β-Arrestin-1 is required for adaptive β-cell mass expansion during obesity

Luiz F. Barella (), Mario Rossi, Sai P. Pydi, Jaroslawna Meister, Shanu Jain, Yinghong Cui, Oksana Gavrilova, Gianluca Fulgenzi, Lino Tessarollo and Jürgen Wess ()
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Luiz F. Barella: National Institute of Diabetes and Digestive and Kidney Diseases
Mario Rossi: National Institute of Diabetes and Digestive and Kidney Diseases
Sai P. Pydi: National Institute of Diabetes and Digestive and Kidney Diseases
Jaroslawna Meister: National Institute of Diabetes and Digestive and Kidney Diseases
Shanu Jain: National Institute of Diabetes and Digestive and Kidney Diseases
Yinghong Cui: National Institute of Diabetes and Digestive and Kidney Diseases
Oksana Gavrilova: Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda
Gianluca Fulgenzi: National Cancer Institute
Lino Tessarollo: National Cancer Institute
Jürgen Wess: National Institute of Diabetes and Digestive and Kidney Diseases

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Obesity is the key driver of peripheral insulin resistance, one of the key features of type 2 diabetes (T2D). In insulin-resistant individuals, the expansion of beta-cell mass is able to delay or even prevent the onset of overt T2D. Here, we report that beta-arrestin-1 (barr1), an intracellular protein known to regulate signaling through G protein-coupled receptors, is essential for beta-cell replication and function in insulin-resistant mice maintained on an obesogenic diet. Specifically, insulin-resistant beta-cell-specific barr1 knockout mice display marked reductions in beta-cell mass and the rate of beta-cell proliferation, associated with pronounced impairments in glucose homeostasis. Mechanistic studies suggest that the observed metabolic deficits are due to reduced Pdx1 expression levels caused by beta-cell barr1 deficiency. These findings indicate that strategies aimed at enhancing barr1 activity and/or expression in beta-cells may prove useful to restore proper glucose homeostasis in T2D.

Date: 2021
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DOI: 10.1038/s41467-021-23656-1

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