Hira Tohru, Koga Toshiki, Sasaki Kazuyo, Hara Hiroshi
Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan; Graduate School of Agriculture, Hokkaido University, Sapporo, Japan.
Graduate School of Agriculture, Hokkaido University, Sapporo, Japan.
Biochem Biophys Res Commun. 2017 Oct 14;492(2):161-165. doi: 10.1016/j.bbrc.2017.08.031. Epub 2017 Aug 10.
The glucose-induced secretion of incretins, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), is dependent on luminal glucose levels and transport of glucose via the sodium-glucose transporter 1 (SGLT1) in the small intestine. Because GLP-1 and GIP function in decreasing and increasing the body weight, respectively, we aimed to analyze the effect of transient inhibition of SGLT1 by canagliflozin on incretin secretion in an obese rat model. Male Sprague-Dawley rats were maintained on a high-fat high-sucrose diet for 6-7 weeks, and plasma GLP-1 and GIP levels were measured during an oral glucose tolerance test (OGTT). In addition, GLP-1 secretion was examined in a murine GLP-1 producing enteroendocrine cell line, GLUTag. Concomitant administration of 10 mg/kg canagliflozin with glucose loading suppressed glucose excursion, increased total GLP-1 levels, and reduced total GIP levels in systemic circulation, as revealed in the OGTT. Total and active GLP-1 levels were increased in portal blood, whereas total and active GIP levels tended to be decreased 15 min after the administration of canagliflozin with glucose. Canagliflozin (at 0.1-30 μM) did not directly affect release of GLP-1 in vitro. These results suggest that the oral administration of canagliflozin suppresses GIP secretion via the inhibition of SGLT1 in the upper part of the intestine and enhances GLP-1 secretion by increasing the glucose delivery to the lower part of the small intestine in an obese rodent model.
葡萄糖诱导的肠促胰岛素分泌，包括胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP），取决于肠腔葡萄糖水平以及葡萄糖通过小肠中的钠-葡萄糖转运蛋白1（SGLT1）的转运。由于GLP-1和GIP分别具有减轻和增加体重的功能，我们旨在分析在肥胖大鼠模型中，卡格列净对SGLT1的短暂抑制作用对肠促胰岛素分泌的影响。雄性Sprague-Dawley大鼠维持高脂高糖饮食6 - 7周，并在口服葡萄糖耐量试验（OGTT）期间测量血浆GLP-1和GIP水平。此外，在小鼠GLP-1产生肠内分泌细胞系GLUTag中检测了GLP-1分泌。OGTT结果显示，与葡萄糖负荷同时给予10 mg/kg卡格列净可抑制血糖波动，增加全身循环中的总GLP-1水平，并降低总GIP水平。在门静脉血中，总GLP-1和活性GLP-1水平升高，而在给予卡格列净和葡萄糖后15分钟，总GIP和活性GIP水平趋于降低。卡格列净（0.1 - 30 μM）在体外不直接影响GLP-1的释放。这些结果表明，在肥胖啮齿动物模型中，口服卡格列净通过抑制小肠上部的SGLT1来抑制GIP分泌，并通过增加向小肠下部的葡萄糖输送来增强GLP-1分泌。
