Following a meal, glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the two major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L- and K-cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity of G protein-coupled receptors (GPCRs) expressed by K-cells. GPCRs couple to one or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K-cell Gs. First, we generated a mouse model that allowed us to selectively stimulate K-cell Gs signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas, the gene encoding the alpha-subunit of Gs, selectively in K-cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K-cell Gs signaling greatly improved impaired glucose homeostasis in obese mice and in a mouse model of type 2 diabetes, due to enhanced GIP secretion. In contrast, K-cell-specific Gnas knockout mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K-cell Gs signaling may prove useful for the treatment of diabetes and related metabolic diseases.

中文翻译：

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小鼠肠内分泌 K 细胞中 Gs 信号转导的激活可显著改善肥胖和糖尿病相关的代谢缺陷。


饭后，胰高血糖素样肽-1 （GLP1） 和葡萄糖依赖性促胰岛素多肽 （GIP） 是促进胰岛素释放的两种主要肠促胰岛素，由专门的肠内分泌细胞（分别为 L 细胞和 K 细胞）分泌。尽管 GIP 是人类中的主要肠促胰岛素，但控制其释放的详细分子机制仍有待探索。GIP 分泌受 K 细胞表达的 G 蛋白偶联受体 （GPCR） 活性的调节。GPCR 偶联到一类或多类特异性异源三聚体 G 蛋白。在本研究中，我们专注于 K 细胞 G 的潜在代谢作用。首先，我们生成了一个小鼠模型，该模型使我们能够选择性地刺激 K 细胞 Gs 信号传导。其次，我们在 K 细胞中选择性地生成了一种小鼠品系，该菌株携带 Gnas 的失活突变，Gnas 是编码 Gs α 亚基的基因。代谢表型研究表明，由于 GIP 分泌增强，K 细胞 Gs 信号传导的急性或慢性刺激大大改善了肥胖小鼠和 2 型糖尿病小鼠模型中受损的葡萄糖稳态。相比之下，K 细胞特异性 Gnas 敲除小鼠血浆 GIP 水平显著降低。这些数据强烈表明，旨在增强 K 细胞 Gs 信号传导的策略可能被证明对治疗糖尿病和相关代谢疾病有用。