Liver-Specific igf-1 Gene Deletion Leads to Muscle Insulin Insensitivity

Abstract

Insulin and insulin-like growth factors (IGFs) mediate a variety of signals involved in mammalian development and metabolism. To study the metabolic consequences of IGF-I deficiency, we used the liver IGF-I-deficient (LID) mouse model. The LID mice show a marked reduction (ϳ75%) in circulating IGF-I and elevated growth hormone (GH) levels. Interestingly, LID mice show a fourfold increase in serum insulin levels (2.2 vs. 0.6 ng/ml in control 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 of circulating insulin enable the LID mice to maintain normoglycemia in the presence of apparent insulin insensitivity. Insulin-induced autophosphorylation of the insulin receptor and tyrosine phosphorylation of insulin receptor substrate (IRS)-1 were absent in muscle, but were normal in liver and white adipose tissue of the LID mice. In contrast, IGF-I-induced autophosphorylation of its cognate receptor and phosphorylation of IRS-1 were normal in muscle of LID mice. Thus, the insulin insensitivity seen in the LID mice is muscle specific. Recombinant human IGF-I treatment of the LID mice caused a reduction in insulin levels and an increase in insulin sensitivity. Treatment of the LID mice with GH-releasing hormone antagonist, which reduces GH levels, also increased insulin sensitivity. These data provide evidence of the role of circulating IGF-I as an important component of overall insulin action in peripheral tissues.

Insulin‐like growth factor 1 has multisystem effects on foetal and preterm infant development

“…This was demonstrated in a liver‐specific IGF‐1 deficient mouse model, which showed a 75% reduction in circulating IGF‐1 with insulin insensitivity in muscle. Treatment of these animals with IGF‐1 reduced hyperinsulinemia and improved insulin sensitivity, providing evidence for IGF‐1 as an important component of overall insulin action in peripheral tissues 33.…”

Changes in bioactive IGF-I and IGF-binding protein-1 during an oral glucose tolerance test in patients with liver cirrhosis

“…Accordingly, there is strong experimental evidence thatl ow levels of circulatingIGF-I result in peripheral insulin resistance. Thisappearstob emediated through twomechanisms: first, an inadequate IGF-I-mediated negative feedback at thel evel of theh ypothalamus/pituitaryl eading to chronic GH hypersecretiona nd secondly, IGF-I has been suggestedt oe xert ad irect stimulating effect on insulin sensitivity in skeletal muscles (53).However,we acknowledgethatthese hypotheses remain to be tested.…”

Association between hepatic steatosis and serum IGF1 and IGFBP-3 levels in a population-based sample

“…Animals with liver-specific insulin-like growth factor-1 (IGF1) gene deletion are characterized by insulin resistance and hyperinsulinemia (12,13). Low serum IGF1 levels are also associated with determinants of the metabolic syndrome including insulin resistance, serum leptin levels, waist-to-hip ratio, and type 2 diabetes mellitus (14)(15)(16)(17)(18).…”