Gastric inhibitory polypeptide is the major insulinotropic factor in K(ATP) null mice.
OBJECTIVE
ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells are crucial in the regulation of glucose-induced insulin secretion. Recently, K(ATP) channel-deficient mice were generated by genetic disruption of Kir6.2, the pore-forming component of K(ATP) channels, but the mice still showed a significant insulin response after oral glucose loading in vivo. Gastric inhibitory polypeptide (GIP) is a physiological incretin that stimulates insulin release upon ingestion of nutrients. To determine if GIP is the insulinotropic factor in insulin secretion in K(ATP) channel-deficient mice, we generated double-knockout Kir6.2 and GIP receptor null mice and compared them with Kir6.2 knockout mice.


METHODS
Double-knockout mice were generated by intercrossing Kir6.2-knockout mice with GIP receptor-knockout mice. An oral glucose tolerance test, insulin tolerance test and batch incubation study of pancreatic islets were performed on double-knockout mice and Kir6.2-knockout mice.


RESULTS
Fasting glucose and insulin levels were similar in both groups. After oral glucose loading, blood glucose levels of double-knockout mice became elevated compared with Kir6.2-knockout mice, especially at 15 min (345+/-10 mg/dl vs 294+/-20 mg/dl, P<0.05) and 30 min (453+/-20 mg/dl vs 381+/-26 mg/dl, P<0.05). The insulin response was almost completely lost in double-knockout mice, although insulin secretion from isolated islets was stimulated by another incretin, glucagon-like peptide-1 in the double-knockout mice. Double-knockout mice and Kir6.2-knockout mice were similarly insulin sensitive as assessed by the insulin tolerance test.


CONCLUSIONS
GIP is the major insulinotropic factor in the secretion of insulin in response to glucose load in K(ATP) channel-deficient mice.
Tsukiyama
Katsushi
K
Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. tukiyama@metab.kuhp.kyoto-u.ac.jp
Yamada
Yuichiro
Y
Miyawaki
Kazumasa
K
Hamasaki
Akihiro
A
Nagashima
Kazuaki
K
Hosokawa
Masaya
M
Fujimoto
Shimpei
S
Takahashi
Akira
A
Toyoda
Kentaro
K
Toyokuni
Shinya
S
Oiso
Yutaka
Y
Seino
Yutaka
Y
D000818:Animals; D001786:Blood Glucose; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D005947:Glucose / Q000493:pharmacokinetics; D018149:Glucose Intolerance / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D005947:Glucose