Phosphatidylinositol-4-phosphate-5-kinase alpha deficiency alters dynamics of glucose-stimulated insulin release to improve glucohomeostasis and decrease obesity in mice.
Phosphatidylinositol-4-phosphate-5-kinase alpha deficiency alters dynamics of glucose-stimulated insulin release to improve glucohomeostasis and decrease obesity in mice.
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DOI：
10.2337/db10-0614
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发表时间：
2011-02
期刊：
影响因子：
7.7
通讯作者：
Frohman MA
中科院分区：
文献类型：
--
作者：
Huang P;Yeku O;Zong H;Tsang P;Su W;Yu X;Teng S;Osisami M;Kanaho Y;Pessin JE;Frohman MA
磷脂酰肌醇 4-磷酸 5-激酶 (PI4P5K) 已被提议通过生成磷脂酰肌醇 4,5-二磷酸 (PIP2) 来促进调节的胞吐作用，特别是胰岛素分泌。我们试图研究 PI4P5K α 亚型在糖稳态和胰岛素分泌中的作用。在体内检查了 PI4P5Kα−/− 小鼠对葡萄糖激发和诱发 2 型糖尿病的高脂肪饮食的反应。在培养物中对葡萄糖刺激的反应和 PI4P5Kα−/− 胰岛和 β 细胞进行了表征。我们发现 PI4P5Kα−/− 小鼠表现出第一相胰岛素释放增加和葡萄糖清除率改善，并能抵抗高脂饮食诱导的 2 型糖尿病和肥胖症的发展。体外培养的 PI4P5Kα−/− 胰岛表现出停靠在质膜上的胰岛素颗粒数量减少，并且在静止条件下释放较少的胰岛素，但随后在葡萄糖刺激下分泌相似量的胰岛素。刺激依赖性 PIP2 耗竭发生在 PI4P5Kα−/− 胰腺 β 细胞的质膜上，伴随着皮质 F 肌动蛋白几乎完全丧失，而在静息条件下，PI4P5Kα−/− β 细胞中的 F 肌动蛋白已经减少。我们的研究结果表明，PI4P5Kα 通过在基础和刺激条件下帮助维持质膜 PIP2 水平和肌动蛋白细胞骨架的完整性，在限制胰腺 β 细胞释放胰岛素方面发挥着复杂的作用。正常饮食中观察到的第一相葡萄糖刺激胰岛素释放增加可能是对 2 型糖尿病样模型系统中出现的血清葡萄糖升高和肥胖的部分保护的基础。
Phosphatidylinositol-4-phosphate-5-kinase (PI4P5K) has been proposed to facilitate regulated exocytosis and specifically insulin secretion by generating phosphatidylinositol-4,5-bisphosphate (PIP2). We sought to examine the role of the α isoform of PI4P5K in glucohomeostasis and insulin secretion. The response of PI4P5Kα−/− mice to glucose challenge and a type 2-like diabetes-inducing high-fat diet was examined in vivo. Glucose-stimulated responses and PI4P5Kα−/− pancreatic islets and β-cells were characterized in culture. We show that PI4P5Kα−/− mice exhibit increased first-phase insulin release and improved glucose clearance, and resist high-fat diet-induced development of type 2-like diabetes and obesity. PI4P5Kα−/− pancreatic islets cultured in vitro exhibited decreased numbers of insulin granules docked at the plasma membrane and released less insulin under quiescent conditions, but then secreted similar amounts of insulin on glucose stimulation. Stimulation-dependent PIP2 depletion occurred on the plasma membrane of the PI4P5Kα−/− pancreatic β-cells, accompanied by a near-total loss of cortical F-actin, which was already decreased in the PI4P5Kα−/− β-cells under resting conditions. Our findings suggest that PI4P5Kα plays a complex role in restricting insulin release from pancreatic β-cells through helping to maintain plasma membrane PIP2 levels and integrity of the actin cytoskeleton under both basal and stimulatory conditions. The increased first-phase glucose-stimulated release of insulin observed on the normal diet may underlie the partial protection against the elevated serum glucose and obesity seen in type 2 diabetes-like model systems.