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胰腺十二指肠同源盒-1(PDX1)有助于 Akt/PKB 通路诱导的β细胞质量扩增和增殖。

Pancreatic and duodenal homeobox-1 (PDX1) contributes to β-cell mass expansion and proliferation induced by Akt/PKB pathway.

机构信息

Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami , Miami, FL, USA.

Miami VA Health Care System , Miami, FL, USA.

出版信息

Islets. 2020 Mar 3;12(2):32-40. doi: 10.1080/19382014.2020.1762471.

Abstract

Maintenance of pancreatic β-cell mass and function is fundamental to glucose homeostasis and to prevent diabetes. The PI3 K-Akt-mTORC1 pathway is critical for β-cells mass and function, while PDX1 has been implicated in β-cell development, maturation, and function. Here we tested whether Akt signaling requires PDX1 expression to regulate β-cell mass, proliferation, and glucose homeostasis. In order to address that, we crossed a mouse model overexpressing constitutively active Akt mutant in β-cells () with mice lacking one allele of PDX1gene (. While the mice exhibit higher plasma insulin levels, greater β-cell mass and improved glucose tolerance compared to control mice, the mice are hyperglycemic and intolerant to glucose. The changes in glucose homeostasis in were associated with a 60% reduction in β-cell mass compared to mice. The impaired β-cell mass in the mice can be explained by a lesser β-cell proliferation measured by the number of Ki67 positive β-cells. We did not observe any differences in apoptosis between and mice. In conclusion, PDX1 contributes to β-cell mass expansion and glucose metabolism induced by activation of Akt signaling.

摘要

维持胰腺 β 细胞的质量和功能对于葡萄糖稳态和预防糖尿病至关重要。PI3K-Akt-mTORC1 途径对于 β 细胞的质量和功能至关重要,而 PDX1 已被牵连到 β 细胞的发育、成熟和功能中。在这里,我们测试了 Akt 信号是否需要 PDX1 表达来调节 β 细胞的质量、增殖和葡萄糖稳态。为了做到这一点,我们将在 β 细胞中过表达组成型激活 Akt 突变体的小鼠模型()与 PDX1 基因缺失一个等位基因的小鼠()进行杂交。虽然与对照小鼠相比, 小鼠表现出更高的血浆胰岛素水平、更大的 β 细胞质量和改善的葡萄糖耐量,但 小鼠则表现为高血糖和葡萄糖不耐受。与 小鼠相比, 小鼠葡萄糖稳态的变化与 β 细胞质量减少 60%有关。在 小鼠中,β 细胞质量受损可以通过 Ki67 阳性 β 细胞的数量减少来解释。我们没有观察到 和 小鼠之间的细胞凋亡有任何差异。总之,PDX1 有助于 Akt 信号激活诱导的 β 细胞质量扩张和葡萄糖代谢。

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