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.

Glutathione and a Pool of Metabolites Partly Related to Oxidative Stress Are Associated with Low and High Myopia in an Altered Bioenergetic Environment

“…The redox state of the GSH/GSSG couple serves as a leading indicator of a redox environment. Both GSH and GSSG are exported from cells through multidrug resistance protein; extracellular GSH is metabolized by membrane-bound γ-glutamyl transpeptidase into cysteinylglycine and γ-glutamyl products, and dipeptidase hydrolyzes cysteinylglycine to cysteine and glycine [31]. We observed markedly diminished GSH levels in the LM and HM groups in the second set of patients.…”

The link between theANPEPgene and type 2 diabetes mellitus may be mediated by the disruption of glutathione metabolism and redox homeostasis

“…The same can be said for ANPEP, whose expression level is increased both in the plasma and beta cells of the pancreatic islets in patients with type 2 diabetes [23,50,96]. The main assumption is that increased expression of amino acid and peptide metabolism enzymes is required to provide amino acid precursors for the biosynthesis of glutathione, the deficit of which is considered a primary cause of type 2 diabetes [21,31,35]. Numerous studies (reviewed in [22]) have shown that glutathione deficiency and impaired redox homeostasis are etiologically associated with key changes found in type 2 diabetes, such as oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, disruption of the ubiquitin-proteasome system and autophagy, disruption of insulin secretion, beta cell dysfunction, and insulin resistance.…”

“…Third, decreased glutathione levels are closely correlated with the pathological conditions found in T2D, and replenishment of glutathione deficiency improves them. These pathological changes include oxidative stress and mitochondrial dysfunction [31,32,35–37], β-cell dedifferentiation and failure [38], impaired glucose tolerance, insulin secretion [39–41] and sensitivity [42,43]. In addition, the depletion of endogenous glutathione is correlated with increased blood glucose levels and contributes to the complications of type 2 diabetes [33,34,38].…”

Glutathione Induces Keap1 S-Glutathionylation and Mitigates Oscillating Glucose-Induced β-Cell Dysfunction by Activating Nrf2

“…GSH plays a crucial role in maintaining cellular redox homeostasis and regulating various cell functions such as cell cycle, apoptosis, immunological defense, and pathological abnormality [19,20,52,53]. GSH also interacts with other enzymes and proteins, including glutathione peroxidases and glyoxylases, to engage and regulate cellular processes [20,52].…”