Deletion of Protein Kinase D1 in Pancreatic β-Cells Impairs Insulin Secretion in High-Fat Diet-Fed Mice
Deletion of Protein Kinase D1 in Pancreatic β-Cells Impairs Insulin Secretion in High-Fat Diet-Fed Mice
复制标题
DOI：
10.2337/db17-0982
复制
发表时间：
2018-01-01
期刊：
影响因子：
7.7
通讯作者：
Poitout, Vincent
中科院分区：
文献类型：
--
作者：
Bergeron, Valerie;Ghislain, Julien;Poitout, Vincent
β-细胞对胰岛素抵抗的适应对于维持肥胖症中的葡萄糖稳态是必要的。这种机制的失败是2型糖尿病（T2 D）的标志。因此，控制功能性β细胞补偿的因素是治疗T2 D的潜在重要靶点。蛋白激酶D1（PKD 1）整合β细胞中的多种信号，并在控制胰岛素分泌中起关键作用。然而，β-细胞PKD 1在体内葡萄糖稳态中的作用基本上是未知的。使用β-细胞特异性，诱导PKD 1基因敲除小鼠（PKD 1 KO），我们研究了β-细胞PKD 1在基础条件下和高脂喂养期间的作用。与单独表达Cre转基因的小鼠相比，普通饮食下的PKD 1 KO小鼠在葡萄糖耐量或胰岛素分泌方面没有显着差异;然而，与野生型小鼠相比，两组小鼠都出现了葡萄糖耐受不良。在高脂饮食下，β细胞中PKD 1的缺失使高血糖症、高胰岛素血症和葡萄糖耐受不良恶化。这伴随着受损的葡萄糖诱导的胰岛素分泌，无论是在体内高血糖钳夹和离体分离胰岛从高脂肪饮食喂养的β PKD 1 KO小鼠没有胰岛质量的变化。这项研究证明了PKD 1在小鼠对高脂喂养的β细胞适应性分泌反应中的重要作用。
beta-Cell adaptation to insulin resistance is necessary to maintain glucose homeostasis in obesity. Failure of this mechanism is a hallmark of type 2 diabetes (T2D). Hence, factors controlling functional beta-cell compensation are potentially important targets for the treatment of T2D. Protein kinase D1 (PKD1) integrates diverse signals in the beta-cell and plays a critical role in the control of insulin secretion. However, the role of beta-cell PKD1 in glucose homeostasis in vivo is essentially unknown. Using beta-cell-specific, inducible PKD1 knockout mice (PKD1KO), we examined the role of beta-cell PKD1 under basal conditions and during high-fat feeding. PKD1KO mice under a chow diet presented no significant difference in glucose tolerance or insulin secretion compared with mice expressing the Cre transgene alone; however, when compared with wild-type mice, both groups developed glucose intolerance. Under a high-fat diet, deletion of PKD1 in beta-cells worsened hyperglycemia, hyperinsulinemia, and glucose intolerance. This was accompanied by impaired glucose-induced insulin secretion both in vivo in hyperglycemic clamps and ex vivo in isolated islets from high-fat diet-fed beta PKD1KO mice without changes in islet mass. This study demonstrates an essential role for PKD1 in the beta-cell adaptive secretory response to high-fat feeding in mice.