L-Methionine prevents β-cell damage by modulating the expression of Arx, MafA and regulation of FOXO1 in type 1 diabetic rats

Navik, Umashanker; Rawat, Kajal; Tikoo, Kulbhushan

doi:10.1016/j.acthis.2021.151820

Cited by 8 publications

(6 citation statements)

References 54 publications

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“…MafA is a late β cell marker and an important transcriptional factor for the production and secretion of insulin from the cell. It is documented that diabetic rats display decreased levels of MafA 44,45 . Several other studies also report the increased expression MafA in treated rats compared with the diabetic rats 46–48 .…”

Section: Discussionmentioning

confidence: 87%

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Effect of lawsone‐preconditioned mesenchymal stem cells on the regeneration of pancreatic β cells in Type 1 diabetic rats

Masnoon

Ishaque

Khan

et al. 2023

Cell Biochemistry & Function

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Diabetes is one of the major health issues globally. Type 1 diabetes mellitus develops due to the destruction of pancreatic β cells. Mesenchymal stem cells (MSCs) having remarkable self‐renewal and differentiation potential, can regenerate β cells. MSCs preconditioned with bioactive small molecules possess enhanced biological features and therapeutic potential under in vivo environment. Interestingly, compounds of naphthoquinone class possess antidiabetic and anti‐inflammatory properties, and can be explored as potential candidates for preconditioning MSCs. This study analyzed the effect of lawsone‐preconditioned human umbilical cord MSCs (hUMSCs) on the regeneration of β cells in the streptozotocin (STZ)‐induced Type 1 diabetes (T1D) rats. hUMSCs were isolated and characterized for the presence of surface markers. MSCs were preconditioned with optimized concentration of lawsone. T1D rat model was established by injecting 50 mg/kg of STZ intraperitoneally. Untreated and lawsone‐preconditioned hUMSCs were transplanted into the diabetic rats via tail vein. Fasting blood sugar and body weight were monitored regularly for 4 weeks. Pancreas was harvested and β cell regeneration was evaluated by hematoxylin and eosin staining, and gene expression analysis. Immunohistochemistry was also done to assess the insulin expression. Lawsone‐preconditioned hUMSCs showed better anti‐hyperglycemic effect in comparison with untreated hUMSCs. Histological analysis presented the regeneration of islets of Langerhans with upregulated expression of βcell genes and reduced expression of inflammatory markers. Immunohistochemistry revealed strong insulin expression in the preconditioned hUMSCs compared with the untreated hUMSCs. It is concluded from the present study that lawsone‐preconditioned hMSCs were able to exhibit pronounced anti‐hyperglycemic effect in vivo compared with hUMSCs alone.

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Section: Discussionmentioning

confidence: 87%

“…It is documented that diabetic rats display decreased levels of MafA. 44,45 Several other studies also report the increased expression MafA in treated rats compared with the diabetic rats. [46][47][48] Therefore, lawsone preconditioning appears to preferentially increase the expression of NGN3…”

Section: Discussionmentioning

confidence: 92%

Effect of lawsone‐preconditioned mesenchymal stem cells on the regeneration of pancreatic β cells in Type 1 diabetic rats

Masnoon

Ishaque

Khan

et al. 2023

Cell Biochemistry & Function

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“…The role of methionine in T1D pathogenesis and progression has also been indicated in several studies. In T1D rats, L-methionine also protected pancreatic β-cells by regulating FOXO1 expression [ 46 ]. According to the German BABYDIAB study, children who developed autoantibodies by the age of two had a 2-fold lower methionine content than those who developed autoantibodies later or autoantibody-negative controls [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Serum Metabolomics Reveals a Potential Benefit of Methionine in Type 1 Diabetes Patients with Poor Glycemic Control and High Glycemic Variability

et al. 2023

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Glycemic variability (GV) in some patients with type 1 diabetes (T1D) remains heterogeneous despite comparable clinical indicators, and whether other factors are involved is yet unknown. Metabolites in the serum indicate a broad effect of GV on cellular metabolism and therefore are more likely to indicate metabolic dysregulation associated with T1D. To compare the metabolomic profiles between high GV (GV-H, coefficient of variation (CV) of glucose ≥ 36%) and low GV (GV-L, CV < 36%) groups and to identify potential GV biomarkers, metabolomics profiling was carried out on serum samples from 17 patients with high GV, 16 matched (for age, sex, body mass index (BMI), diabetes duration, insulin dose, glycated hemoglobin (HbA1c), fasting, and 2 h postprandial C-peptide) patients with low GV (exploratory set), and another 21 (GV-H/GV-L: 11/10) matched patients (validation set). Subsequently, 25 metabolites were significantly enriched in seven Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways between the GV-H and GV-L groups in the exploratory set. Only the differences in spermidine, L-methionine, and trehalose remained significant after validation. The area under the curve of these three metabolites combined in distinguishing GV-H from GV-L was 0.952 and 0.918 in the exploratory and validation sets, respectively. L-methionine was significantly inversely related to HbA1c and glucose CV, while spermidine was significantly positively associated with glucose CV. Differences in trehalose were not as reliable as those in spermidine and L-methionine because of the relatively low amounts of trehalose and the inconsistent fold change sizes in the exploratory and validation sets. Our findings suggest that metabolomic disturbances may impact the GV of T1D. Additional in vitro and in vivo mechanistic studies are required to elucidate the relationship between spermidine and L-methionine levels and GV in T1D patients with different geographical and nutritional backgrounds.

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“…Therefore, activating FoxO1 could prove effective. For example, L-Methionine (L-Met) regulates FoxO1 by altering the bivalent domain histone methylation marks H3K27me3 and H3K4me3 to increase FoxO1-mediated upregulation of the insulin transcription factor MafA and mitigate type 1 diabetes mellitus in rats ( 174 ). Given that Obex ® , a supplement containing L-Met, caused weight loss and improved insulin homeostasis in overweight and obese participants of a double−blind, randomized, controlled phase III clinical trial, future studies should explore how altering bivalent domain controls FoxO1 regulation of β-cells during T2D ( 175 ).…”

Section: Foxo1 and T2d – Pancreatic β-Cellsmentioning

confidence: 99%

FoxO1 as a tissue-specific therapeutic target for type 2 diabetes

Teaney,

Cyr

2023

Front. Endocrinol.

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Forkhead box O (FoxO) proteins are transcription factors that mediate many aspects of physiology and thus have been targeted as therapeutics for several diseases including metabolic disorders such as type 2 diabetes mellitus (T2D). The role of FoxO1 in metabolism has been well studied, but recently FoxO1’s potential for diabetes prevention and therapy has been debated. For example, studies have shown that increased FoxO1 activity in certain tissue types contributes to T2D pathology, symptoms, and comorbidities, yet in other tissue types elevated FoxO1 has been reported to alleviate symptoms associated with diabetes. Furthermore, studies have reported opposite effects of active FoxO1 in the same tissue type. For example, in the liver, FoxO1 contributes to T2D by increasing hepatic glucose production. However, FoxO1 has been shown to either increase or decrease hepatic lipogenesis as well as adipogenesis in white adipose tissue. In skeletal muscle, FoxO1 reduces glucose uptake and oxidation, promotes lipid uptake and oxidation, and increases muscle atrophy. While many studies show that FoxO1 lowers pancreatic insulin production and secretion, others show the opposite, especially in response to oxidative stress and inflammation. Elevated FoxO1 in the hypothalamus increases the risk of developing T2D. However, increased FoxO1 may mitigate Alzheimer’s disease, a neurodegenerative disease strongly associated with T2D. Conversely, accumulating evidence implicates increased FoxO1 with Parkinson’s disease pathogenesis. Here we review FoxO1’s actions in T2D conditions in metabolic tissues that abundantly express FoxO1 and highlight some of the current studies targeting FoxO1 for T2D treatment.

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L-Methionine prevents β-cell damage by modulating the expression of Arx, MafA and regulation of FOXO1 in type 1 diabetic rats

Cited by 8 publications

References 54 publications

Effect of lawsone‐preconditioned mesenchymal stem cells on the regeneration of pancreatic β cells in Type 1 diabetic rats

Effect of lawsone‐preconditioned mesenchymal stem cells on the regeneration of pancreatic β cells in Type 1 diabetic rats

Serum Metabolomics Reveals a Potential Benefit of Methionine in Type 1 Diabetes Patients with Poor Glycemic Control and High Glycemic Variability

FoxO1 as a tissue-specific therapeutic target for type 2 diabetes

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