Potential Role of Insulin Growth-Factor-Binding Protein 2 as Therapeutic Target for Obesity-Related Insulin Resistance

Figures

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  Figure 1. Human representative of IGFBP2 genetic and molecular structure. (A) Human representative of genetic structure of IGFBP2. There are three regulatory elements, ranging from distal, middle to proximal elements. The structure gene contains four exons and three introns. The product is a mature mRNA of 1414 pb. (B) Human representative structure of IGFBP2 protein domain for the mature protein of 289 amino acids residues. There are three principal domains. The N-terminal domain, the middle domain or the middle region and the C-terminal domain. The N- (extracted from Galea C. et al. [9]) and C-terminal (PDB: 2H7T for the C-domain of IGFBP2) domain are presented. Both N- and C-terminal domains contain IGF binding sites, which suggests that these domains are highly conserved. However, the middle region has a proteolytic cleavage and phosphorylation sites, which indicates that this domain may be implicated in the regulation of bioavailability of IGF1 and stability of the protein structure.

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  Figure 2. The cellular action of IGFBP2 is mediated by two principal models. The IGF-dependent model (A) modulates the activity and bioavailability of IGFs, which prevents the binding of IGFs to their receptor. The IGF-independent model (B) constitutes the physical interaction between IGFBP2 and specific receptors at the cell surface and extracellular matrix, which acts as a ligand. The main function of both models is regulating cell cycle, insulin, and glucose metabolism and angiogenesis.

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  Figure 3. Proposed mechanism of action of IGFBP2 in obesity and insulin sensitivity. Dietary components and lifestyle modifications could affect circulating levels and mRNA expression of IGFBP2. The combination of these factors could provide a functional role of IGFBP2 on several metabolic disorders, and assign different strategies of prevention. In health state, higher levels of IGFBP2 act in both dependent and independent models to inhibit adipogenesis and activate the translocation of GLUT4, and improve the insulin sensitivity. In obese and insulin resistant state, lower IGFBP2 levels are the results of multiple factors, such as diet, sedentary, and low component and supplement from diet. When IGFBP2 is decreased, the adipogenesis process is activated and the translocation of GLUT4 is reduced, which results in increased body fat and poor insulin sensitivity.