Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity

Insulin and insulin-like growth factors (IGFs) mediate a variety of signals involved in mammalian development and metabolism. To study the metabolic c onsequences of IGF-I deficiency, we used the liver IGF-I-deficient (LID) mo use model. The LID mice show a marked reduction (similar to 75%) in circula ting IGF-I and elevated growth hormone (GH) levels. Interestingly, LTD mice show a fourfold increase in serum insulin levels (2.2 vs. 0.6 ng/ml in con trol mice) and abnormal glucose clearance after insulin injection. Fasting blood glucose levels and those after a glucose tolerance test were similar between the LID mice and their control littermates. Thus, the high levels o f circulating insulin enable the LID mice to maintain normoglycemia in the presence of apparent insulin insensitivity. Insulin-induced autophosphoryla tion of the insulin receptor and tyrosine phosphorylation of insulin recept or substrate (IRS)-1 were absent in muscle, but were normal in liver and wh ite adipose tissue of the LLD mice. In contrast, IGF-I-induced autophosphor ylation of its cognate receptor and phosphorylation of IRS-l were normal in muscle of LID mice. Thus, the insulin insensitivity seen in the LID mice i s muscle specific. Recombinant human IGF-I treatment of the LID mice caused a reduction in insulin levels and an increase in insulin sensitivity. Trea tment of the LID mice with GH-releasing hormone antagonist, which reduces G H levels, also increased insulin sensitivity. These data provide evidence o f the role of circulating IGF-I as an important component of overall insuli n action in peripheral tissues.