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A double negative: inhibition of hepatic Gi signaling improves glucose homeostasis
Allen M. Spiegel
Allen M. Spiegel
Published January 16, 2018
Citation Information: J Clin Invest. 2018;128(2):567-569. https://doi.org/10.1172/JCI99037.
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Commentary

A double negative: inhibition of hepatic Gi signaling improves glucose homeostasis

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Abstract

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.

Authors

Allen M. Spiegel

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Figure 1

Indirect and direct mechanisms regulate HGP.

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Indirect and direct mechanisms regulate HGP.
Free fatty acids (FFAs) and...
Free fatty acids (FFAs) and glycerol from adipose cells and amino acids from skeletal muscle provide substrate for liver gluconeogenesis, resulting in increased HGP. HGP is also modulated by adipose-derived cytokines and through neural inputs from the CNS. Additionally, pancreatic islet hormones, insulin, via tyrosine kinase–stimulated phosphorylation of the insulin receptor (IR), and glucagon, via Gs-coupled receptor stimulation of cAMP production, act directly on hepatocytes to decrease and increase HGP, respectively. Hepatocytes also contain other GPCRs that are Gi coupled. In this issue, Rossi and colleagues (7) show, surprisingly, that activation of Gi-coupled receptors increases HGP.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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