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Distinct Effects of Glucose-Dependent Insulinotropic Polypeptide and Glucagon-Like Peptide-1 on Insulin Secretion and Gut Motility

¹ Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
² Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, Japan
³ Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
⁴ Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
⁵ Department of Medical Physiology, University of Copenhagen, The Panum Institute, Copenhagen, Denmark

Glucose-induced insulin secretion from pancreatic ß-cells depends critically on ATP-sensitive K⁺ channel (K_ATP channel) activity, but it is not known whether K_ATP channels are involved in the potentiation of insulin secretion by glucose-dependent insulinotropic polypeptide (GIP). In mice lacking K_ATP channels (Kir6.2^–/– mice), we found that pretreatment with GIP in vivo failed to blunt the rise in blood glucose levels after oral glucose load. In Kir6.2^–/– mice, potentiation of insulin secretion by GIP in vivo was markedly attenuated, indicating that K_ATP channels are essential in the insulinotropic effect of GIP. In contrast, pretreatment with glucagon-like peptide-1 (GLP-1) in Kir6.2^–/– mice potentiated insulin secretion and blunted the rise in blood glucose levels. We also found that GLP-1 inhibited gut motility whereas GIP did not. Perfusion experiments of Kir6.2^–/– mice revealed severely impaired potentiation of insulin secretion by 1 nmol/l GIP and substantial potentiation by 1 nmol/l GLP-1. Although both GIP and GLP-1 increase the intracellular cAMP concentration and potentiate insulin secretion, these results demonstrate that the GLP-1 and GIP signaling pathways involve the K_ATP channel differently.

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