High protein feeding improves glucose homeostasis in rodents and humans with diabetes, but the mechanisms that underlie this improvement remain elusive. Here we show that acute administration of casein hydrolysate directly into the upper small intestine increases glucose tolerance and inhibits glucose production in rats, independently of changes in plasma amino acids, insulin levels, and food intake. Inhibition of upper small intestinal peptide transporter 1 (PepT1), the primary oligopeptide transporter in the small intestine, reverses the preabsorptive ability of upper small intestinal casein infusion to increase glucose tolerance and suppress glucose production. The glucoregulatory role of PepT1 in the upper small intestine of healthy rats is further demonstrated by glucose homeostasis disruption following high protein feeding when PepT1 is inhibited. PepT1-mediated protein-sensing mechanisms also improve glucose homeostasis in models of early-onset insulin resistance and obesity. We demonstrate that preabsorptive upper small intestinal protein-sensing mechanisms mediated by PepT1 have beneficial effects on whole-body glucose homeostasis.

中文翻译：

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上小肠PepT1介导的蛋白质传感对葡萄糖稳态的生理和治疗调节。

高蛋白喂养可以改善啮齿动物和糖尿病人的葡萄糖体内稳态，但是这种改善的基础机制仍然难以捉摸。在这里，我们显示了酪蛋白水解物直接向上部小肠中的急性给药可增加大鼠的葡萄糖耐量并抑制葡萄糖的产生，而与血浆氨基酸，胰岛素水平和食物摄入量的变化无关。抑制小肠中的主要小肽转运蛋白上部小肠肽转运蛋白1（PepT1）会逆转上部小肠酪蛋白输注的吸收能力，从而增加葡萄糖耐量并抑制葡萄糖的产生。PepT1在健康大鼠上部小肠中的糖调节作用进一步被抑制PepT1的高蛋白喂养后的葡萄糖稳态破坏所证实。PepT1介导的蛋白质传感机制还可以改善早期发作的胰岛素抵抗和肥胖症模型中的葡萄糖稳态。我们证明了由PepT1介导的吸收前上小肠蛋白质传感机制对全身葡萄糖稳态具有有益作用。