DataSheet_1_PTEN Deletion in Adult Mice Induces Hypoinsulinemia With Concomitant Low Glucose Levels.zip

The PI3K/AKT pathway, negatively regulated by PTEN, plays a paramount role in glucose metabolism regulation due to its activation by the insulin receptor signaling pathway. We generated a PTEN-KO mouse to evaluate the systemic effect of the overactivation of the PI3K/AKT pathway in insulin signaling and glucose homeostasis. Our results demonstrate that PTEN-KO mice show very low glucose levels in the fasted state, which poorly respond to glucose and pyruvate administration. Insulinemia decreased without alterations in pancreatic islets. Among the possible reasons, we uncover the deregulation of the expression of proximal tubule glucose transporter and consequent glycosuria. Moreover, we evidence an altered activation of hepatic gluconeogenesis-related genes. In addition, the expression of several genes related to β-oxidation showed a delayed or even absent response to fasting, suggesting that the lack of PTEN not only impairs glucose metabolism but also slows down the use of lipids as a metabolic fuel. We conclude that the inducible full PTEN-KO mice could be a good model to study the metabolic interactions between glycidic and lipidic metabolism in hypoinsulinemic hypoglycemia and that PTEN could be an important mediator in the disease and/or a potential drug target.

由磷酸酶与张力蛋白同源物（PTEN）负调控的PI3K/AKT通路（PI3K/AKT pathway）可经胰岛素受体信号通路（insulin receptor signaling pathway）激活，在葡萄糖代谢调控中发挥关键作用。本研究构建了PTEN基因敲除（PTEN-KO）小鼠，以评估PI3K/AKT通路过度激活对胰岛素信号转导及葡萄糖稳态的系统性影响。研究结果显示，PTEN-KO小鼠在禁食状态下血糖水平极低，且对葡萄糖与丙酮酸注射的应答不佳；其血浆胰岛素水平下降，但胰岛未出现明显异常改变。在诸多潜在机制中，我们发现近端小管葡萄糖转运蛋白（proximal tubule glucose transporter）的表达失调，进而引发糖尿（glycosuria）。此外，我们证实肝脏糖异生相关基因的激活状态发生异常。除此之外，多项与β氧化（β-oxidation）相关的基因的表达对禁食的应答呈现延迟甚至缺失的特征，这表明PTEN缺失不仅会损害葡萄糖代谢，还会减缓脂质作为代谢燃料的利用效率。综上，我们认为诱导型全PTEN-KO小鼠可作为研究低胰岛素血症性低血糖中糖脂代谢相互作用的理想模型，且PTEN有望成为该类疾病的重要介导因子及潜在药物靶点。