Hormonal Regulation of Glycine Metabolism And Its Potential Role in Diabetes Susceptibility

Abstract

Type II diabetes (T2D) is characterized by insulin resistance, β cell dysfunction and impaired glucose tolerance. Multiple large‐scale metabolomics studies have demonstrated that diabetes is accompanied by alterations in amino acid metabolism. Interestingly, in both humans and animal models, circulating glycine levels are strongly reduced in obesity, glucose intolerance and T2D. These observations identify glycine as an important biomarker of T2D, and raise the possibility that altered glycine metabolism may play an active role in the development of the disease. The goals of our study are to determine if altered glycine metabolism plays a role in the etiology of diabetes, and to characterize the regulatory pathways that control plasma glycine levels. Glycine cleavage system (GCS), a multimeric enzyme complex, represents the only biochemical route that degrades glycine in human body. Human genetic evidences indicate that loss‐of‐function mutations of GCS cause hyperglycinemia and neurodevelopmental disorders resulting in early death. Given the key role of GCS in control of circulating level of glycine, we hypothesize that during progression of T2D, GCS‐mediated glycine catabolism may be altered in main metabolic organs including liver. Here, we show that in hepatoma cell lines both insulin and glucocorticoids strongly stimulate transcription of glycine decarboxylase (GLDC) gene that encodes the rate‐limiting component of GCS. We also show that the insulin responsive transcription factor sterol‐regulatory element binding protein‐1c (SREBP‐1c) regulates GLDC gene transcription and likely mediates the stimulatory effect of insulin. SREBP‐1c is known to mediate insulin's stimulatory effect on lipogenesis genes even in the presence of hepatic insulin resistance. These observations strengthen a working model that insulin‐mediated stimulation of GLDC, even in insulin resistant states, increases the activity of the glycine cleavage system and contributes to the low levels of glycine observed in T2D.Support or Funding InformationMichigan Diabetes Research and Training Center Pilot/Feasibility Grant