Abstract
In both humans and rodent models, circulating glycine levels are significantly reduced in obesity, glucose intolerance, type II diabetes, and non-alcoholic fatty liver disease. The glycine cleavage system and its rate-limiting enzyme, glycine decarboxylase (GLDC), is a major determinant of plasma glycine levels. The goals of this study were to determine if the increased expression of GLDC contributes to the reduced plasma glycine levels seen in disease states, to characterize the hormonal regulation of GLDC gene expression, and to determine if altered GLDC expression has physiological effects that might affect the development of diabetes. The findings presented here show that hepatic GLDC gene expression is elevated in mouse models of obesity and diabetes, as well as by fasting. We demonstrated that GLDC gene expression is strongly regulated by the metabolic hormones glucagon and insulin, and we identified the signaling pathways involved in this regulation. Finally, we found that GLDC expression is linked to glutathione levels, with increased expression associated with elevated levels of glutathione and reduced expression associated with a suppression of glutathione and increased cellular ROS levels. These findings suggest that the hormonal regulation of GLDC contributes not only to the changes in circulating glycine levels seen in metabolic disease, but also affects glutathione production, possibly as a defense against metabolic disease-associated oxidative stress.