J Clin Invest. 2018 Feb 1;128(2):567-569. doi: 10.1172/JCI99037. Epub 2018 Jan 16.
Hepatic glucose production (HGP) is a key determinant of glucose homeostasis. Glucagon binding to its cognate seven-transmembrane Gs-coupled receptor in hepatocytes stimulates cAMP production, resulting in increased HGP. In this issue of the JCI, Rossi and colleagues tested the hypothesis that activation of hepatic Gi-coupled receptors, which should inhibit cAMP production, would oppose the cAMP-inducing action of glucagon and thereby decrease HGP. Surprisingly, however, the opposite occurred: activation of Gi signaling increased HGP via a novel mechanism, while inhibition of Gi signaling reduced HGP. These results define a new physiologic role for hepatic Gi signaling and identify a potential therapeutic target for HGP regulation.
肝脏葡萄糖生成 (HGP) 是葡萄糖稳态的关键决定因素。胰高血糖素与肝细胞中同源的七跨膜 Gs 偶联受体结合，刺激 cAMP 的产生，从而增加 HGP。在本期 JCI 中，Rossi 及其同事检验了这样一个假设，即激活肝 Gi 偶联受体（应该会抑制 cAMP 的产生）会拮抗胰高血糖素诱导 cAMP 的作用，从而降低 HGP。然而，令人惊讶的是，实际情况正好相反：Gi 信号的激活通过一种新的机制增加了 HGP，而 Gi 信号的抑制则降低了 HGP。这些结果定义了肝 Gi 信号的新的生理作用，并确定了 HGP 调节的一个潜在治疗靶点。
