Metabolic effects of IGF-I deficiency: lessons from mouse models.
Insulin and insulin-like growth factors (IGFs) belong to the most biologically characterized family of peptides involved in metabolism, growth and development. The cellular responses to the IGFs are mediated primarily by the IGF-I receptor. The IGF-I receptor is a member of the family of tyrosine kinase growth factor receptors, and is highly homologous (70%) to the insulin receptor, especially in the tyrosine kinase domain (84%) ADDIN. Upon ligand binding to the extracellular region, the intrinsic tyrosine kinase domain of the receptor is activated. In the past it was believed that insulin activates primarily metabolic processes while IGFs promote cell growth and differentiation. However, in the last two decades many animal models of IGFI deficiency and excess revealed the importance of IGF-I in carbohydrate and lipid metabolism and now it is clear that these peptide hormones together with growth hormone (GH) work in a coordinate and interdependent manner. In the circulation, IGFs are bound in a binary complex with a family of high affinity IGF-binding proteins (IGFBPs) ADDIN. However, most of the circulating IGF-I associates with a high molecular weight complex approximately 150 KDa consisting of IGFBP-3 and the acid labile subunit (ALS) ADDIN. Once the ternary complex dissociates, the binary complexes of IGFBP-IGFs are removed from the circulation and by crossing the endothelium to reach the target tissues and to interact with cell surface receptors. In the present review we will summarize the role of GH and IGF in somatic growth and focus on the metabolic effects of IGF-I deficiency as assessed in various mouse models.
Yakar
Shoshana
S
Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. ShoshanaY@intra.niddk.nih.gov
Sun
Hui
H
Zhao
Hong
H
Pennisi
Patricia
P
Toyoshima
Yuka
Y
Setser
Jennifer
J
Stannard
Bethel
B
Scavo
Louis
L
Leroith
Derek
D
D000818:Animals; D004195:Disease Models, Animal; D004347:Drug Interactions; D019382:Human Growth Hormone / Q000494:pharmacology / Q000502:physiology; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008660:Metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic
D007328:Insulin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I