Increased insulin sensitivity and hypoinsulinemia in APS knockout mice.
A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS(-/-)) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. APS(-/-) mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS(-/-) mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes.
Division of Molecular Genetics, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan.
Asako
A
Minami
Masanori
M
Iseki
Kazuhiro
K
Kishi
Miao
M
Wang
Makoto
M
Ogura
Noboru
N
Furukawa
Sanae
S
Hayashi
Mizuki
M
Yamada
Toshiyuki
T
Obata
Yukari
Y
Takeshita
Yutaka
Y
Nakaya
Yoshimi
Y
Bando
Keisuke
K
Izumi
Shonna A
SA
Moodie
Fumiko
F
Kajiura
Mitsuru
M
Matsumoto
Kiyoshi
K
Takatsu
Satoshi
S
Takaki
Yousuke
Y
Ebina
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight; D002149:Energy Intake; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000097:blood; D007328:Insulin / Q000097:blood / Q000172:deficiency* / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D052242:Adiponectin; D001786:Blood Glucose; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D011506:Proteins; C488161:Sh2b2 protein, mouse; D014280:Triglycerides; D005934:Glucagon; D011972:Receptor, Insulin; D005947:Glucose