A Potential Link between Glycine Metabolism, Glutathione and Diabetes

Abstract

Type 2 diabetes (T2D) is accompanied by alterations in amino acid metabolism. Interestingly, in both humans and rodents, circulating glycine levels are significantly reduced in obesity, glucose intolerance and T2D identifying glycine as a biomarker of T2D and raising the possibility that altered glycine metabolism plays an active role in the etiology of the disease. The goals of our study are to determine if altered glycine metabolism plays a functional role in the development of diabetes. The glycine cleavage system (GCS) is the only biochemical route that degrades glycine in humans and loss‐of‐function mutations of GCS cause hyperglycinemia. Here, we show that the expression of the rate‐limiting enzyme of GCS, Glycine Decarboxylase (GLDC), is upregulated in livers of hyperinsulinemic mouse models of diabetes, and in hepatoma cell lines insulin stimulates transcription of the GLDC gene. We identified the insulin responsive transcription factor Sterol regulatory element binding protein 1c (SREBP‐1c) as the primary mediator of this insulin stimulatory effect. We also observed that altering GLDC expression levels strongly affected intracellular glutathione levels and levels of reactive oxygen species (ROS). Our findings suggest a working model in which Srebp1c‐mediated regulation of GLDC is responsible for the reduction of glycine levels seen in insulin resistant states and may play function as a compensatory mechanism to increase glutathione production as a defense against diabetes‐induced oxidative stress.Support or Funding InformationThis work is supported by NIH R21AG050741, and the Michigan Diabetes Research and Training Center.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.