Efficient Restoration of Beta Cell Dedifferentiation by Calorie Restriction With High Fat/Low Carbohydrate Diet in Obese Diabetes Model and the Possible Role of GLP-1
Efficient Restoration of Beta Cell Dedifferentiation by Calorie Restriction With High Fat/Low Carbohydrate Diet in Obese Diabetes Model and the Possible Role of GLP-1
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DOI：
10.1210/jendso/bvab048.896
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发表时间：
2021-05-03
影响因子：
4.1
通讯作者：
Yamada M
中科院分区：
文献类型：
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作者：
Ishida E;Lei X;Horiguchi K;Matsumoto S;Yoshino S;Nakajima Y;Yamada E;Yamada M
在2型糖尿病中，胰腺β细胞逐渐“耗尽”并陷入β细胞功能障碍，从而导致更严重的胰岛素依赖。在β细胞功能障碍如内质网应激和氧化应激等提出的机制中，β细胞异质性最近引起了研究人员的兴趣。 2012 年，塔尔猜等人。研究表明，糖尿病小鼠模型中的β细胞是去分化的，现在它被认为是β细胞异质性的一种形式，并且在糖尿病动物模型和人类患者中广泛观察到。此前，我们表明，在我们测试的已知糖尿病治疗方法中，食物限制对于恢复肥胖糖尿病模型小鼠的β细胞基因表达具有最佳效果。在当前的研究中，我们旨在揭示热量限制期间改善β细胞去分化的分子基础。首先，我们利用高脂肪/低碳水化合物饮食（HF）或低脂肪/高碳水化合物（HC）饮食来确定脂肪限制或糖限制是否会减少肥胖小鼠的β细胞去分化。当热量摄入受到均匀限制时，HF 饮食和 HC 饮食均同等地降低了 db/db 小鼠的体重和高血糖。尽管代谢特征相同，但饲喂 HC 饮食的 db/db 组比饲喂 HF 饮食的 db/db 组具有更多的增大的胰岛和更多的去分化 β 细胞特征，这表明 HC 饮食组中的补偿性 β 细胞反应。此外，HC饮食组比HF饮食组表现出更严重的脂肪肝，并且肝脏中甘油三酯和胆固醇的合成和积累增加。推测肝脏的胰岛素抵抗可能影响β细胞的去分化。接下来，我们分析了胰高血糖素样肽 1 (GLP-1) 对 β 细胞去分化的影响，因为 GLP-1 更多地通过蛋白质和脂肪摄入从肠道分泌，而不是通过糖摄入。此外，越来越多的报告表明 GLP-1 对 β 细胞功能障碍和脂肪肝具有改善作用。事实上，GLP-1 给药改变了 db/db 小鼠中降低的 β 细胞/α 细胞比率，这表明 β 细胞异质性的恢复。我们现在正在研究 GLP-1 给药是否可以补偿 HC 饮食喂养的 db/db 小鼠的 β 细胞去分化，以阐明肠降血糖素在饮食期间营养不平衡诱导的 β 细胞去分化中的作用。此外，我们还将展示喂食 HF 和 HC 饮食的 db/db 小鼠肝脏的 RNA 测序数据，以阐明连接肝脏 β 细胞功能和代谢状态的关键分子和基因。
In type 2 diabetes, pancreatic beta cells are gradually ‘exhausted’ and fall into beta cell dysfunction, which proceeds more severe insulin dependence. Among the proposed mechanisms of beta cell dysfunction such as endoplasmic reticulum stress and oxidative stress, the beta cell heterogeneity has attracted the researcher’s interest recently. In 2012, Talchai et al. revealed that the beta cells were dedifferentiated in diabetic mice model, and nowadays it is considered as one form of the beta cell heterogeneity and is observed broadly among diabetic animal models and human patients. Previously we showed that food restriction had the best effect to restore beta cell gene expression in obese diabetic model mice, among the known diabetic treatments which we tested. In the current study, we aimed to unveil the molecular basis in the improvement of beta cell dedifferentiation during the calorie restriction. First, we utilized the high-fat/low carbohydrate diet (HF) or low-fat/high carbohydrate (HC) diet, to determine whether fat restriction or sugar restriction reduces the beta cell dedifferentiation in obese mice. When calorie intake was restricted evenly, both HF diet and HC diet decreased the body weight and hyperglycemia in db/db mice equally. Albeit the same metabolic profile, db/db group fed with HC diet had more enlarged islets and more dedifferentiated beta cell features than db/dbs fed with HF diet, which indicated the compensatory beta cell response in HC diet group. Moreover, HC diet group showed more severe fatty liver than HF diet group, along with the elevated synthesis and accumulation of triglycerides and cholesterol in liver. It is speculated that the insulin resistance in liver might impact on the beta cell dedifferentiation. Next, we analyzed the effect of glucagon-like peptide 1 (GLP-1) on beta cell dedifferentiation, since GLP-1 is secreted more from intestine by protein and fat intake, rather than by sugar intake. Also, increasing number of reports have suggested the improving effect of GLP-1 on beta cell dysfunction and fatty liver. Indeed, GLP-1 administration altered the reduced beta cell/alpha cell ratio in db/db mice, which indicated the restoration of beta cell heterogeneity. We are now investigating if GLP-1 administration reimburse the beta cell dedifferentiation in db/db mice fed with HC diet, to illuminate the role of incretins in beta cell dedifferentiation induced by unbalanced nutrition during diet. Also, we will present the RNA sequencing data of the liver in db/db mice fed with HF and HC diet, to elucidate the key molecules and genes which connect the beta cell function and metabolic state in liver.