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_12/13, 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_12/13 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_12/13-dependent fashion. Studies with human liver samples indicate that hepatic GNA12 (encoding Gα₁₂) expression levels positively correlate with indices of insulin resistance and impaired glucose homeostasis, consistent with a potential pathophysiological role of enhanced hepatic G_12/13 signaling.

肝葡萄糖通量改变在 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因子。最近的研究表明，肝细胞表达的 GPCR 可以与 G_{12/13 偶联，G 12/13} 是异源三聚体 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来表明，肝细胞 G_12/13 信号传导的选择性激活导致明显的高血糖，并且这种作用涉及 ROCK1-JNK 信号级联反应的刺激。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_12/13 依赖性方式强烈促进葡萄糖释放。对人肝样本的研究表明，肝脏 GNA12 （编码 Gα₁₂） 表达水平与胰岛素抵抗指数和葡萄糖稳态受损呈正相关，这与增强的肝脏 G_12/13 信号转导的潜在病理生理作用一致。