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Am J Physiol Endocrinol Metab 285: E1289-E1296, 2003. First published August 21, 2003; doi:10.1152/ajpendo.00278.2003
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ATP-sensitive K+ channel-mediated glucose uptake is independent of IRS-1/phosphatidylinositol 3-kinase signaling

Kohtaro Minami,1,3 Mizuo Morita,1,2 Atsunori Saraya,1 Hideki Yano,1 Yasuo Terauchi,4 Takashi Miki,1 Takayuki Kuriyama,2 Takashi Kadowaki,4 and Susumu Seino1,5

Departments of 1Cellular and Molecular Medicine and 2Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670; 3Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto 606-8507; 4Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655; and 5Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan

Submitted 19 June 2003 ; accepted in final form 11 August 2003

We previously found that disruption of Kir6.2-containing ATP-sensitive K+ (KATP) channels increases glucose uptake in skeletal muscle, but the mechanism is not clear. In the present study, we generated knockout mice lacking both Kir6.2 and insulin receptor substrate-1 (IRS-1). Because IRS-1 is the major substrate of insulin receptor kinase, we expected disruption of the IRS-1 gene to reduce glucose uptake in Kir6.2 knockout mice. However, the double-knockout mice do not develop insulin resistance or glucose intolerance. An insulin tolerance test reveals the glucose-lowering effect of exogenous insulin in double-knockout mice and in Kir6.2 knockout mice to be similarly enhanced compared with wild-type mice. The basal 2-deoxyglucose uptake rate in skeletal muscle of double-knockout mice is increased similarly to the rate in Kir6.2 knockout mice. Accordingly, disruption of the IRS-1 gene affects neither systemic insulin sensitivity nor glucose uptake in skeletal muscles of Kir6.2-deficient mice. In addition, no significant changes were observed in phosphatidylinositol 3-kinase (PI3K) activity and its downstream signal in skeletal muscle due to lack of the Kir6.2 gene. Disruption of Kir6.2-containing KATP channels clearly protects against IRS-1-associated insulin resistance by increasing glucose uptake in skeletal muscles by a mechanism separate from the IRS-1/PI3K pathway.

insulin receptor substrate-1; insulin secretion; insulin sensitivity; pancreatic {beta}-cell; skeletal muscle


K. Minami and M. Morita contributed equally to this work. Address for reprint requests and other correspondence: Susumu Seino, Division of Cellular and Molecular Medicine, Kobe Univ. Graduate School of Medicine, Kobe 650-0017, Japan (E-mail: seino{at}med.kobeu.ac.jp).




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