%0 Journal Article
%T Variants of Insulin-Signaling Inhibitor Genes in Type 2 Diabetes and Related Metabolic Abnormalities
%A Carlo de Lorenzo
%A Annalisa Greco
%A Teresa Vanessa Fiorentino
%A Gaia Chiara Mannino
%A Marta Letizia Hribal
%J International Journal of Genomics
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/376454
%X Insulin resistance has a central role in the pathogenesis of several metabolic diseases, including type 2 diabetes, obesity, glucose intolerance, metabolic syndrome, atherosclerosis, and cardiovascular diseases. Insulin resistance and related traits are likely to be caused by abnormalities in the genes encoding for proteins involved in the composite network of insulin-signaling; in this review we have focused our attention on genetic variants of insulin-signaling inhibitor molecules. These proteins interfere with different steps in insulin-signaling: ENPP1/PC-1 and the phosphatases PTP1B and PTPRF/LAR inhibit the insulin receptor activation; INPPL1/SHIP-2 hydrolyzes PI3-kinase products, hampering the phosphoinositide-mediated downstream signaling; and TRIB3 binds the serine-threonine kinase Akt, reducing its phosphorylation levels. While several variants have been described over the years for all these genes, solid evidence of an association with type 2 diabetes and related diseases seems to exist only for rs1044498 of the ENPP1 gene and for rs2295490 of the TRIB3 gene. However, overall the data recapitulated in this Review article may supply useful elements to interpret the results of novel, more technically advanced genetic studies; indeed it is becoming increasingly evident that genetic information on metabolic diseases should be interpreted taking into account the complex biological pathways underlying their pathogenesis. 1. Introduction Insulin is the primary anabolic hormone known and it regulates several processes, including cellular growth, differentiation, apoptosis, and lipid, protein, and glucose synthesis and breakdown [1]. The first step of insulin action involves its binding to the insulin receptor (IR) and the consequent activation of the receptor intrinsic tyrosine kinase activity. Once activated, the IR catalyzes phosphorylation of other proteins, such as the IR substrate proteins (IRS1, IRS2, IRS3, and IRS4), which, in turn, act as docking molecules for SH2-domain containing proteins, including the regulatory subunits of Phosphoinositides 3 kinase (PI3K). PI3K then catalyzes the phosphorylation of the 3กไ hydroxyl subunit of phosphoinositides (PIs), notably converting PtdIns(4,5)P2 (PIP2) to PtdIns(3,4,5)P3 (PIP3), thus activating an assorted group of signaling proteins, containing phosphoinositide-binding domains. The activation of these proteins subsequently leads to the phosphorylation and activation of the serine-threonine kinase Akt (also known as protein kinase B) that ultimately transmits the insulin signal to a branching series
%U http://www.hindawi.com/journals/ijg/2013/376454/