Molecular Signaling Section, Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, MD, USA.
Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Nat Commun. 2024 Nov 19;15(1):9996. doi: 10.1038/s41467-024-54299-7.
Altered hepatic glucose fluxes are critical during the pathogenesis of type 2 diabetes. G protein-coupled receptors represent important regulators of hepatic glucose production. Recent studies have shown that hepatocytes express GPCRs that can couple to G, a subfamily of heterotrimeric G proteins that has attracted relatively little attention in the past. Here we show, by analyzing several mutant mouse strains, that selective activation of hepatocyte G signaling leads to pronounced hyperglycemia and that this effect involves the stimulation of the ROCK1-JNK signaling cascade. Using both mouse and human hepatocytes, we also show that activation of endogenous sphingosine-1-phosphate type 1 receptors strongly promotes glucose release in a G-dependent fashion. Studies with human liver samples indicate that hepatic GNA12 (encoding Gα) expression levels positively correlate with indices of insulin resistance and impaired glucose homeostasis, consistent with a potential pathophysiological role of enhanced hepatic G signaling.
肝脏葡萄糖通量的改变在 2 型糖尿病的发病机制中至关重要。G 蛋白偶联受体是肝脏葡萄糖产生的重要调节剂。最近的研究表明，肝细胞表达可以与 G 蛋白偶联的 G 蛋白偶联受体，G 蛋白是异三聚体 G 蛋白的一个亚家族，过去受到的关注相对较少。在这里，我们通过分析几种突变小鼠品系表明，选择性激活肝细胞 G 信号会导致明显的高血糖，而这种作用涉及 ROCK1-JNK 信号级联的刺激。使用小鼠和人肝细胞，我们还表明，内源性鞘氨醇 1-磷酸 1 型受体的激活以 G 蛋白依赖的方式强烈促进葡萄糖释放。对人类肝组织样本的研究表明，肝 GNA12（编码 Gα）表达水平与胰岛素抵抗和葡萄糖稳态受损的指标呈正相关，这与增强的肝 G 信号转导的潜在病理生理学作用一致。
