Regulation of Glucose Insulinotropic Peptide and Intestinal Glucose Transporters in the Diet-Induced Obese Mouse.

Regulation of Glucose Insulinotropic Peptide and Intestinal Glucose Transporters in the Diet-Induced Obese Mouse.
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DOI:
10.1155/2022/5636499
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发表时间:
2022
影响因子:
4.3
通讯作者:
Coon SD
Coon SD
中科院分区:
医学3区
文献类型:
--
作者:
Rhodes RSS;Singh SK;Rajendran VM;Walk ST;Coon SD

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我们最近的研究表明,葡萄糖依赖性胰岛素性多肽(GIP),而不是胰高血糖素样肽1 (GLP-1),增加了小鼠空肠中na -葡萄糖转运蛋白1- (SGLT1-)介导的葡萄糖吸收。与正常(正常体重)饮食喂养的动物相比,高脂肪(即肥胖)动物的na依赖性葡萄糖吸收在3个月内急剧上升并达到峰值。先前的研究表明,小鼠空肠中gip增强的SGLT1和PEPT1(肽转运蛋白1)受蛋白激酶A (PKA)信号的调控。其他研究表明,cAMP和PI3激酶信号分别通过EPAC和AKT激活途径增强PEPT1,通过增加肠上皮细胞中PEPT1的顶端运输。然而,对于信号葡萄糖转运模式在长时间内是如何改变的,我们知之甚少。早期,增加的葡萄糖吸收是通过SGLT1发生的,但随着肥胖和糖尿病的进展,有一个戏剧性的转变,向na独立的机制。令人惊讶的是,在肥胖进展的第5个月葡萄糖吸收高峰期,SGLT1活性严重下降,同时开始出现不依赖na的葡萄糖吸收过程。由于葡萄糖转运蛋白2 (GLUT2)在肥胖患者和肥胖动物模型的小肠顶端膜上表达,因此它被假设为新的更有效的途径。Western blot分析和根尖膜生物素化分析显示,肥胖动物根尖膜中GIP的表达增加,并且随着GIP的处理,其向根尖膜的转运增加。
Our recent studies have shown that glucose-dependent insulinotropic polypeptide (GIP), but not glucagon-like peptide 1 (GLP-1), augments Na-glucose transporter 1- (SGLT1-) mediated glucose absorption in mouse jejunum. Na-dependent glucose absorption sharply rose and peaked in 3 months of high-fat (i.e., obese) compared to normal (i.e., normal weight) diet fed animals. Previous studies have shown that GIP-augmented SGLT1 and PEPT1 (peptide transporter 1) are regulated by protein kinase A (PKA) signaling in mouse jejunum. Additional studies have indicated that cAMP and PI3 kinase signaling augment PEPT1 through EPAC and AKT activation pathways, respectively, through increased apical PEPT1 trafficking in intestinal epithelial cells. However, little is known about how the signaling glucose transport paradigm is altered over a long period. Early on, increased glucose absorption occurs through SGLT1, but as the obesity and diabetes progress, there is a dramatic shift towards a Na-independent mechanism. Surprisingly, at the peak of glucose absorption during the fifth month of the progression of obesity, the SGLT1 activity was severely depressed, while a Na-independent glucose absorptive process begins to appear. Since glucose transporter 2 (GLUT2) is expressed on the apical membrane of the small intestine in obese patients and animal models of obesity, it was hypothesized to be the new more efficient route. Western blot analyses and biotinylation of the apical membrane revealed that the GIP expression increases in the obese animals and its trafficking to the apical membrane increases with the GIP treatment.
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