Meg1/Grb10 overexpression causes postnatal growth retardation and insulin resistance via negative modulation of the IGF1R and IR cascades.
The Meg1/Grb10 protein has been implicated as an adapter protein in the signaling pathways from insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in vitro. To elucidate its in vivo function, four independent Meg1/Grb10 transgenic mouse lines were established, and the effects of excess Meg1/Grb10 on both postnatal growth and glucose metabolism were examined. All of the Meg1/Grb10 transgenic mice showed growth retardation after weaning (3-4 weeks), which indicates that ectopic overexpression of Meg1/Grb10 inhibits postnatal growth that is mediated by IGF1 via IGF1R. In addition, the mice became hyperinsulinemic owing to high levels of insulin resistance, which demonstrates that Meg1/Grb10 also modulates the insulin receptor cascade negatively in vivo. Type II diabetes arose frequently in the two transgenic lines, which also showed impaired glucose tolerance. In these mice, severe atrophy of the pancreatic acinus cells was associated with high-level production of Meg1/Grb10 in the pancreas. These results suggest that Meg1/Grb10 inhibits the function of both insulin and IGF1 receptors in these cells, since a similar phenotype has been reported for Ir and Igf1r double knockout mice. Taken together, these results indicate that Meg1/Grb10 interacts with both insulin and IGF1 receptors in vivo, and negatively regulates the IGF growth pathways via these receptors.
Shiura
Hirosuke
H
Department of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
Miyoshi
Naoki
N
Konishi
Atsuo
A
Wakisaka-Saito
Noriko
N
Suzuki
Rika
R
Muguruma
Kaori
K
Kohda
Takashi
T
Wakana
Shigeharu
S
Yokoyama
Minesuke
M
Ishino
Fumitoshi
F
Kaneko-Ishino
Tomoko
T
D000818:Animals; D000831:Animals, Newborn; D015536:Down-Regulation; D051383:GRB10 Adaptor Protein; D005947:Glucose / Q000378:metabolism*; D006130:Growth Disorders / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic / Q000378:metabolism; D009928:Organ Specificity; D015202:Protein Engineering / Q000379:methods; D011506:Proteins / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014018:Tissue Distribution
C495959:Grb10 protein, mouse; D007328:Insulin; D011506:Proteins; D011994:Recombinant Proteins; D051383:GRB10 Adaptor Protein; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D005947:Glucose