KATP channel as well as SGLT1 participates in GIP secretion in the diabetic state
KATP channel as well as SGLT1 participates in GIP secretion in the diabetic state
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DOI：
10.1530/joe-14-0161
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发表时间：
2014-08-01
影响因子：
4
通讯作者：
Oiso, Yutaka
中科院分区：
文献类型：
--
作者：
Ogata, Hidetada;Seino, Yusuke;Oiso, Yutaka
葡萄糖依赖性促胰岛素多肽（GIP）是一种由肠道K细胞分泌的肠道激素，可增强胰岛素分泌。K细胞和胰腺β细胞都是葡萄糖响应性的，并且配备有类似的葡萄糖传感装置，其包括葡萄糖激酶和ATP敏感性K+（K-ATP）通道，所述ATP敏感性K+（K-ATP）通道包括KIR6.2和磺酰脲受体1。在吸收上皮细胞和肠内分泌细胞中，钠葡萄糖协同转运蛋白1（SGLT 1）也已知在葡萄糖吸收和葡萄糖诱导的肠促胰岛素分泌中发挥重要作用。然而，K细胞中的葡萄糖敏感机制尚未完全了解。在这项研究中，我们研究了SGLT 1（SLC 5A 1）和K-ATP通道参与正常和链脲佐菌素诱导的糖尿病小鼠GIP分泌的葡萄糖感知。格列美脲（一种磺酰脲类药物）不诱导GIP分泌，用二氮嗪（一种K-ATP通道激活剂）预处理不影响正常状态下葡萄糖诱导的GIP分泌。在缺乏K-ATP通道的小鼠（Kir6.2（-/-）小鼠）中，与对照（Kir6.2（+/+））小鼠相比，葡萄糖诱导的GIP分泌增强，但被SGLT 1抑制剂根皮苷完全阻断。与Kir6.2（+/+）小鼠相比，Kir6.2（-/-）小鼠通过SGLT 1的肠道葡萄糖吸收增强。另一方面，在Kir6.2（+/+）小鼠的糖尿病状态下，葡萄糖诱导的GIP分泌增强。这种GIP分泌被根皮苷部分阻断，但完全阻断预处理与二氮嗪除了根皮苷管理。这些结果表明，在正常状态下，葡萄糖诱导的GIP分泌主要依赖于SGLT 1，而在体内糖尿病状态下，K-ATP通道以及SGLT 1参与GIP分泌。
Glucose-dependent insulinotropic polypeptide (GIP), a gut hormone secreted from intestinal K-cells, potentiates insulin secretion. Both K-cells and pancreatic beta-cells are glucose-responsive and equipped with a similar glucose-sensing apparatus that includes glucokinase and an ATP-sensitive K+ (K-ATP) channel comprising KIR6.2 and sulfonylurea receptor 1. In absorptive epithelial cells and enteroendocrine cells, sodium glucose co-transporter 1 (SGLT1) is also known to play an important role in glucose absorption and glucose-induced incretin secretion. However, the glucose-sensing mechanism in K-cells is not fully understood. In this study, we examined the involvement of SGLT1 (SLC5A1) and the K-ATP channels in glucose sensing in GIP secretion in both normal and streptozotocin-induced diabetic mice. Glimepiride, a sulfonylurea, did not induce GIP secretion and pretreatment with diazoxide, a K-ATP channel activator, did not affect glucose-induced GIP secretion in the normal state. In mice lacking K-ATP channels (Kir6.2(-/-) mice), glucose-induced GIP secretion was enhanced compared with control (Kir6.2(+/+)) mice, but was completely blocked by the SGLT1 inhibitor phlorizin. In Kir6.2(-/-) mice, intestinal glucose absorption through SGLT1 was enhanced compared with that in Kir6.2(+/+) mice. On the other hand, glucose-induced GIP secretion was enhanced in the diabetic state in Kir6.2(+/+) mice. This GIP secretion was partially blocked by phlorizin, but was completely blocked by pretreatment with diazoxide in addition to phlorizin administration. These results demonstrate that glucose-induced GIP secretion depends primarily on SGLT1 in the normal state, whereas the K-ATP channel as well as SGLT1 is involved in GIP secretion in the diabetic state in vivo.