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An increase in hepatic glucose production (HGP) is a key feature of type 2 diabetes. Excessive signaling through hepatic [G.sub.s]-linked glucagon receptors critically contributes to pathologically elevated HGP. Here, we tested the hypothesis that this metabolic impairment can be counteracted by enhancing hepatic [G.sub.i] signaling. Specifically, we used a chemogenetic approach to selectively activate [G.sub.i]-type G proteins in mouse hepatocytes in vivo. Unexpectedly, activation of hepatic [G.sub.i] signaling triggered a pronounced increase in HGP and severely impaired glucose homeostasis. Moreover, increased [G.sub.i] signaling stimulated glucose release in human hepatocytes. A lack of functional [G.sub.i]- type G proteins in hepatocytes reduced blood glucose levels and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Additionally, we delineated a signaling cascade that links hepatic [G.sub.i] signaling to ROS production, JNK activation, and a subsequent increase in HGP. Taken together, our data support the concept that drugs able to block hepatic G-coupled GPCRs may prove beneficial as antidiabetic drugs., Introduction Type 2 diabetes (T2D) has emerged as a major health problem worldwide (1). In addition to other pathophysiological features, T2D is characterized by an increase in hepatic glucose production [...]