A double negative: Inhibition of hepatic g_i signaling improves glucose homeostasis

Hepatic glucose production (HGP) is a key determinant of glucose homeostasis. Glucagon binding to its cognate seven-transmembrane G_s-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 G_i–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 G_i signaling increased HGP via a novel mechanism, while inhibition of G_i signaling reduced HGP. These results define a new physiologic role for hepatic G_i signaling and identify a potential therapeutic target for HGP regulation.