Hypoglycemic effect of insulin-like growth factor-1 in mice lacking insulin receptors.

Abstract

We have investigated the metabolic actions of recombinant human IGF-1 in mice genetically deficient of insulin receptors ( IR ϪրϪ ). After intraperitoneal administration, IGF-1 caused a prompt and sustained decrease of plasma glucose levels in IR ϪրϪ mice. Plasma free fatty acid concentrations were unaffected. Interestingly, the effects of IGF-1 were identical in normal mice ( IR ϩրϩ ) and in IR ϪրϪ mice. Despite decreased glucose levels, IR ϪրϪ mice treated with IGF-1 died within 2 Ϫ 3 d of birth, like sham-treated IR ϪրϪ controls. In skeletal muscle, IGF-1 treatment caused phosphorylation of IGF-1 receptors and increased the levels of the phosphatidylinositol-3-kinase p85 subunit detected in antiphosphotyrosine immunoprecipitates, consistent with the possibility that IGF-1 stimulates glucose uptake in a phosphatidylinositol-3-kinase-dependent manner. IGF-1 receptor phosphorylation and coimmunoprecipitation of phosphatidylinositol-3-kinase by antiphosphotyrosine antibodies was also observed in liver, and was associated with a decrease in mRNA levels of the key gluconeogenetic enzyme phosphoenolpyruvate carboxykinase. Thus, the effect of IGF-1 on plasma glucose levels may be accounted for by increased peripheral glucose use and by inhibition of hepatic gluconeogenesis. These data indicate that IGF-1 can mimic insulin's effects on glucose metabolism by acting through its own receptor. The failure of IGF-1 to rescue the lethal phenotype due to lack of insulin receptors suggests that IGF-1 receptors cannot effectively mediate all the metabolic actions of insulin receptors. ( J. Clin. Invest. 1997. 99:2538-2544.)

Long‐lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high‐fat diet on metabolic function and energy expenditure

“…Previous studies have reported that IGF‐1 can mimic the metabolic effects of insulin to stimulate glucose uptake (Blundell & Humbel, 1980; Di Cola et al ., 1997). To further clarify endocrine function, we evaluated IGF‐1 levels in Ames dwarf and control mice fed either diets.…”

Lack of insulin receptors affects the formation of white adipose tissue in mice. A morphometric and ultrastructural analysis

“…On the other hand, IGF-1 seems to be unable to substitute for insulin's actions on terminally differentiated adipocytes. In this respect it is interesting to note that IGF-1 can exert hypoglycaemic, but not lipogenic effects, in IR ±/± mice [27]. In a different model, we have previously shown that partial inactivation of the IR gene in 3T3-L1 cells is associated with impaired adipocyte differentiation, and that this defect can be reversed by over-expression of IRs [28].…”

Oilseeds ameliorate metabolic parameters in male mice, while contained lignans inhibit 3T3-L1 adipocyte differentiation in vitro

“…A major regulatory action is exerted by six IGF-binding proteins (IGFBP-1 to 6), which show high affinity for IGFs [49,50]. The IGF/IGFBP complexes prolong the half-lives of IGFs and thus may buffer the potential hypoglycemic effects that could result from high concentrations of circulating unbound IGFs [51]. IGFBP-5 is thus a key gene of glucose metabolism and has been shown to be associated with control of adiposity and is supposed to mediate a mechanism used to limit further fat gain [50].…”