title: Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding.
abstract: Insulin receptor substrate (Irs) mediates metabolic actions of insulin. Here, we show that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis. The PI3K activity associated with Irs2 began to increase during fasting, reached its peak immediately after refeeding, and decreased rapidly thereafter. By contrast, the PI3K activity associated with Irs1 began to increase a few hours after refeeding and reached its peak thereafter. The data indicate that Irs2 mainly functions during fasting and immediately after refeeding, and Irs1 functions primarily after refeeding. In fact, liver-specific Irs1-knockout mice failed to exhibit insulin resistance during fasting, but showed insulin resistance after refeeding; conversely, liver-specific Irs2-knockout mice displayed insulin resistance during fasting but not after refeeding. We propose the concept of the existence of a dynamic relay between Irs1 and Irs2 in hepatic insulin signaling during fasting and feeding.
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kubota
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Itoh
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kumagai
authors.forename: Hideki
authors.initials: H
authors.lastname: Kozono
authors.forename: Iseki
authors.initials: I
authors.lastname: Takamoto
authors.forename: Tomoka
authors.initials: T
authors.lastname: Mineyama
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ogata
authors.forename: Kumpei
authors.initials: K
authors.lastname: Tokuyama
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohsugi
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Sasako
authors.forename: Masao
authors.initials: M
authors.lastname: Moroi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Sugi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kakuta
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Shin
authors.initials: S
authors.lastname: Ohnishi
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D004435:Eating; D005215:Fasting / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose