Homocysteine levels and outside‐in insulin signaling in human and mouse tissues

Abstract

Hyperhomocysteinemia (HHcy) and insulin resistance both are associated with the atherosclerotic cardiovascular disease. However, the effect and mechanism of homocysteine (Hcy) metabolism on insulin signaling genes has not been studied. We examined the expression profiles of insulin signaling genes involved in PI3K and MAPK pathway through database mining approach. Furthermore, we analyzed the relationship between mRNA levels of insulin signaling genes, tissue Hcy, S‐adenosyl homocysteine (SAH), and S‐adenosyl methionine (SAM)/SAH ratio in mouse tissues. We found PI3K pathway genes are differentially expressed in both human and mouse tissues, with humans having the high expression of PI3K pathway genes in classic insulin sensitive tissues (muscle, liver, and adipose tissue). This suggests that humans have tissue specific regulation of insulin signaling genes involved in PI3K pathway. Moreover, PI3K pathway genes PDK1, Akt1, RPS6KB1, and HSL were negatively correlated with tissue Hcy and SAH levels. In contrast, MAPK pathway genes were mostly ubiquitously expressed in human tissues examined. MAPK pathway genes Grb2, MAP3K2, and Erk2 were negatively correlated with tissue Hcy and SAH levels. Our study indicates that Hcy metabolism is negatively correlated with insulin signaling genes. HHcy may impact on obesity and type 2 diabetes via suppression of insulin signaling. Our work is supported by NIH grant.