Homocysteine Inhibits Pro-Insulin Receptor Cleavage and Causes Insulin Resistance Via Protein Cysteine-Homocysteinylation

Abstract

Elevation in homocysteine (Hcy) level is associated with insulin resistance; however, the causality between them, and the underlying mechanism remain elusive. Here, we demonstrated that Hcy induced insulin resistance and caused phenotypes of diabetes via protein cysteine-homocysteinylation (C-Hcy) of the pro-insulin receptor (pro-IR). Mechanistically, Hcy reacted and modified cysteine-825 of pro-IR in the endoplasmic reticulum (ER) and abrogated the formation of the original disulfide bond. C-Hcy impaired the interaction between pro-IR and the Furin protease in the Golgi apparatus, thereby hindering the cleavage of pro-IR. In mouse, increase in Hcy level decreased the mature IR level in various tissues, thereby inducing insulin resistance and type-2 diabetes phenotype. Furthermore, inhibition of C-Hcy in vivo and in vitro by overexpressing protein disulfide isomerase rescued the Hcy-induced phenotypes. Thus, C-Hcy in the ER might be a potential pharmacological target for the development of drugs that prevent insulin resistance and increase insulin sensitivity.