Mosaic analysis of insulin receptor function.
Insulin promotes both metabolism and growth. However, it is unclear whether insulin-dependent growth is merely a result of its metabolic actions. Targeted ablation of insulin receptor (Insr) has not clarified this issue, because of early postnatal lethality. To examine this question, we generated mice with variable cellular mosaicism for null Insr alleles. Insr ablation in approximately 80% of cells caused extreme growth retardation, lipoatrophy, and hypoglycemia, a clinical constellation that resembles the human syndrome of leprechaunism. Insr ablation in 98% of cells, while resulting in similar growth retardation and lipoatrophy, caused diabetes without beta-cell hyperplasia. The growth retardation was associated with a greater than 60-fold increase in the expression of hepatic insulin-like growth factor binding protein-1. These findings indicate that insulin regulates growth independently of metabolism and that the number of insulin receptors is an important determinant of the specificity of insulin action.
Kitamura
Tadahiro
T
Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA.
Kitamura
Yukari
Y
Nakae
Jun
J
Giordano
Antonio
A
Cinti
Saverio
S
Kahn
C Ronald
CR
Efstratiadis
Argiris
A
Accili
Domenico
D
D000273:Adipose Tissue / Q000378:metabolism; D000483:Alleles; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division; D005838:Genotype; D006965:Hyperplasia; D007003:Hypoglycemia / Q000235:genetics; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009030:Mosaicism; D010641:Phenotype; D011972:Receptor, Insulin / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D008024:Ligands; D011972:Receptor, Insulin