Departments of Endocrinology and DiabetesMetabolic MedicineNagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, JapanDepartment of DiabetesEndocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Oral and Maxillofacial SurgeryNagoya University Graduate School of Medicine, Nagoya, JapanResearch Center of HealthPhysical Fitness, and SportsDivision of Stress Adaptation and RecognitionDepartment of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, JapanDepartment of Medical PhysiologyGraduate School of Medicine, Chiba University, Chiba, JapanDivision of Molecular and Metabolic MedicineKobe University Graduate School of Medicine, Kobe, Japan.
Departments of Endocrinology and DiabetesMetabolic MedicineNagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, JapanDepartment of DiabetesEndocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Oral and Maxillofacial SurgeryNagoya University Graduate School of Medicine, Nagoya, JapanResearch Center of HealthPhysical Fitness, and SportsDivision of Stress Adaptation and RecognitionDepartment of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, JapanDepartment of Medical PhysiologyGraduate School of Medicine, Chiba University, Chiba, JapanDivision of Molecular and Metabolic MedicineKobe University Graduate School of Medicine, Kobe, JapanDepartments of Endocrinology and DiabetesMetabolic MedicineNagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, JapanDepartment of DiabetesEndocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Oral and Maxillofacial SurgeryNagoya University Graduate School of Medicine, Nagoya, JapanResearch Center of HealthPhysical Fitness, and SportsDivision of Stress Adaptation and RecognitionDepartment of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, JapanDepartment of Medical PhysiologyGraduate School of Medicine, Chiba University, Chiba, JapanDivision of Molecular and Metabolic MedicineKobe University Graduate School of Medicine, Kobe, Japan
J Endocrinol. 2014 Aug;222(2):191-200. doi: 10.1530/JOE-14-0161. Epub 2014 Jun 2.
Glucose-dependent insulinotropic polypeptide (GIP), a gut hormone secreted from intestinal K-cells, potentiates insulin secretion. Both K-cells and pancreatic β-cells are glucose-responsive and equipped with a similar glucose-sensing apparatus that includes glucokinase and an ATP-sensitive K(+) (KATP) 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 KATP 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 KATP channel activator, did not affect glucose-induced GIP secretion in the normal state. In mice lacking KATP 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 KATP channel as well as SGLT1 is involved in GIP secretion in the diabetic state in vivo.
葡萄糖依赖性胰岛素促分泌多肽（GIP）是一种从肠道 K 细胞分泌的肠激素，可增强胰岛素分泌。K 细胞和胰腺β细胞均对葡萄糖有反应，并具有相似的葡萄糖感应装置，包括葡糖激酶和包含 Kir6.2 和磺酰脲受体 1 的 ATP 敏感 K(+)（KATP）通道。在吸收性上皮细胞和肠内分泌细胞中，也已知钠-葡萄糖共转运蛋白 1（SGLT1）在葡萄糖吸收和葡萄糖诱导肠降血糖素分泌中发挥重要作用。然而，K 细胞中的葡萄糖感应机制尚不完全清楚。在这项研究中，我们研究了 SGLT1（SLC5A1）和 KATP 通道在正常和链脲佐菌素诱导的糖尿病小鼠的 GIP 分泌中的葡萄糖感应中的作用。磺酰脲格列美脲（glimepiride）不会诱导 GIP 分泌，并且 KATP 通道激活剂二氮嗪（diazoxide）预处理不会影响正常状态下葡萄糖诱导的 GIP 分泌。在缺乏 KATP 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 SGLT1 抑制剂根皮苷（phlorizin）完全阻断。在 Kir6.2(-/-) 小鼠中，通过 SGLT1 的肠道葡萄糖吸收增强与 Kir6.2(+) (/) (+) 小鼠相比。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，但在用根皮苷预处理后，除了根皮苷给药外，还被完全阻断。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 SGLT1，而在体内糖尿病状态下，KATP 通道以及 SGLT1 参与 GIP 分泌。
