Sun Emily W, Martin Alyce M, de Fontgalland Dayan, Sposato Luigi, Rabbitt Philippa, Hollington Paul, Wattchow David A, Colella Alexander D, Chataway Tim, Wewer Albrechtsen Nicolai J, Spencer Nick J, Young Richard L, Keating Damien J
Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.
Department of Surgery, Flinders Medical Centre, Bedford Park, SA, Australia.
Endocrinology. 2021 Apr 1;162(4). doi: 10.1210/endocr/bqab022.
Glucagon is secreted by pancreatic α cells in response to hypoglycemia and increases hepatic glucose output through hepatic glucagon receptors (GCGRs). There is evidence supporting the notion of extrapancreatic glucagon but its source and physiological functions remain elusive. Intestinal tissue samples were obtained from patients undergoing surgical resection of cancer. Mass spectrometry analysis was used to detect glucagon from mucosal lysate. Static incubations of mucosal tissue were performed to assess glucagon secretory response. Glucagon concentration was quantitated using a highly specific sandwich enzyme-linked immunosorbent assay. A cholesterol uptake assay and an isolated murine colonic motility assay were used to assess the physiological functions of intestinal GCGRs. Fully processed glucagon was detected by mass spectrometry in human intestinal mucosal lysate. High glucose evoked significant glucagon secretion from human ileal tissue independent of sodium glucose cotransporter and KATP channels, contrasting glucose-induced glucagon-like peptide 1 (GLP-1) secretion. The GLP-1 receptor agonist Exendin-4 attenuated glucose-induced glucagon secretion from the human ileum. GCGR blockade significantly increased cholesterol uptake in human ileal crypt culture and markedly slowed ex vivo colonic motility. Our findings describe the human gut as a potential source of extrapancreatic glucagon and demonstrate a novel enteric glucagon/GCGR circuit with important physiological functions beyond glycemic regulation.
胰高血糖素由胰腺α细胞分泌，以应对低血糖，并通过肝胰高血糖素受体（GCGRs）增加肝脏葡萄糖输出。有证据支持胰外胰高血糖素的概念，但其来源和生理功能仍不清楚。从接受癌症手术切除的患者获取肠道组织样本。采用质谱分析从黏膜裂解物中检测胰高血糖素。对黏膜组织进行静态孵育以评估胰高血糖素分泌反应。使用高度特异性的夹心酶联免疫吸附测定法定量胰高血糖素浓度。采用胆固醇摄取试验和分离的小鼠结肠动力试验评估肠道GCGRs的生理功能。通过质谱在人肠道黏膜裂解物中检测到完全加工的胰高血糖素。高糖可诱发人回肠组织显著的胰高血糖素分泌，且不依赖于钠葡萄糖共转运蛋白和KATP通道，这与葡萄糖诱导的胰高血糖素样肽1（GLP-1）分泌形成对比。GLP-1受体激动剂艾塞那肽-4可减弱葡萄糖诱导的人回肠胰高血糖素分泌。GCGR阻断显著增加人回肠隐窝培养物中的胆固醇摄取，并显著减缓离体结肠动力。我们的研究结果表明，人类肠道是胰外胰高血糖素的潜在来源，并证明了一种新的肠胰高血糖素/GCGR回路，其具有超出血糖调节的重要生理功能。
