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首页> 外文期刊>Cell metabolism >Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health
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Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health

机译：线粒体磷酸胆酚丙酮酸循环的多组织加速度改善了全身代谢健康

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摘要

The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle couples mitochondrial PEPCK (PCK2) to pyruvate kinase (PK) in the liver and pancreatic islets to regulate glucose homeostasis. Here, small molecule PK activators accelerated the PEP cycle to improve islet function, as well as metabolic homeostasis, in preclinical rodent models of diabetes. In contrast, treatment with a PK activator did not improve insulin secretion in pck2(-/-) mice. Unlike other clinical secretagogues, PK activation enhanced insulin secretion but also had higher insulin content and markers of differentiation. In addition to improving insulin secretion, acute PK activation short-circuited gluconeogenesis to reduce endogenous glucose production while accelerating red blood cell glucose turnover. Four-week delivery of a PK activator in vivo remodeled PK phosphorylation, reduced liver fat, and improved hepatic and peripheral insulin sensitivity in HFD-fed rats. These data provide a preclinical rationale for PK activation to accelerate the PEP cycle to improve metabolic homeostasis and insulin sensitivity.
机译：线粒体GTP（mtGTP）依赖的磷酸烯醇式丙酮酸（PEP）循环将肝脏和胰岛中的线粒体PEPCK（PCK2）与丙酮酸激酶（PK）偶联，以调节葡萄糖稳态。在临床前糖尿病啮齿动物模型中，小分子PK激活剂加速PEP循环，以改善胰岛功能和代谢稳态。相比之下，PK激活剂治疗并不能改善pck2（-/-）小鼠的胰岛素分泌。与其他临床促泌剂不同，PK激活可增强胰岛素分泌，但也具有较高的胰岛素含量和分化标志物。除了改善胰岛素分泌外，急性PK激活还缩短了糖异生反应，以减少内源性葡萄糖生成，同时加速红细胞葡萄糖周转。在HFD喂养的大鼠体内，为期四周的PK激活剂注射可重塑PK磷酸化，降低肝脏脂肪，改善肝脏和外周胰岛素敏感性。这些数据为PK激活以加速PEP循环以改善代谢稳态和胰岛素敏感性提供了临床前理论基础。

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