K_ATP channel as well as SGLT1 participates in GIP secretion in the diabetic state

Glucose-dependent insulinotropic polypeptide (GIP), a gut hormone secreted from intestinal K-cells, potentiates insulin secretion. Both K-cells and pancreatic β-cells are glucoseresponsive and equipped with a similar glucose-sensing apparatus that includes glucokinase and an ATP-sensitive K⁺ (K_ATP) 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 K_ATP 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 K_ATP channel activator, did not affect glucose-induced GIP secretion in the normal state. In mice lacking K_ATP 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 K_ATP channel as well as SGLT1 is involved in GIP secretion in the diabetic state in vivo.