Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China.
Center for Drug Safety Evaluation and Research of Zhejiang University, 310058, Hangzhou, China.
Cell Death Differ. 2020 Jan;27(1):130-145. doi: 10.1038/s41418-019-0344-3. Epub 2019 May 16.
Insufficient pancreatic β-cell mass or insulin-producing β-cells are implicated in all forms of diabetes mellitus. However, the molecular mechanisms underlying β-cell destruction are complex and not fully defined. Here we observed that activation of STAT3 is intensely and specifically inhibited in β-cells under hyperglycemic conditions. By knocking out STAT3 specifically in mouse β-cells, we found that the loss of STAT3 sensitized mice to three low doses of STZ stimulation resulting in hyperglycemia. Mechanistically, accumulating PTEN, induced by STAT3 deficiency, directly represses phosphorylation of AKT, which negatively modulates transcription factor activation, dysregulates β-cell function, positively promotes apoptotic signaling, and finally induces β-cell apoptosis. Notably, the defective secretion of insulin and β-cells apoptosis was completely rescued by PTEN ablation in STAT3-null islets or PTEN inhibitor bpv(phen) treatment. Thus our data suggest that STAT3 is a vital modulator of β-cell survival and function, highlighting a critical role for STAT3 in the negative regulation of PTEN-AKT signaling pathway associated with β-cell dysfunction and apoptosis.
胰岛β细胞数量不足或产生胰岛素的β细胞与所有类型的糖尿病都有关。然而，β细胞破坏的分子机制非常复杂，尚未完全确定。在这里，我们观察到在高血糖条件下β细胞中的 STAT3 活性被强烈且特异性地抑制。通过在小鼠β细胞中特异性敲除 STAT3，我们发现 STAT3 的缺失使小鼠对三种低剂量 STZ 刺激更敏感，导致高血糖。从机制上讲，由 STAT3 缺陷引起的 PTEN 积累直接抑制 AKT 的磷酸化，这负调控转录因子的激活，使β细胞功能失调，促进凋亡信号，最终导致β细胞凋亡。值得注意的是，在 STAT3 缺失的胰岛中或使用 PTEN 抑制剂 bpv(phen)处理后，胰岛素分泌缺陷和β细胞凋亡完全得到了挽救。因此，我们的数据表明 STAT3 是β细胞存活和功能的重要调节剂，强调了 STAT3 在与β细胞功能障碍和凋亡相关的 PTEN-AKT 信号通路负调控中的关键作用。
