Abstract
Modern lifestyles have altered diet and metabolic homeostasis, with increased sugar intake, glycemic index, and prediabetes. A strong positive correlation between sugar consumption and diabetic incidence is revealed, but the underlying mechanisms remain obscure. Here we show that oral intake of long-term oscillating glucose (LOsG) (4 times/day) for 38 days, which produces physiological glycemic variability in rats, can lead to β-cells gaining metabolic memory in reactive oxygen species (ROS) stress. This stress leads to suppression of forkhead box O1 (FoxO1) signaling and subsequent upregulation of thioredoxin interacting protein, inhibition of insulin and SOD-2 expression, re-expression of Neurog3, and β-cell dedifferentiation and functional failure. LOsG-treated animals develop prediabetes exhibiting hypoinsulinemia and glucose intolerance. Dynamic and timely administration of antioxidant glutathione prevents LOsG/ROS-induced β-cell failure and prediabetes. We propose that ROS stress is the initial step in LOsG-inducing prediabetes. Manipulating glutathione-related pathways may offer novel options for preventing the occurrence and development of diabetes.
Highlights
Pancreatic β-cell is the primary regulatory center that controls the primary-fuel glucose homeostasis
We have previously shown that GSH (50 mg/kg/6 h) totally blocks Oscillating glucose (OsG)/oxidative stress-induced disarrangement of partitions of circulating immune cells and neutrophil/lymphocyte ratio[17]
We demonstrated that timely administration of GSH (TdGSH) eliminated the detrimental effects of long-term oscillating glucose (LOsG) on glucose tolerances (GT) (Fig. 1d) and kept the fast plasma insulin level at normal levels (Fig. 1e), and could prevent the glucotoxicity-induced occurrence of prediabetes
Summary
Pancreatic β-cell is the primary regulatory center that controls the primary-fuel glucose homeostasis. Excessive nutrient intake relative to energy expenditure has fueled a dramatic increase in the incidence of diabetes[1], which is mainly due to a relentless decline in β-cell function. It was estimated that the population with diabeties worldwide would increase from 451 million people in 2017 to 693 million by 20452. Meta-analyses have indicated a strong relationship between sugar consumption and obesity, diabetes, and the metabolic syndrome[3]. No Official journal of the Cell Death Differentiation Association. Zhang et al Cell Death and Disease (2019)10:321 administration of antioxidant glutathione (GSH) can block the glucose/ROS-induced β-cell damages
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