Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
Nat Commun. 2021 Jun 7;12(1):3385. doi: 10.1038/s41467-021-23656-1.
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.
肥胖是外周胰岛素抵抗的关键驱动因素，也是 2 型糖尿病（T2D）的主要特征之一。在胰岛素抵抗个体中，β细胞质量的扩张能够延迟甚至预防显性 T2D 的发生。在这里，我们报告β-arrestin-1（barr1），一种已知通过 G 蛋白偶联受体调节信号的细胞内蛋白，对于肥胖饮食维持的胰岛素抵抗小鼠的β细胞复制和功能是必需的。具体而言，胰岛素抵抗的β细胞特异性 barr1 敲除小鼠显示β细胞质量和β细胞增殖率的显著降低，与葡萄糖稳态的明显损害相关。机制研究表明，观察到的代谢缺陷是由于β细胞 barr1 缺陷导致 Pdx1 表达水平降低所致。这些发现表明，旨在增强β细胞 barr1 活性和/或表达的策略可能有助于恢复 T2D 中的适当葡萄糖稳态。
