protein (FOXO1) phosphorylation and the transcription factors pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 protein (NKX6.1) and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MAFA) were monitored by immunohistochemistry for 16 days. Dietary carbohydrates produced a rapid and continuous increase in plasma glucose in NZO mice between day 2 and 16 after the dietary challenge. Hyperglycaemia caused a dramatic dephosphorylation of FOXO1 at day 2, followed by a progressive depletion of insulin stores. The loss of beta cells was triggered by apoptosis (detectable at day 8), associated with reduction of crucial transcription factors (PDX1, NKX6.1 and MAFA). Incubation of isolated islets from carbohydrate-restricted NZO mice or MIN6 cells with palmitate and glucose for 48 h resulted in a dephosphorylation of FOXO1 and thymoma viral proto-oncogene 1 (AKT) without changing the protein levels of both proteins. The dietary regimen dissociates the effects of obesity (lipotoxicity) from those of hyperglycaemia (glucotoxicity) in NZO mice. Obese NZO mice are unable to compensate for the carbohydrate challenge by increasing insulin secretion or synthesising adequate amounts of insulin. In response to the hyperglycaemia, FOXO1 is dephosphorylated, leading to reduced levels of beta cell-specific transcription factors and to apoptosis of the cells. The online version of this article (doi:10.1007/s00125-010-1973-8) contains supplementary material, which is available to authorised users.
登录
查看更多内容
影响因子：
3.9
作者：
Li, Ning;Frigerio, Francesca;Maechler, Pierre
通讯作者：
Maechler, Pierre
影响因子：
7.7
作者：
LACY, PE;KOSTIANOVSKY, M
通讯作者：
KOSTIANOVSKY, M
影响因子：
15.9
作者：
Kitamura, T;Nakae, J;Accili, D
通讯作者：
Accili, D
影响因子：
8.2
作者：
Juergens, H. S.;Neschen, S.;Joost, H.-G.
通讯作者：
Joost, H.-G.
影响因子：
7.7
作者：
Leibowitz, G;Yuli, M;Kaiser, N
通讯作者：
Kaiser, N