Gastric inhibitory polypeptide is the major insulinotropic factor in KATP null mice

Abstract

Objective: ATP-sensitive K+ (KATP) channels in pancreatic β-cells are crucial in the regulation of glucose-induced insulin secretion. Recently, KATP channel-deficient mice were generated by genetic disruption of Kir6.2, the pore-forming component of KATP 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 KATP 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 15min (345±10mg/dl vs 294±20mg/dl, P<0.05 and 30min (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. Conclusion: GIP is the major insulinotropic factor in the secretion of insulin in response to glucose load in KATP channel-deficient mice. © 2004 Society of the European Journal of Endocrinology.