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1 Department of Cellular and Molecular Medicine, Chiba University, Graduate School of Medicine, Chiba, Japan; Department of Experimental Therapeutics, Kyoto University Hospital, Kyoto, Japan
2 Department of Cellular and Molecular Medicine, Chiba University, Graduate School of Medicine, Chiba, Japan; Department of Respirology, Chiba University, Graduate School of Medicine, Chiba, Japan
3 Department of Cellular and Molecular Medicine, Chiba University, Graduate School of Medicine, Chiba, Japan
4 Department of Metabolic Diseases, University of Tokyo, Graduate School of Medicine, Tokyo, Japan
5 Department of Respirology, Chiba University, Graduate School of Medicine, Chiba, Japan
6 Department of Cellular and Molecular Medicine, Chiba University, Graduate School of Medicine, Chiba, Japan; Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
* To whom correspondence should be addressed. E-mail: seino{at}med.kobe-u.ac.jp.
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 Kri6.2 and insulin receptor substrate-1 (IRS-1). Since 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. 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 to wild-type mice. The basal 2-deoxyglucose uptake rate in skeletal muscle of double knockout mice is increased similarly to 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.
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