NAG-1/GDF15 protects against streptozotocin-induced type 1 diabetes by inhibiting apoptosis, preserving beta-cell function, and suppressing inflammation in pancreatic islets

Wang, Ying; Chen, Jiajun; Sang, Tingting; Chen, Chaojie; He, Peng; Lin, Xiaojian; Zhao, Qian; Chen, Shengjia; Eling, Thomas E.; Wang, Xingya

doi:10.1016/j.mce.2022.111643

Cited by 11 publications

(10 citation statements)

References 80 publications

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“…43 Furthermore, increased levels of GDF15 attenuate NFkb, JNK, and Caspase-3, which results in antiapoptotic action. 44 Recently, Wang et al 45 found that GDF15 significantly reversed the deregulations of the expressions of As demonstrated in this study, reduced expression of Gdf15 in INS-1 cells impairs insulin secretion at stimulation levels (16.7 mM glucose) without affecting insulin content. Our data agree with Asrih et al 26 study, which showed that silencing of Gdf15 expression in mouse pancreatic β-cells reduces insulin secretion with no impact on the insulin content.…”

Section: Discussionsupporting

confidence: 69%

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GDF15plays a critical role in insulin secretion in INS-1 cells and human pancreatic islets

Mohammad

Saeed

Mohammed

et al. 2023

Exp Biol Med (Maywood)

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Mounting evidence points to a link between growth differentiation factor-15 ( GDF15) expression and the onset and progression of diabetes mellitus. However, the exact role of GDF15 in pancreatic β-cell function is unclear. To examine the role of GDF15 in β-cell function, bioinformatics analysis and functional experiments involving GDF15 silencing and overexpression were performed in INS-1 cells and human islets. Public microarray and RNA-seq expression data showed that islets obtained from diabetic donors express high levels of GDF15 compared to islets obtained from normal donors. Moreover, analysis of RNA-seq expression data revealed that GDF15 expression correlates positively with that of insulin ( INS), KCNJ11, GLUT1, MAFA, INSR and negatively with that of Glucokinase ( GCK) and Alpha-Ketoglutarate Dependent Dioxygenase ( FTO). No T2D-associated genetic variants in the GDF15 were found to pass genome-wide significance in the TIGER portal. Expression silencing of Gdf15 in INS-1 cells reduced insulin release, glucose uptake levels, increased reactive oxygen species (ROS) production and apoptosis levels. While Gdf15-silenced cells downregulated mRNA expression of Ins, Pdx1, Mafa, and Glut2 genes, its overexpression human islets was associated with increased insulin secretion and upregulated expression of MAFA and GLUT1 but not INS or GCK. Silencing of Pdx1 or Mafa in INS-1 cells did not affect the expression of GDF15. These findings suggest that GDF15 plays a significant role in pancreatic β-cell function.

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Section: Discussionsupporting

confidence: 69%

“…44 Recently, Wang et al . 45 found that GDF15 significantly reversed the deregulations of the expressions of cleaved caspase-3, Bax, and BCL2 in the islet of Tg mice compared to their WT mice on Streptozotocin (STZ) treatment.…”

Section: Discussionmentioning

confidence: 97%

GDF15plays a critical role in insulin secretion in INS-1 cells and human pancreatic islets

Mohammad

Saeed

Mohammed

et al. 2023

Exp Biol Med (Maywood)

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“…LPS activation of TLR4 induces the transcription factors, NF-κB and YY1, in many cell types, including leukocytes, macrophages, microglia, and astrocytes [ 36 , 47 ]. The induction of pro-inflammatory processes in pancreatic β-cells is intimately linked to NF-κB upregulation [ 31 , 48 , 49 ]. The downstream consequences of NF-κB upregulation are associated with a diverse array of factors, including non-steroidal anti-inflammatory drug activated gene-1, growth differentiation factor-15 (NAG-1/GDF15) [ 48 ], or intercellular adhesion molecule (ICAM)-1 [ 31 ].…”

Section: Wider T1dm Pathophysiologymentioning

confidence: 99%

“…The induction of pro-inflammatory processes in pancreatic β-cells is intimately linked to NF-κB upregulation [ 31 , 48 , 49 ]. The downstream consequences of NF-κB upregulation are associated with a diverse array of factors, including non-steroidal anti-inflammatory drug activated gene-1, growth differentiation factor-15 (NAG-1/GDF15) [ 48 ], or intercellular adhesion molecule (ICAM)-1 [ 31 ]. YY1 knockout in pancreatic β-cells leads to rapid hyperglycemia onset, impaired glucose tolerance, and suppressed pancreatic β-cell mass, both in neonates and adult murine models [ 32 ].…”

Section: Wider T1dm Pathophysiologymentioning

confidence: 99%

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

Anderson¹

2023

IJMS

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Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic β-cell apoptosis remain to be determined, resulting in a failure to prevent ongoing cellular destruction. Alteration in mitochondrial function is clearly the major pathophysiological process underpinning pancreatic β-cell loss in T1DM. As with many medical conditions, there is a growing interest in T1DM as to the role of the gut microbiome, including the interactions of gut bacteria with Candida albicans fungal infection. Gut dysbiosis and gut permeability are intimately associated with raised levels of circulating lipopolysaccharide and suppressed butyrate levels, which can act to dysregulate immune responses and systemic mitochondrial function. This manuscript reviews broad bodies of data on T1DM pathophysiology, highlighting the importance of alterations in the mitochondrial melatonergic pathway of pancreatic β-cells in driving mitochondrial dysfunction. The suppression of mitochondrial melatonin makes pancreatic β-cells susceptible to oxidative stress and dysfunctional mitophagy, partly mediated by the loss of melatonin’s induction of PTEN-induced kinase 1 (PINK1), thereby suppressing mitophagy and increasing autoimmune associated major histocompatibility complex (MHC)-1. The immediate precursor to melatonin, N-acetylserotonin (NAS), is a brain-derived neurotrophic factor (BDNF) mimic, via the activation of the BDNF receptor, TrkB. As both the full-length and truncated TrkB play powerful roles in pancreatic β-cell function and survival, NAS is another important aspect of the melatonergic pathway relevant to pancreatic β-cell destruction in T1DM. The incorporation of the mitochondrial melatonergic pathway in T1DM pathophysiology integrates wide bodies of previously disparate data on pancreatic intercellular processes. The suppression of Akkermansia muciniphila, Lactobacillus johnsonii, butyrate, and the shikimate pathway—including by bacteriophages—contributes to not only pancreatic β-cell apoptosis, but also to the bystander activation of CD8+ T cells, which increases their effector function and prevents their deselection in the thymus. The gut microbiome is therefore a significant determinant of the mitochondrial dysfunction driving pancreatic β-cell loss as well as ‘autoimmune’ effects derived from cytotoxic CD8+ T cells. This has significant future research and treatment implications.

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“…Emerging evidence shows that NAG-1/GDF-15 is associated with low back pain-associated disability [ 13 ], suggesting that the pathological changes in the nervous system could be related to the function of NAG-1. Furthermore, the function of NAG-1 is involved in the reduction of inflammatory responses [ 14 , 15 ], while there is limited understanding of the role of NAG-1 in inflammation-induced spinal pain processing.…”

Section: Introductionmentioning

confidence: 99%

NAG-1/GDF-15 Transgenic Female Mouse Shows Delayed Peak Period of the Second Phase Nociception in Formalin-induced Inflammatory Pain

Choi,

Lee,

Moon

et al. 2023

Exp Neurobiol

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Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1), also known as growth differentiation factor-15 (GDF-15), is associated with cancer, diabetes, and inflammation, while there is limited understanding of the role of NAG-1 in nociception. Here, we examined the nociceptive behaviors of NAG-1 transgenic (TG) mice and wild-type (WT) littermates. Mechanical sensitivity was evaluated by using the von Frey filament test, and thermal sensitivity was assessed by the hot-plate, Hargreaves, and acetone tests. c-Fos, glial fibrillary acidic protein (GFAP), and ionized calcium binding adaptor molecule-1 (Iba-1) immunoreactivity was examined in the spinal cord following observation of the formalin-induced nociceptive behaviors. There was no difference in mechanical or thermal sensitivity for NAG-1 TG and WT mice. Intraplantar formalin injection induced nociceptive behaviors in both male and female NAG-1 TG and WT mice. The peak period in the second phase was delayed in NAG-1 TG female mice compared with that of WT female mice, while there was no difference in the cumulative time of nociceptive behaviors between the two groups of mice. Formalin increased spinal c-Fos immunoreactivity in both TG and WT female mice. Neither GFAP nor Iba-1 immunoreactivity was increased in the spinal cord of TG and WT female mice. These findings indicate that NAG-1 TG mice have comparable baseline sensitivity to mechanical and thermal stimulation as WT mice and that NAG-1 in female mice may have an inhibitory effect on the second phase of inflammatory pain. Therefore, it could be a novel target to inhibit central nervous system response in pain.

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NAG-1/GDF15 protects against streptozotocin-induced type 1 diabetes by inhibiting apoptosis, preserving beta-cell function, and suppressing inflammation in pancreatic islets

Cited by 11 publications

References 80 publications

GDF15plays a critical role in insulin secretion in INS-1 cells and human pancreatic islets

GDF15plays a critical role in insulin secretion in INS-1 cells and human pancreatic islets

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

NAG-1/GDF-15 Transgenic Female Mouse Shows Delayed Peak Period of the Second Phase Nociception in Formalin-induced Inflammatory Pain

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