Insulin resistance caused by a redox-associated hepatokine

Abstract

ISSN 1758-1907 10.2217/DMT.11.12 © 2011 Future Medicine Ltd Diabetes Manage. (2011) 1(3), 255–257 Type 2 diabetes is a multifactorial disease that is caused by the disruption of inter organ networks. These disruptions lead to absolute and/or relative deficiencies in the actions of insulin due to either a genetic disposition or environmental factors. Recent studies have unraveled humoral and nutritional factors, and a neuronal pathway that may govern such inter organ networks [1]. The disruption of these interorgan networks leads to insulin resistance. Several organ-derived bioactive mediators, such as reactive oxygen species, fatty acids, plasminogen activator-1 and cytokines/hormones secreted from the liver and adipose tissue, may cause oxidative stress and thereby promote insulin resistance and vascular complications [2]. Insulin resistance is an underlying feature involved in the pathogenesis of Type 2 diabetes and its related vascular complications. Specifically, the liver plays a central role in energy homeostasis and is a major source of bioactive secretory proteins that contribute to the pathophysiology of diabetes and subsequent complications. Therefore, comprehensive gene expression analyses of the liver are important steps for understanding the molecular signature of Type 2 diabetes. By using an in-house cDNA microarray, we found that hepatic expression of genes encoding angiogenic factors, fibrogenic factors and redox-associated factors are altered in people with Type 2 diabetes compared with those without diabetes [3–6]. This differential expression may contribute to the pathophysio logy of Type 2 diabetes and its clinical manifestations. Based on these findings, we hypothesized that in a manner analogous to adipose tissues [7] the liver may also contribute to the development of diabetes and insulin resistance through the production of secretory proteins, termed hepatokines. To identify a novel hepatokine, we first applied a serial ana lysis of gene expression (SAGE) technique that makes it possible to compare tag levels among independent libraries and to identify previously unrecognized genes encoding hepatokines that may regulate the pathophysio logy of diabetes [8]. Samples for SAGE were obtained from five patients with Type 2 diabetes