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Hepatic Gi signaling regulates whole-body glucose homeostasis.
Rossi M, Zhu L, McMillin SM, Pydi SP, Jain S, Wang L, Cui Y, Lee RJ, Cohen AH,
Kaneto H, Birnbaum MJ, Ma Y, Rotman Y, Liu J, Cyphert TJ, Finkel T, McGuinness
OP, Wess J
Submitted Externally on 2/19/2018
The Journal of clinical investigation
Volume : Pages
128 : 746 - 759
An increase in hepatic glucose production (HGP) is a key feature of type 2
diabetes. Excessive signaling through hepatic Gs-linked glucagon receptors
critically contributes to pathologically elevated HGP. Here, we tested the
hypothesis that this metabolic impairment can be counteracted by enhancing
hepatic Gi signaling. Specifically, we used a chemogenetic approach to
selectively activate Gi-type G proteins in mouse hepatocytes in vivo.
Unexpectedly, activation of hepatic Gi signaling triggered a pronounced increase
in HGP and severely impaired glucose homeostasis. Moreover, increased Gi
signaling stimulated glucose release in human hepatocytes. A lack of functional
Gi-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 Gi
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
Gi-coupled GPCRs may prove beneficial as antidiabetic drugs.
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