Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 on insulin secretion and gut motility.
Glucose-induced insulin secretion from pancreatic beta-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.
Miki
Takashi
T
Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Minami
Kohtaro
K
Shinozaki
Hidehiro
H
Matsumura
Kimio
K
Saraya
Atsunori
A
Ikeda
Hiroki
H
Yamada
Yuichiro
Y
Holst
Jens Juul
JJ
Seino
Susumu
S
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose / Q000502:physiology; D005502:Food; D005749:Gastric Inhibitory Polypeptide / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000502:physiology*; D005934:Glucagon / Q000502:physiology*; D052216:Glucagon-Like Peptide 1; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000502:physiology; D010446:Peptide Fragments / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology; D011498:Protein Precursors / Q000502:physiology*; D013997:Time Factors; D000099161:Kcnj11 Channel
D001120:Arginine; D001786:Blood Glucose; D005749:Gastric Inhibitory Polypeptide; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D007328:Insulin; D010446:Peptide Fragments; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011498:Protein Precursors; D000099161:Kcnj11 Channel