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

Zhang, Jitai; An, Hee Jung; Ni, Kaidi; Cui, Bin; Li, Hui; Li, Yanqin; Sheng, Guilian; Zhou, Chuanzan; Xie, Mengzhen; Chen, Saijing; Zhou, Tong; Yang, Gaoxiong; Chen, Xiufang; Wu, Gaojun; Jin, Shengwei; Li, Ming

doi:10.1038/s41419-019-1552-y

Cited by 27 publications

(32 citation statements)

References 39 publications

(49 reference statements)

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“…Similar observations have recently been reported by Zhang et al (2019) in diabetic rats where ROS-induced damages to β-cell were prevented by administration of oral GSH. Islets isolated from type 2 diabetic cadaveric organ donors showed impairment in insulin secretion in response to glucose and increased level of oxidative damage markers; treating these islets with GSH led to an improvement in their functionality and also alleviated oxidative damage markers, suggesting that reducing OS in islets could be a potential target for treating type 2 diabetes (Del Guerra et al, 2005).…”

Section: Discussionsupporting

confidence: 90%

Randomised clinical trial of long term glutathione supplementation offers protection from oxidative damage, improves HbA1c in elderly type 2 diabetic patients

Kalamkar

et al. 2021

Preprint

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Sustained hyperglycemia in type 2 diabetes is associated with low levels of the endogenous antioxidant glutathione (GSH), which leads to oxidative stress and tissue damage. It is therefore important to investigate whether oral GSH supplementation would restore GSH levels, and also help improve redox state and glycaemia in diabetic individuals. We conducted a pragmatic clinical trial to assess effectiveness of oral GSH supplementation along with anti-diabetic treatment. 104 non-diabetic and 250 diabetic individuals were recruited. All the 250 diabetic individuals were on anti-diabetic therapy; of these 125 were given oral GSH supplementation additionally for a period of six months. Fasting and PP glucose and insulin, HbA1c, GSH and the oxidative DNA damage marker 8-OHdG were measured at the recruitment time and after three and six months of supplementation. GSH supplementation increased blood GSH and decreased 8-OHdG significantly within three months in diabetic individuals. It also reduced HbA1c within three months and stabilized it thereafter in diabetic population overall. Patients above 55 years benefited more as evidenced by a significant decrease in HbA1c and 8-OHdG and an increase in fasting insulin. Data suggest that GSH supplementation can be used as an adjunct therapy to anti-diabetic treatment to achieve better glycemic targets, especially in elderly population.

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Section: Discussionsupporting

confidence: 90%

Randomised clinical trial of long term glutathione supplementation offers protection from oxidative damage, improves HbA1c in elderly type 2 diabetic patients

Kalamkar

et al. 2021

Preprint

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“…Thus, defects in mitochondrial function impair the metabolic functions of β-cells [ 63 ]. Oral intake of long-term oscillating glucose (LOsG) in rodents leads to ROS stress in β-cells, which induces β-cell dedifferentiation and functional failure by disrupting FOXO1-thioredoxin interacting protein pathway [ 12 , 64 , 65 ]. In contrast, administration of the antioxidant glutathione prevented intracellular ROS elevation and LOsG-induced functional failure of dedifferentiated β-cells [ 64 ].…”

Section: Potential Mechanisms Regulating β-Cell Dedifferentiationmentioning

confidence: 99%

A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes

Khin

Lee

2021

Nutrients

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Diabetes is a metabolic disease characterized by hyperglycemia. Over 90% of patients with diabetes have type 2 diabetes. Pancreatic β-cells are endocrine cells that produce and secrete insulin, an essential endocrine hormone that regulates blood glucose levels. Deficits in β-cell function and mass play key roles in the onset and progression of type 2 diabetes. Apoptosis has been considered as the main contributor of β-cell dysfunction and decrease in β-cell mass for a long time. However, recent studies suggest that β-cell failure occurs mainly due to increased β-cell dedifferentiation rather than limited β-cell proliferation or increased β-cell death. In this review, we summarize the current advances in the understanding of the pancreatic β-cell dedifferentiation process including potential mechanisms. A better understanding of β-cell dedifferentiation process will help to identify novel therapeutic targets to prevent and/or reverse β-cell loss in type 2 diabetes.

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“…These effects were mediated by the negative regulation of the antioxidant protein thioredoxin, regulation of specific microRNAs, and activation of the inflammasome 106 . Moreover, upregulation of glutathione metabolism genes is adaptive and may promote survival and oppose beta‐cell dedifferentiation 107 . Nevertheless, given the low basal expression of some key antioxidant genes in beta‐cells, it might be insufficient to face the important ROS generation under chronic hyperglycemia (reviewed in Refs.…”

Section: Resultsmentioning

confidence: 99%

Transcriptome analysis of islets from diabetes‐resistant and diabetes‐prone obese mice reveals novel gene regulatory networks involved in beta‐cell compensation and failure

et al. 2021

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The mechanisms underpinning beta-cell compensation for obesity-associated insulin resistance and beta-cell failure in type 2 diabetes remain poorly understood. We used a large-scale strategy to determine the time-dependent transcriptomic changes in islets of diabetes-prone db/db and diabetes-resistant ob/ob mice at 6 and 16 weeks of age. Differentially expressed genes were subjected to cluster, gene ontology, pathway and gene set enrichment analyses. A distinctive gene expression pattern was observed in 16 week db/db islets in comparison to the other groups with alterations in transcriptional regulators of islet cell identity, upregulation of glucose/lipid metabolism, and various stress response genes, and downregulation of specific amino acid transport and metabolism genes. In contrast, ob/ob islets displayed a coordinated downregulation of metabolic and stress response genes at 6 weeks of age, suggestive of a preemptive reconfiguration in these islets to lower the threshold of metabolic activation in response to increased insulin demand thereby preserving beta-cell function and preventing cellular stress. In addition, amino acid transport and metabolism genes were upregulated in ob/ob islets, suggesting an important role of glutamate metabolism in beta-cell compensation. Gene set enrichment analysis of differentially expressed genes identified the enrichment of binding motifs for transcription factors, FOXO4, NFATC1, and MAZ. siRNA-mediated knockdown of these genes in MIN6 cells altered cell death, insulin secretion, and stress gene expression. In conclusion, these data revealed novel gene regulatory networks involved in beta-cell compensation and failure. Preemptive metabolic reconfiguration in diabetes-resistant islets may dampen metabolic activation and cellular stress during obesity.

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

Cited by 27 publications

References 39 publications

Randomised clinical trial of long term glutathione supplementation offers protection from oxidative damage, improves HbA1c in elderly type 2 diabetic patients

Randomised clinical trial of long term glutathione supplementation offers protection from oxidative damage, improves HbA1c in elderly type 2 diabetic patients

A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes

Transcriptome analysis of islets from diabetes‐resistant and diabetes‐prone obese mice reveals novel gene regulatory networks involved in beta‐cell compensation and failure

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