Moriya Ryuichi, Shirakura Takashi, Ito Junko, Mashiko Satoshi, Seo Toru
Banyu Tsukuba Research Institute, Merck Research Laboratory, Tsukuba, Ibaraki, Japan.
Am J Physiol Endocrinol Metab. 2009 Dec;297(6):E1358-65. doi: 10.1152/ajpendo.00412.2009. Epub 2009 Oct 6.
Glucose ingestion stimulates the secretion of the incretin hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). Despite the critical role of incretins in glucose homeostasis, the mechanism of glucose-induced incretin secretion has not been established. We investigated the underlying mechanism of glucose-induced incretin secretion in vivo in mice. Injection of glucose at 1 g/kg in the upper intestine significantly increased plasma GIP and GLP-1 levels, whereas injection of glucose in the colon did not increase GIP or GLP-1 levels. This finding indicates that the glucose sensor for glucose-induced incretin secretion is in the upper intestine. Coadministration of a sodium-glucose cotransporter-1 (SGLT1) inhibitor, phloridzin, with glucose in the upper intestine blocked glucose absorption and glucose-induced incretin secretion. alpha-methyl-d-glucopyranoside (MDG), an SGLT1 substrate that is a nonmetabolizable sugar, significantly increased plasma GIP and GLP-1 levels, whereas phloridzin blocked these increases, indicating that concomitant transport of sodium ions and glucose (substrate) via SGLT1 itself triggers incretin secretion without the need for subsequent glucose metabolism. Interestingly, oral administration of MDG significantly increased plasma GIP, GLP-1, and insulin levels and reduced blood glucose levels during an intraperitoneal glucose tolerance test. Furthermore, chronic MDG treatment in drinking water (3%) for 13 days reduced blood glucose levels after a 2-h fast and in an oral glucose tolerance test in diabetic db/db mice. Our findings indicate that SGLT1 serves as the intestinal glucose sensor for glucose-induced incretin secretion and that a noncalorigenic SGLT1 substrate ameliorates hyperglycemia by stimulating incretin secretion.
摄入葡萄糖会刺激肠促胰岛素激素、葡萄糖依赖性促胰岛素多肽（GIP）和胰高血糖素样肽-1（GLP-1）的分泌。尽管肠促胰岛素在葡萄糖稳态中起着关键作用，但葡萄糖诱导肠促胰岛素分泌的机制尚未明确。我们研究了小鼠体内葡萄糖诱导肠促胰岛素分泌的潜在机制。在上段小肠以1 g/kg的剂量注射葡萄糖可显著提高血浆GIP和GLP-1水平，而在结肠注射葡萄糖则不会增加GIP或GLP-1水平。这一发现表明，葡萄糖诱导肠促胰岛素分泌的葡萄糖传感器位于上段小肠。在上段小肠将钠-葡萄糖协同转运蛋白-1（SGLT1）抑制剂根皮苷与葡萄糖共同给药，可阻断葡萄糖吸收和葡萄糖诱导的肠促胰岛素分泌。α-甲基-D-吡喃葡萄糖苷（MDG）是一种SGLT1底物，属于不可代谢糖，可显著提高血浆GIP和GLP-1水平，而根皮苷可阻断这些升高，这表明通过SGLT1本身伴随转运钠离子和葡萄糖（底物）可触发肠促胰岛素分泌，而无需随后的葡萄糖代谢。有趣的是，在腹腔葡萄糖耐量试验期间，口服MDG可显著提高血浆GIP、GLP-1和胰岛素水平，并降低血糖水平。此外，在糖尿病db/db小鼠中，连续13天饮用含3% MDG的水进行慢性治疗，可降低禁食2小时后以及口服葡萄糖耐量试验后的血糖水平。我们的研究结果表明，SGLT1作为葡萄糖诱导肠促胰岛素分泌的肠道葡萄糖传感器，并且一种无热量的SGLT1底物通过刺激肠促胰岛素分泌来改善高血糖症。
