Glutathione prevents chronic oscillating glucose intake-induced β-cell dedifferentiation and failure.

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.

• Authors: Jitai Zhang, Hui An, Kaidi Ni, Bin Chen, Hui Li, Yanqin Li, Guilian Sheng, Chuanzan Zhou, Mengzhen Xie, Saijing Chen, Tong Zhou, Gaoxiong Yang, Xiufang Chen, Gaojun Wu, Shengwei Jin, Ming Li
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 4 Pg. 321 (04 11 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 30975975 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Blood Glucose
• Cell Cycle Proteins
• Insulin
• Nerve Tissue Proteins
• Reactive Oxygen Species
• TXNIP protein, rat
• Foxo1 protein, rat
• Superoxide Dismutase
• superoxide dismutase 2
• Glutathione
• Glucose

Topics

• Animals
• Antioxidants (metabolism)
• Apoptosis (drug effects)
• Blood Glucose (drug effects, metabolism)
• Cell Cycle Proteins (genetics, metabolism)
• Cell Dedifferentiation (drug effects, genetics)
• Female
• Glucose (metabolism, toxicity)
• Glucose Intolerance (metabolism)
• Glutathione (pharmacology)
• Insulin (metabolism)
• Insulin-Secreting Cells (cytology, drug effects, metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Pancreas (drug effects, metabolism)
• Prediabetic State (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Superoxide Dismutase (genetics, metabolism)