Abstract
It has been well established that insulin-like growth factors (IGFs) mainly mediate long-term actions in cell fates, whereas insulin predominantly exerts its role on metabolic activity. Indeed, insulin mediates multiple anabolic biological activities in glucose and amino acid transport, lipid and protein synthesis, the induction of glycogen, the inhibition of gluconeogenesis, lipolysis, and protein degradation. The interactions and differences between insulin receptor signaling and IGF-I receptor signaling in the metabolism and the cell fates are quite complicated. Because of the overlapping actions of IGF-I singling with insulin signaling, it has been difficult to distinguish the role of both signaling mechanisms on the metabolism. Furthermore, comprehensive information on the IGF-I function in respective tissues remains insufficient. Therefore, we need to clarify the precise roles of IGF-I signaling on the metabolism separate from those of insulin signaling. This review focuses on the metabolic roles of IGFs in the respective tissues, especially in terms of comparison with those of insulin, by overviewing the metabolic phenotypes of tissue-specific IGF-I and insulin receptor knockout mice, as well as those in mice treated with the dual insulin receptor/IGF-I receptor inhibitor OSI-906.
Highlights
Insulin-like growth factors (IGFs: IGF-I and IGF-II) have been shown to possess a variety of bioactivities in growth, cell differentiation, cell survival, and the maintenance of cell function
Since IGFs potently bind to IGF-I receptor (IGF-insulin receptor (IR)) and activate pathways associated with cellular proliferation, the IGF axis has been recognized for its contribution to cancer growth and a propensity for metastasis
Insulin and IGF-I action through their respective receptors are essential for the development and function of brown adipose tissue (BAT) and white adipose tissue (WAT) [31,32]
Summary
Insulin-like growth factors (IGFs: IGF-I and IGF-II) have been shown to possess a variety of bioactivities in growth, cell differentiation, cell survival, and the maintenance of cell function. Shc. The phosphorylated tyrosine residues of IRS-1, IRS-2, and Shc are recognized by various signaling molecules that contain an Src homology 2 (SH2) domain, including Grb and the 85 kDa regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase), leading to the activation of multiple downstream cascades (Figure 1). Hepatocyte-specific insulin receptor knockout (LIRKO) mice exhibited severe insulin resistance and glucose intolerance, leading to a significant increase in β-cell mass as well as the failure of insulin to suppress hepatic glucose production. LIRKO mice showed an age-dependent progression of liver dysfunction without steatosis [19] These reports indicate the significance of IR and IGF-IR signaling in hepatic insulin action and the metabolism of glucose and fatty acids through inter-organ networks
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