Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion
Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion
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DOI：
10.1096/fj.201801783rr
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发表时间：
2019-05-01
期刊：
影响因子：
4.8
通讯作者：
Inagaki, Nobuya
中科院分区：
文献类型：
--
作者：
Liu, Yanyan;Harashima, Shin-ichi;Inagaki, Nobuya
我们先前的研究表明，鞘氨醇激酶1相互作用蛋白（SKIP，或Sphkap）在胰腺细胞中表达，SKIP的缺失增强葡萄糖刺激的胰岛素分泌。我们发现SKIP也在肠K-和L-细胞中表达，并且与野生型小鼠相比，SKIP缺陷（SKIP-/-）小鼠中胃抑制多肽（GIP）和胰高血糖素样肽-1（GLP-1）以及胰岛素的分泌显著增加，血糖水平降低。血浆甘油三酯（Tg），低密度脂蛋白胆固醇，和促炎细胞因子在脂肪组织，肝脏和肠道的mRNA水平被发现在SKIP-/-小鼠显着降低。SKIP-/-小鼠的表型特征，包括肥胖和基础炎症的减弱，通过GIP的遗传耗竭而被消除。GLP-1受体拮抗剂exendin-（9-39）治疗取消了SKIP-/-小鼠中葡萄糖耐量和脂质特征的改善。总之，SKIP的消耗通过增强胰岛素和肠促胰岛素的分泌来改善葡萄糖耐量，改善脂质代谢，并降低基础炎症水平。因此，抑制SKIP作用可能成为治疗伴有代谢功能障碍的2型糖尿病的新选择。Harashima，S.，王玉，铃木，K.，Tokumoto，S.，Alzhei河，Tatsuoka，H.，Tanaka，D.，Yabe，D.，Harada，N.，Hayashi，Y.，Inagaki，N.鞘氨醇激酶1相互作用蛋白是胰岛素和肠促胰岛素分泌的双重调节剂。
Our previous study demonstrated that sphingosine kinase 1-interacting protein (SKIP, or Sphkap) is expressed in pancreatic -cells, and depletion of SKIP enhances glucose-stimulated insulin secretion. We find here that SKIP is also expressed in intestinal K- and L-cells and that secretion of gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) as well as insulin are significantly increased, and blood glucose levels are decreased in SKIP-deficient (SKIP-/-) mice compared with those in wild-type mice. Plasma triglyceride (Tg), LDL cholesterol, and mRNA levels of proinflammatory cytokines in adipose tissues, livers, and intestines were found to be significantly decreased in SKIP-/- mice. The phenotypic characteristics of SKIP-/- mice, including adiposity and attenuation of basal inflammation, were abolished by genetic depletion of GIP. The improvement of glucose tolerance and lipid profiles in SKIP-/- mice were cancelled by GLP-1 receptor antagonist exendin-(9-39) treatment. In summary, depletion of SKIP ameliorates glucose tolerance by enhancing secretion of insulin and incretins, improves lipid metabolism, and reduces basal inflammation levels. Thus, inhibition of SKIP action may emerge as a new option for treatment of type 2 diabetes mellitus with metabolic dysfunction.Liu, Y., Harashima, S., Wang, Y., Suzuki, K., Tokumoto, S., Usui, R., Tatsuoka, H., Tanaka, D., Yabe, D., Harada, N., Hayashi, Y., Inagaki, N. Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion.