Prosidion, Windrush Court, Oxford OX4 6LT, UK.
J Physiol. 2012 Jun 15;590(12):2917-36. doi: 10.1113/jphysiol.2011.223800. Epub 2012 Apr 10.
Intestinal enteroendocrine cells (IECs) secrete gut peptides in response to both nutrients and non-nutrients. Glucose and amino acids both stimulate gut peptide secretion. Our hypothesis was that the facilitative glucose transporter, GLUT2, could act as a glucose sensor and the calcium-sensing receptor, CasR, could detect amino acids in the intestine to modify gut peptide secretion. We used isolated loops of rat small intestine to study the secretion of gluco-insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) secretion stimulated by luminal perfusion of nutrients or bile acid. Inhibition of the sodium-dependent glucose cotransporter 1 (SGLT1) with phloridzin partially inhibited GIP, GLP-1 and PYY secretion by 45%, suggesting another glucose sensor might be involved in modulating peptide secretion. The response was completely abolished in the presence of the GLUT2 inhibitors phloretin or cytochalasin B. Given that GLUT2 modified gut peptide secretion stimulated by glucose, we investigated whether it was involved in the secretion of gut peptide by other gut peptide secretagogues. Phloretin completely abolished gut peptide secretion stimulated by artificial sweetener (sucralose), dipeptide (glycylsarcosine), lipid (oleoylethanolamine), short chain fatty acid (propionate) and major rat bile acid (taurocholate) indicating a fundamental position for GLUT2 in the gut peptide secretory mechanism. We investigated how GLUT2 was able to influence gut peptide secretion mediated by a diverse range of stimulators and discovered that GLUT2 affected membrane depolarisation through the closure of K+(ATP)-sensitive channels. In the absence of SGLT1 activity (or presence of phloridzin), the secretion of GIP, GLP-1 and PYY was sensitive to K+(ATP)-sensitive channel modulators tolbutamide and diazoxide. L-amino acids phenylalanine (Phe), tryptophan (Trp), asparagine (Asn), arginine (Arg) and glutamine (Gln) also stimulated GIP, GLP-1 and PYY secretion, which was completely abolished when extracellular Ca2+ was absent. The gut peptide response stimulated by the amino acids was also blocked by the CasR inhibitor Calhex 231 and augmented by the CasR agonist NPS-R568. GLUT2 and CasR regulate K- and L-cell activity in response to nutrient and non-nutrient stimuli.
肠内分泌细胞 (IECs) 会响应营养素和非营养素而分泌肠道肽。葡萄糖和氨基酸都能刺激肠道肽的分泌。我们的假设是，易化型葡萄糖转运蛋白 GLUT2 可以作为葡萄糖传感器，钙敏感受体 CasR 可以检测肠道中的氨基酸，以调节肠道肽的分泌。我们使用大鼠小肠环段来研究腔灌注营养物质或胆汁酸刺激下 GIP、GLP-1 和 PYY 分泌的变化。用根皮苷抑制钠依赖型葡萄糖共转运蛋白 1（SGLT1）可使 GIP、GLP-1 和 PYY 分泌减少 45%，提示可能存在另一种葡萄糖传感器来调节肽的分泌。在存在 GLUT2 抑制剂根皮素或细胞松弛素 B 的情况下，反应完全被阻断。鉴于 GLUT2 可调节葡萄糖刺激的肠道肽分泌，我们研究了 GLUT2 是否参与其他肠道肽分泌激动剂刺激的肠道肽分泌。根皮素完全阻断了人工甜味剂（蔗糖素）、二肽（甘氨酰肌氨酸）、脂质（油酰乙醇胺）、短链脂肪酸（丙酸盐）和主要大鼠胆汁酸（牛磺胆酸钠）刺激的肠道肽分泌，表明 GLUT2 在肠道肽分泌机制中处于基础地位。我们研究了 GLUT2 如何影响由多种刺激物介导的肠道肽分泌，并发现 GLUT2 通过关闭 K+(ATP)-敏感通道来影响膜去极化。在不存在 SGLT1 活性（或存在根皮苷的情况下），GIP、GLP-1 和 PYY 的分泌对 K+(ATP)-敏感通道调节剂甲苯磺丁脲和二氮嗪敏感。L-氨基酸苯丙氨酸 (Phe)、色氨酸 (Trp)、天冬酰胺 (Asn)、精氨酸 (Arg) 和谷氨酰胺 (Gln) 也刺激 GIP、GLP-1 和 PYY 的分泌，当细胞外 Ca2+不存在时，这种反应完全被阻断。氨基酸刺激的肠道肽反应也被 CasR 抑制剂 Calhex 231 阻断，并被 CasR 激动剂 NPS-R568 增强。GLUT2 和 CasR 调节 K 和 L 细胞对营养和非营养刺激的反应。
