An article published in the Nature Communications in October 2016 tried to investigate whether the glycine transporter 1 inhibitor, commonly used as a schizophrenia medication, has any impact on metabolic homeostasis of healthy, obese and diabetic rats.
Central nervous system-based therapies could present a potential therapeutic to help restore glucose and energy homeostasis in diabetes and obesity, which are two major diseases in the world. The N-methyl-d-aspartate (NMDA) receptors in the dorsal vagal complex (DVC, responsible for regulating digestive organs) are known to lower glucose production and food intake in rodents, and are activated by glycine. The glycine transporter 1 (GlyT1) acts as the main regulator of glycine levels for NMDA receptors and its inhibition results in increased extracellular glycine levels, which then activate the NMDA receptors. Previous studies have shown that the direct administration of glycine is able to lower glucose production in mice, but the direct administration of glycine is not a reliable therapy. A new study examined whether GlyT1 inhibition regulates glucose and energy homeostasis in healthy, obese and diabetic rodents.
GlyT1 inhibitors, which were the focus of this study, have been previously used to help treat schizophrenia. It is hypothesized that schizophrenia is often the result of a decrease in function of NMDA receptors. In clinical studies, GlyT1 inhibitors have been shown to improve schizophrenic symptoms by inhibiting GlyT1, resulting in the activation of NMDA receptors by glycine. However, there are no studies to date that have examined the role of GlyT1 inhibitors in treating obesity and diabetes.
The glucoregulatory role of GlyT1 inhibition was assessed by infusing the GlyT1 inhibitor ALX into the DVC of healthy rats and monitoring their plasma glucose via a glucose tolerance tests. In order to compare to a control group, the DVCs of another group of healthy, obese and diabetic rats were infused with saline solutions. The DVC ALX infusion improved glucose tolerance and decreased glucose production, compared with DVC saline infusions. The effectiveness of GLyT1 inhibitors was independent of body weight, plasma glucose, or plasma insulin differences in the mice. In order to understand the mechanism by which DVC GlyT1 inhibition improves glucose tolerance, authors investigated whether DVC GlyT1 inhibition regulates glucose production or glucose uptake during normal insulin sensitivity in both rats and mice. By performing a microdialysis, researchers were able to determine that GlyT1 inhibition works by causing a reduction in glucose production and does not impact glucose uptake. Researchers also systemically administered ALX, and found that this resulted in similar impacts on NMDA receptors.
The ability of GlyT1 inhibitors to exert a positive effect on NMDA receptor activation was seen in diabetic, healthy and high-fat-diet-fed mice, indicating that they have a potential use as obesity and diabetes therapies. These inhibitors showed both short-term and long-term positive effects on glucose production. As well, a lower food intake and a decreased body weight were seen in mice after ALX injection. Future studies should look at the role of GlyT1 inhibition in both type 1 and type 2 diabetes, to investigate whether targeting GlyT1 for inhibition can serve as viable treatment options for diabetes and weight loss.
Written By: Hummara Aslam, BSc