Modeling GSH Metabolism in Diabetes to Study the Role of Redox Status in Anti-diabetic Treatment

Abstract

Hyperglycemia-induced oxidative stress leads to the development and progression of complications associated with type 2 diabetes (T2D). The cellular antioxidant glutathione (GSH) is crucial in maintaining systemic redox balances. Studies have reported low GSH concentration in individuals with T2D, and alleviating systemic oxidative stress through GSH supplementation could help control the complications. A six-month-long pragmatic prospective clinical trial was conducted to investigate the effect of oral GSH supplementation on erythrocytic GSH stores and glucose homeostasis in individuals with T2D undergoing anti-diabetic treatment. GSH supplementation was observed to improve body stores of GSH and offered protection from oxidative damage in these individuals. It also helped maintain lower HbA1c and improved fasting insulin in elder individuals with T2D. Inter-individual variations of biochemical changes were observed to be very evident in this clinical study. In order to understand the dynamics of biochemical responses and their inter-individual variation for elucidating effective personalized interventions with GSH, we analyzed the clinical trial data with the framework of linear mixed-effects (LME) models. We modeled longitudinal changes in individuals with T2D and obtained the distribution of subject-wise trajectories and overall rates of changes across various study groups of GSH supplementation. We modeled the serial changes in elder and younger individuals with T2D during the study period separately to investigate the variations in their progression. The model-derived average linear trajectories elucidate the progression of biochemical parameters in individuals with T2D over the six-month study period. The response to GSH supplementation was observed to differ between elder and younger individuals with T2D. GSH was observed to replenish faster in younger than in elder individuals with T2D. It enhances the reduction rates in HbA1c and boosts fasting insulin levels in elder individuals with T2D. The reduction in 8- OHdG occurred at a faster rate in older individuals compared to their younger counterparts. Further, we monitored imbalances in cellular GSH and their turnover to provide quantitative insights into the recovery path of individuals with T2D. We propose a minimal mathematical model based on physiology for describing erythrocytic GSH turnover under varying extracellular conditions. This model was used to understand the glutathione response profiles in erythrocytic treatment experiments conducted in nondiabetic, prediabetic, and diabetic individuals. Model estimates of relevant parameters described the restoration of cellular GSH pools and stress under varying extracellular conditions, thereby allowing us to demonstrate patient recovery as a quantal response to GSH supplementation. Therefore, the research conducted in this thesis indicates that oral GSH supplementation has the potential to complement anti-diabetic therapy, leading to improved glycemic targets, particularly in the elderly. Model results and predictions assist in evaluating treatment progress and personalizing treatment goals for using oral GSH supplementation as an adjunct therapy in T2D.