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Hepatic β-arrestin 2 is essential for maintaining euglycemia
Lu Zhu, … , Wei Chen, Jürgen Wess
Lu Zhu, … , Wei Chen, Jürgen Wess
Published June 26, 2017
Citation Information: J Clin Invest. 2017;127(8):2941-2945. https://doi.org/10.1172/JCI92913.
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Brief Report Endocrinology Metabolism

Hepatic β-arrestin 2 is essential for maintaining euglycemia

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Abstract

An increase in hepatic glucose production (HGP) represents a key feature of type 2 diabetes. This deficiency in metabolic control of glucose production critically depends on enhanced signaling through hepatic glucagon receptors (GCGRs). Here, we have demonstrated that selective inactivation of the GPCR-associated protein β-arrestin 2 in hepatocytes of adult mice results in greatly increased hepatic GCGR signaling, leading to striking deficits in glucose homeostasis. However, hepatocyte-specific β-arrestin 2 deficiency did not affect hepatic insulin sensitivity or β-adrenergic signaling. Adult mice lacking β-arrestin 1 selectively in hepatocytes did not show any changes in glucose homeostasis. Importantly, hepatocyte-specific overexpression of β-arrestin 2 greatly reduced hepatic GCGR signaling and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Our data support the concept that strategies aimed at enhancing hepatic β-arrestin 2 activity could prove useful for suppressing HGP for therapeutic purposes.

Authors

Lu Zhu, Mario Rossi, Yinghong Cui, Regina J. Lee, Wataru Sakamoto, Nicole A. Perry, Nikhil M. Urs, Marc G. Caron, Vsevolod V. Gurevich, Grzegorz Godlewski, George Kunos, Minyong Chen, Wei Chen, Jürgen Wess

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Figure 3

In vivo studies with hep-barr2–OE mice and their control littermates.

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In vivo studies with hep-barr2–OE mice and their control littermates.
(A...
(A–H) In vivo metabolic tests carried out with mice maintained on RC (A–D) or HFD (E–H). Animals were maintained on the HFD for at least 8 weeks. Mice were subjected to i.p. glucose tolerance test (A and E), pyruvate tolerance test (B and F), glucagon challenge test (C and G), and ITT (D and H). Data are shown as mean ± SEM (8–10 mice per group; 12- to 16-week-old males). *P < 0.05; **P < 0.01, versus control (Student’s t test).
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