Senescence Marker Protein-30/Gluconolactonase Deletion Worsens Glucose Tolerance through Impairment of Acute Insulin Secretion
Senescence Marker Protein-30/Gluconolactonase Deletion Worsens Glucose Tolerance through Impairment of Acute Insulin Secretion
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DOI：
10.1210/en.2009-1163
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发表时间：
2010-02-01
期刊：
影响因子：
4.8
通讯作者：
Ishigami, Akihito
中科院分区：
文献类型：
--
作者：
Hasegawa, Goji;Yamasaki, Masahiro;Ishigami, Akihito
衰老标记蛋白-30（SMP 30）是一种雄激素非依赖性因子，随着年龄的增长而减少。我们最近确定SMP 30为内酯水解酶β-内酯酶（GNL），其参与动物物种中维生素C的生物合成。为了检查年龄相关的SMP 30/GNL降低是否对葡萄糖稳态有影响，我们使用了用L-抗坏血酸处理的SMP 30/GNL敲除（KO）小鼠。在15周龄的ip葡萄糖耐量试验中，与野生型（WT）小鼠相比，在葡萄糖施用后30分钟，SMP 30/GNL KO小鼠的血糖水平显著增加25%。与WT小鼠相比，SMP 30/GNL KO小鼠中的胰岛素水平在葡萄糖后30分钟显著降低37%。有趣的是，胰岛素耐受性试验显示在SMP 30/GNL KO小鼠中具有更大的降糖作用。高脂饮食喂养严重恶化WT和SMP 30/GNL KO小鼠的葡萄糖耐量。形态学分析显示，高脂饮食诱导的β细胞质量和增殖的代偿性增加程度无差异。在胰岛的静态孵育研究中，在SMP 30/GNL KO小鼠中，响应于20 mM葡萄糖或KCl的胰岛素分泌显著降低。另一方面，SMP 30/GNL KO小鼠中20 mM的胰岛ATP含量与WT小鼠相似。总的来说，这些数据表明，由于分泌途径远端部分功能障碍导致的胰岛素分泌早期受损是SMP 30/GNL KO小鼠葡萄糖耐受不良的基础。降低的SMP 30/GNL可能导致正常衰老中发生的葡萄糖耐量恶化。（内分泌学151：529-536，2010）
Senescence marker protein-30 (SMP30) is an androgen-independent factor that decreases with age. We recently identified SMP30 as the lactone-hydrolyzing enzyme gluconolactonase (GNL), which is involved in vitamin C biosynthesis in animal species. To examine whether the age-related decrease in SMP30/GNL has effects on glucose homeostasis, we used SMP30/GNL knockout ( KO) mice treated with L-ascorbic acid. In an ip glucose tolerance test at 15 wk of age, blood glucose levels in SMP30/GNL KO mice were significantly increased by 25% at 30 min after glucose administration compared with wildtype (WT) mice. Insulin levels in SMP30/GNL KO mice were significantly decreased by 37% at 30 min after glucose compared with WT mice. Interestingly, an insulin tolerance test showed a greater glucose-lowering effect in SMP30/GNL KO mice. High-fat diet feeding severely worsened glucose tolerance in both WT and SMP30/GNL KO mice. Morphometric analysis revealed no differences in the degree of high-fat diet-induced compensatory increase in beta-cell mass and proliferation. In the static incubation study of islets, insulin secretion in response to 20 mM glucose or KCl was significantly decreased in SMP30/GNL KO mice. On the other hand, islet ATP content at 20 mM in SMP30/GNL KO mice was similar to that in WT mice. Collectively, these data indicate that impairment of the early phase of insulin secretion due to dysfunction of the distal portion of the secretion pathway underlies glucose intolerance in SMP30/GNL KO mice. Decreased SMP30/GNL may contribute to the worsening of glucose tolerance that occurs in normal aging. (Endocrinology 151: 529-536, 2010)