Resveratrol inhibits macrophage infiltration of pancreatic islets in streptozotocin-induced type 1 diabetic mice via attenuation of the CXCL16/NF-κΒ p65 signaling pathway

The role of FGF21 plays in the development and progression of diabetic cardiomyopathy (DCM) has not been addressed. Here we demonstrated that type 1 diabetes decreased FGF21 levels in the blood, but up-regulated cardiac fgf21 expression about 40 fold at 2 months and 3-1.5 fold at 4 and 6 months after diabetes, which indicated a cardiac specific FGF21 adaptive up-regulation. To define the critical role of FGF21 in DCM, type 1 diabetes was induced in FGF21 knock out (FGF21KO) mice. At 1, 2 and 4 months after diabetes onset, no significant differences between FGF21KO and wild type (WT) diabetic mice in blood glucose and triglyceride levels were observed. But FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodeling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Mechanistically, FGF21 reduced palmitate-induced cardiac cell death, which was accompanied by up-regulation of cardiac Erk1/2, p38 MAPK and AMPK phosphorylation. Inhibition of each kinase with its inhibitor and/ or siRNA revealed that FGF21 prevents palmitate-induced cardiac cell death via up-regulating the Erk1/2-dependent p38 MAPK/AMPK signaling pathway. In vivo administration of FGF21, but not FGF21 plus ERK1/2 inhibitor, to diabetic mice significantly prevented cardiac cell death and reduced inactivation of Erk1/2, p38 MAPK and AMPK, and prevented cardiac remodeling and dysfunction at late-stage. Our results demonstrate that cardiac FGF21 decompensation may contribute to the development of DCM and FGF21 may be a therapeutic target for the treatment of diabetic cardiac damage via activation of Erk1/2-P38 MAPK-AMPK signaling.

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Metabolic impacts of cordycepin on hepatic proteomic expression in streptozotocin-induced type 1 diabetic mice

PLoS ONE ◽

10.1371/journal.pone.0256140 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0256140

Author(s):

Kongphop Parunyakul ◽

Krittika Srisuksai ◽

Sawanya Charoenlappanit ◽

Narumon Phaonakrop ◽

Sittiruk Roytrakul ◽

...

Keyword(s):

Body Weight ◽

Blood Glucose ◽

Signaling Pathway ◽

Tricarboxylic Acid Cycle ◽

Fasting Blood Glucose ◽

Protein Profiling ◽

Diabetic Mice ◽

Final Body Weight ◽

Significant Difference

Type 1 Diabetes mellitus (T1DM) is associated with abnormal liver function, but the exact mechanism is unclear. Cordycepin improves hepatic metabolic pathways leading to recovery from liver damage. We investigated the effects of cordycepin in streptozotocin-induced T1DM mice via the expression of liver proteins. Twenty-four mice were divided into four equal groups: normal (N), normal mice treated with cordycepin (N+COR), diabetic mice (DM), and diabetic mice treated with cordycepin (DM+COR). Mice in each treatment group were intraperitoneally injection of cordycepin at dose 24 mg/kg for 14 consecutive days. Body weight, blood glucose, and the tricarboxylic acid cycle intermediates were measured. Liver tissue protein profiling was performed using shotgun proteomics, while protein function and protein-protein interaction were predicted using PANTHER and STITCH v.5.0 software, respectively. No significant difference was observed in fasting blood glucose levels between DM and DM+COR for all time intervals. However, a significant decrease in final body weight, food intake, and water intake in DM+COR was found. Hepatic oxaloacetate and citrate levels were significantly increased in DM+COR compared to DM. Furthermore, 11 and 36 proteins were only expressed by the N+COR and DM+COR groups, respectively. Three unique proteins in DM+COR, namely, Nfat3, Flcn, and Psma3 were correlated with the production of ATP, AMPK signaling pathway, and ubiquitin proteasome system (UPS), respectively. Interestingly, a protein detected in N+COR and DM+COR (Gli3) was linked with the insulin signaling pathway. In conclusion, cordycepin might help in preventing hepatic metabolism by regulating the expression of energy-related protein and UPS to maintain cell survival. Further work on predicting the performance of metabolic mechanisms regarding the therapeutic applications of cordycepin will be performed in future.

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Leukotriene Involvement in the Insulin Receptor Pathway and Macrophage Profiles in Muscles from Type 1 Diabetic Mice

Mediators of Inflammation ◽

10.1155/2019/4596127 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

João Pedro Tôrres Guimarães ◽

Luciano Ribeiro Filgueiras ◽

Joilson Oliveira Martins ◽

Sonia Jancar

Keyword(s):

Type 1 Diabetes ◽

Insulin Receptor ◽

Signaling Pathway ◽

Receptor Gene ◽

Tolerance Test ◽

Low Grade ◽

Diabetic Mice ◽

Insulin Receptor Gene ◽

Akt Phosphorylation

Type 1 diabetes (T1D) is a metabolic disease associated with systemic low-grade inflammation and macrophage reprogramming. There is evidence that this inflammation depends on the increased systemic levels of leukotriene (LT) B4 found in T1D mice, which shifts macrophages towards the proinflammatory (M1) phenotype. Although T1D can be corrected by insulin administration, over time T1D patients can develop insulin resistance that hinders glycemic control. Here, we sought to investigate the role of leukotrienes (LTs) in a metabolically active tissue such as muscle, focusing on the insulin signaling pathway and muscle-associated macrophage profiles. Type 1 diabetes was induced in the 129/SvE mouse strain by streptozotocin (STZ) in mice deficient in the enzyme responsible for LT synthesis (5LO-/-) and the LT-sufficient wild type (WT). The response to insulin was evaluated by the insulin tolerance test (ITT), insulin concentration by ELISA, and Akt phosphorylation by western blotting. The gene expression levels of the insulin receptor and macrophage markers Stat1, MCP-1, Ym1, Arg1, and IL-6 were evaluated by qPCR, and that of IL-10 by ELISA. We observed that after administration of a single dose of insulin to diabetic mice, the reduction in glycemia was more pronounced in 5LO-/- than in WT mice. When muscle homogenates were analyzed, diabetic 5LO-/- mice showed a higher expression of the insulin receptor gene and higher Akt phosphorylation. Moreover, in muscle homogenates from diabetic 5LO-/- mice, the expression of anti-inflammatory macrophage markers Ym1, Arg1, and IL-10 was increased, and the relative expression of the proinflammatory cytokine IL-6 was reduced compared with WT diabetic mice. These results suggest that LTs have an impact on the insulin receptor signaling pathway and modulate the inflammatory profile of muscle-resident macrophages from T1D mice.

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ID: 1079 Improved glucose homeostasis effect of conditioned media from adipose-derived stem cells in type 1 diabetic mice

Biomedical Research and Therapy ◽

10.15419/bmrat.v4is.353 ◽

2017 ◽

Vol 4 (S) ◽

pp. 165

Author(s):

Anh Nguyen Tu Bui ◽

Cong Le Thanh Nguyen ◽

Ngoc Kim Phan ◽

Loan Thi-Tung Dang

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Stem Cell ◽

Blood Glucose ◽

Blood Glucose Level ◽

Type 1 Diabetes Mellitus ◽

Pancreatic Islets ◽

Conditioned Medium ◽

Diabetic Mice

Background: Many studies suggested adipose derived stem cell (ASC) transplantation as a new approach to control hyperglycemia in type 1 diabetes mellitus. It is proposed that the effects of these cells could be not only based on the direct cell-cell interaction but also the secretion of cytokines. This study aimed to demonstrate the effect of adipose stem cell-derived conditioned medium (CM) on the treatment of STZ-induced diabetic mice. Methods: CM was obtained from 24-hours-cultured medium of ASCs and centrifuged to remove the debris. Type 1 diabetic mice were intraperitoneally injected CM for 30 consecutive days. Therapeutic efficacy of CM was assessed by survival rate, blood glucose level, serum insulin level, histological structure of pancreatic islets. Results: The results showed that CM treatment could decrease mortality rate (from 33,33% to 0%) as well as blood glucose level (from 425,667±65,753 mg/dl to 203,500 mg ±20,350 mg/dl) and enhance insulin secretion, improve size and function of pancreatic islets of diabetic mice. Conclusion: Conditioned medium maybe a promising therapy for type 1 diabetes mellitus.

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Fibroblast growth factor 21 Ameliorates diabetes-induced endothelial dysfunction in mouse aorta via activation of the CaMKK2/AMPKα signaling pathway

Cell Death and Disease ◽

10.1038/s41419-019-1893-6 ◽

2019 ◽

Vol 10 (9) ◽

Cited By ~ 7

Author(s):

Lei Ying ◽

Na Li ◽

Zhengyue He ◽

Xueqin Zeng ◽

Yan Nan ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Signaling Pathway ◽

Oxidative Capacity ◽

Fibroblast Growth Factor 21 ◽

Diabetic Mice

Abstract Endothelial dysfunction initiates and exacerbates hypertension, atherosclerosis and other cardiovascular complications in diabetic mellitus. FGF21 is a hormone that mediates a number of beneficial effects relevant to metabolic disorders and their associated complications. Nevertheless, it remains unclear as to whether FGF21 ameliorates endothelial dysfunction. Therefore, we investigated the effect of FGF21 on endothelial function in both type 1 and type 2 diabetes. We found that FGF21 reduced hyperglycemia and ameliorated insulin resistance in type 2 diabetic mice, an effect that was totally lost in type 1 diabetic mice. However, FGF21 activated AMPKα, suppressing oxidative stress and enhancing endothelium-dependent vasorelaxation of aorta in both types, suggesting a mechanism that is independent of its glucose-lowering and insulin-sensitizing effects. In vitro, we identified a direct action of FGF21 on endothelial cells of the aorta, in which it bounds to FGF receptors to alleviate impaired endothelial function challenged with high glucose. Furthermore, the CaMKK2-AMPKα signaling pathway was activated to suppress oxidative stress. Apart from its anti-oxidative capacity, FGF21 activated eNOS to dilate the aorta via CaMKK2/AMPKα activation. Our data suggest expanded potential uses of FGF21 for the treatment of vascular diseases in diabetes.

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