Vitamin D and L-cysteine levels correlate positively with GSH and negatively with insulin resistance levels in the blood of type 2 diabetic patients.

G Kahlon,S N Levine,S K Jain,D Micinski,P F Bass,L Huning

doi:10.1038/ejcn.2014.114

Abstract

Background/Objectives:Vitamin D, L-cysteine (LC) and glutathione (GSH) levels are lower in the blood of diabetic patients. This study examined the hypothesis that the levels of vitamin D and LC correlate with those of GSH in the blood of type 2 diabetic patients (T2D), and that vitamin D and LC upregulate glutamate–cysteine ligase (GCLC), which catalyzes GSH biosynthesis, in cultured monocytes.Subjects/Methods:Fasting blood was obtained after written informed consent from T2D (n=79) and healthy controls (n=22). U937 monocytes were pretreated with 1,25 (OH)2 vitamin D (0–25 nM) or LC (0–500 μM) for 24 h and then exposed to control or high glucose (25 mM) for 4 h.Results:Plasma levels of vitamin D, LC, GSH and GCLC protein were significantly lower in T2D versus those in age-matched healthy controls. Multiple linear regression analyses and adjustment for body weight showed a significant positive correlation between plasma levels of vitamin D (r=0.26, P=0.05) and LC (r=0.81, P=0.001) and that of GSH, and between LC and vitamin D (r=0.27, P=0.045) levels. Plasma levels of GSH (r=−0.34, P=0.01) and LC (r=−0.33, r=0.01) showed a negative correlation with triglyceride levels. Vitamin D correlated inversely with HbA1C (−0.30, P=0.01) and homeostatic model assessment insulin resistance (r=−0.31, P=0.03), which showed a significant positive correlation with triglycerides (r=0.44, P=0.001) in T2D. Cell culture studies demonstrate that supplementation with vitamin D and LC significantly increased GCLC expression and GSH formation in control and high-glucose-treated monocytes.Conclusions:This study suggests a positive relationship between the concentrations of the micronutrients vitamin D and LC and that of GSH. Some of the beneficial effects of vitamin D and LC supplementation may be mediated by an increase in the levels of GSH and a decrease in triglyceride levels in T2D patients.

Highlights

Reduced glutathione (GSH) is the most prevalent non-protein thiol found in mammalian cells.[1,2] GSH has a major role in the detoxification of a variety of electrophilic compounds, including peroxides and oxygen radicals catalyzed by glutathione S-transferases, and in the glutathione peroxidase system.[1,2] In addition, the redox status of GSH has a significant role in signal transduction, gene expression, apoptosis, protein glutathionylation and the maintenance of appropriate protein structure and function.[1,2] Alteration in GSH levels is associated with a wide variety of pathologies, such as cancer, HIV, lung disease, Parkinson’s disease and diabetes
This study reports a positive relationship between plasma levels of LC and vitamin D with those of GSH, which in turn shows a negative relationship with the elevated triglycerides and insulin resistance seen in type 2 diabetic (T2D) patients
To determine whether lower LC and vitamin D levels have any role in lowering GSH levels in diabetic patients, we examined the hypothesis that LC and vitamin D upregulate the glycine–cysteine ligase catalytic unit (GCLC) enzyme, which regulates GSH biosynthesis

Summary

Introduction

Reduced glutathione (GSH) is the most prevalent non-protein thiol found in mammalian cells.[1,2] GSH has a major role in the detoxification of a variety of electrophilic compounds, including peroxides and oxygen radicals catalyzed by glutathione S-transferases, and in the glutathione peroxidase system.[1,2] In addition, the redox status of GSH has a significant role in signal transduction, gene expression, apoptosis, protein glutathionylation and the maintenance of appropriate protein structure and function.[1,2] Alteration in GSH levels is associated with a wide variety of pathologies, such as cancer, HIV, lung disease, Parkinson’s disease and diabetes. Elevated glucagon levels increase the uptake of glutamine and glycine by the liver, causing the lower blood levels of glutamate, glycine and L-cysteine (LC) seen in diabetes.[3,4,6,7,8,9] These amino acids are vital for the maintenance of circulating and tissue levels of GSH, which protects against the increased oxidative insults common to diabetes

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Results

Conclusion