title: ATP-sensitive K+ channel-mediated glucose uptake is independent of IRS-1/phosphatidylinositol 3-kinase signaling.
abstract: 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.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Minami
authors.forename: Mizuo
authors.initials: M
authors.lastname: Morita
authors.forename: Atsunori
authors.initials: A
authors.lastname: Saraya
authors.forename: Hideki
authors.initials: H
authors.lastname: Yano
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kuriyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D004789:Enzyme Activation; D005947:Glucose / Q000493:pharmacokinetics*; D007328:Insulin / Q000097:blood*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D024661:Potassium Channels, Inwardly Rectifying; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose