Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding.
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.
Kubota
Naoto
N
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Kubota
Tetsuya
T
Itoh
Shinsuke
S
Kumagai
Hiroki
H
Kozono
Hideki
H
Takamoto
Iseki
I
Mineyama
Tomoka
T
Ogata
Hitomi
H
Tokuyama
Kumpei
K
Ohsugi
Mitsuru
M
Sasako
Takayoshi
T
Moroi
Masao
M
Sugi
Kaoru
K
Kakuta
Shigeru
S
Iwakura
Yoichiro
Y
Noda
Tetsuo
T
Ohnishi
Shin
S
Nagai
Ryozo
R
Tobe
Kazuyuki
K
Terauchi
Yasuo
Y
Ueki
Kohjiro
K
Kadowaki
Takashi
T
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
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