Hepatic Gi signaling regulates whole-body glucose homeostasis

Rossi, Mario; Zhu, Lu; McMillin, Sara M.; Pydi, Sai Prasad; Jain, Shanu; Wang, Lei; Cui, Yinghong; Lee, Regina J.; Cohen, Amanda; Kaneto, Hideaki; Birnbaum, Morris J.; Ma, Yanling; Rotman, Yaron; Liu, Jie; Cyphert, Travis J.; Finkel, Toren; McGuinness, Owen P.; Wess, Jürgen

doi:10.1172/jci94505

Cited by 39 publications

(56 citation statements)

References 64 publications

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“…The small rise in insulin secretion may be responsible for the plateau and slight decrease in glycemia seen in the time points after 10 minutes. However, these data show that 1 mg/kg of glucagon given in the fasted state produces a net increase in glycemia, in line with the counter-regulatory actions of glucagon often described with 20 μg/kg doses (15)(16)(17).…”

Section: Glucagon-stimulated Insulin Secretion Is Dose-dependentsupporting

confidence: 80%

See 1 more Smart Citation

Glucagon lowers glycemia when β cells are active

Capozzi¹,

Wait²,

Koech³

et al. 2019

JCI Insight

127

106

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Section: Glucagon-stimulated Insulin Secretion Is Dose-dependentsupporting

confidence: 80%

“…A standard glucagon tolerance test uses 10-20 μg/kg given intraperitoneally (i.p.) following a 5-to 18-hour fast (15)(16)(17). Under these conditions, glucagon increases glycemia with no appreciable changes in circulating insulin, consistent with its classical counter-regulatory activities.…”

Section: Glucagon-stimulated Insulin Secretion Is Dose-dependentmentioning

confidence: 56%

Glucagon lowers glycemia when β cells are active

Capozzi¹,

Wait²,

Koech³

et al. 2019

JCI Insight

127

106

View full text Add to dashboard Cite

“…Hepatocytes also contain other GPCRs that are G i coupled. In this issue, Rossi and colleagues (7) show, surprisingly, that activation of G i -coupled receptors increases HGP.…”

Section: Unanswered Questions and Future Directionsmentioning

confidence: 92%

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

Spiegel¹

2018

Journal of Clinical Investigation

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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.

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“…As Gi-coupled GPCRs inhibit cAMP production it has been proposed that they could be targeted therapeutically to combat the increased HGP that occurs in T2D. This has recently been investigated by a chemogenetic approach where mice expressing a Gi-coupled GPCR in their hepatocytes were exposed to a ligand that specifically activated that receptor, and the effects on glucose regulation in vivo and in vitro were evaluated (Rossi et al, 2018). Selective activation of Gi in mouse hepatocytes paradoxically led to increased HGP and impaired glucose homeostasis, indicating that this is not an…”

Section: Livermentioning

confidence: 99%