The Role of Glutathione and Its Precursors in Type 2 Diabetes

Abstract

Type 2 diabetes (T2D) is a major worldwide health crisis affecting about 6.2% of the world's population. Alarmingly, about one in five children in the USA have prediabetes. Glutathione (GSH) and its precursors play a promising role in the prevention and management of type T2D. Oxidative stress (OxS) is a probable factor in both T2D initiation and progression. GSH is the major cytosolic water-soluble chemical antioxidant and emerging evidence supports its role in improving T2D outcomes. Dietary supplementation with N-acetyl-cysteine (NAC) and/or glycine (GLY), which are GSH precursors, has also been studied for possible beneficial effects on T2D. This review will focus on the underlying pathophysiological and molecular mechanisms linking GSH and its precursors with T2D and OxS. In addition to their traditional antioxidant roles, the in vivo effects of GSH/NAC/GLY supplements will be evaluated for their potential abilities to modulate the complex pro-oxidant pathophysiological factors (e.g., hyperglycemia) driving T2D progression. Positive feedback loops that amplify OxS over long time intervals are likely to result in irreversible T2D micro- and macro-vascular damage. Most clinical studies with GSH/NAC/GLY have focused on adults or the elderly. Future research with pediatric populations should be a high priority since early intervention is critical.

Keywords: N-acetyl-L-cysteine; glutathione; glycine; oxidative stress; prediabetes; reactive oxygen species; type 2 diabetes.

Figure 1

Glutathione biosynthetic scheme. N-acetyl-L-cysteine (NAC) can supply cysteine (CYS) for the biosynthesis of reduced glutathione (GSH). NAC must first be hydrolyzed by aminoacylase 1 (ACY1) to release CYS. In the first step of GSH synthesis, L-glutamate-L-cysteine ligase (GCL) catalyzes the formation of gamma-L-glutamyl-L-cysteine (GGC) by linking CYS and L-glutamate (GLU). In the second step, glutathione synthetase (GS) catalyzes the formation of GSH by linking GGC to GLY.

Figure 2

The glutathione peroxidase (GPX) system and lipid peroxidation. GPX catalyzes the conversion of lipid hydroperoxides (LOOH), formed from lipid peroxidation to a lipid alcohol (LOH) utilizing GSH as a reducing agent. The oxidized GSH (GSSG) formed by this reaction is reduced back to GSH by glutathione reductase (GR) with the consumption of NADPH. The lipid peroxyl radical (LOO*) formed from lipid peroxidation can undergo chemical decomposition to 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), which are reactive aldehydes that can react with proteins to form carbonylation products.

Figure 3

Simplified scheme connecting oxidative stress (OxS) and T2D risk factors. Two sets of potential positive feedback loops (circles with +) are indicated (blue and red arrows). The text describes these positive feedback loops in more detail. Over prolonged time intervals, systemic OxS can cause beta-cell dysfunction as well as irreversible micro- and macro-vascular damage.