Sphingosine kinase 1-interacting protein is a novel regulator of glucose-stimulated insulin secretion.
Sphingosine kinase 1-interacting protein is a novel regulator of glucose-stimulated insulin secretion.
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DOI：
10.1038/s41598-017-00900-7
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发表时间：
2017-04-10
影响因子：
4.6
通讯作者：
Inagaki N
中科院分区：
文献类型：
--
作者：
Wang Y;Harashima SI;Liu Y;Usui R;Inagaki N
葡萄糖刺激的胰岛素分泌（GSIS）是保持血糖水平在正常范围内的必要条件。GSIS在2型糖尿病中受损，其恢复在疾病的治疗中至关重要。我们发现鞘氨醇激酶1相互作用蛋白（SKIP，也称为Sphkap）在胰腺β细胞中高度表达，但在α细胞中不表达。腹腔内葡萄糖耐量试验显示，与SKIP+/+小鼠相比，SKIP−/−小鼠的血糖水平降低，胰岛素水平升高，但exendin-4增强的胰岛素分泌被掩盖。与SKIP+/+胰岛相比，GSIS在SKIP −/−中扩增更多，但毒蜥外泌肽-4增强的胰岛素分泌被掩盖。在SKIP+/+和SKIP−/−胰岛中，ATP和cAMP含量同样增加;去极化诱发的、PKA和cAMP介导的胰岛素分泌不受影响。PDE活性的抑制同样增加了SKIP+/+和SKIP−/−胰岛中的GSIS。这些结果表明，SKIP调节GSIS的途径不同的cAMP，PDE和鞘氨醇激酶依赖的途径。
Glucose-stimulated insulin secretion (GSIS) is essential in keeping blood glucose levels within normal range. GSIS is impaired in type 2 diabetes, and its recovery is crucial in treatment of the disease. We find here that sphingosine kinase 1-interacting protein (SKIP, also called Sphkap) is highly expressed in pancreatic β-cells but not in α-cells. Intraperitoneal glucose tolerance test showed that plasma glucose levels were decreased and insulin levels were increased in SKIP−/− mice compared to SKIP+/+ mice, but exendin-4-enhanced insulin secretion was masked. GSIS was amplified more in SKIP−/− but exendin-4-enhanced insulin secretion was masked compared to that in SKIP+/+ islets. The ATP and cAMP content were similarly increased in SKIP+/+ and SKIP−/− islets; depolarization-evoked, PKA and cAMP-mediated insulin secretion were not affected. Inhibition of PDE activity equally augmented GSIS in SKIP+/+ and SKIP−/− islets. These results indicate that SKIP modulates GSIS by a pathway distinct from that of cAMP-, PDE- and sphingosine kinase-dependent pathways.