GDF15: a potential therapeutic target for type 1 diabetes

Sarkar, Soumyadeep; Melchior, John T.; Henry, Hayden R.; Syed, Farooq; Mirmira, Raghavendra G.; Nakayasu, Ernesto; Metz, Thomas O.

doi:10.1080/14728222.2022.2029410

Cited by 15 publications

(17 citation statements)

References 126 publications

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“…GDF signaling was specifically involved in FB subsets with DM ( Figure 6 D and Figure S6 ). GDF15 , the only ligand detected in our study, was associated with systematic inflammation, DM and obesity [ 45 , 46 , 47 , 48 ]. Our results showed that ANGPTL7 + FBs and SFRP1 + FBs expressed GDF15 and acted on a variety of cells ( Figure 6 D).…”

Section: Resultsmentioning

confidence: 99%

A Single-Cell Survey of Cellular Heterogeneity in Human Great Saphenous Veins

Sun

Zhang

et al. 2022

Cells

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Background: The great saphenous vein (GSV) is the most commonly used conduit for coronary arterial bypass graft. However, the status of the GSV, including metabolic dysfunction such as diabetes mellitus (DM) complication, is strongly associated with vein graft failure (VGF). To date, the molecular mechanism underlying VGF remains elusive. Detailed characterization of the cellular components and corresponding expression regulation in GSVs would be of great importance for clinical decision making to reduce VGF. Methods: To this end, we performed single-cell RNA sequencing to delineate cellular heterogeneity in three human GSV samples. Results: Scrutinization of cellular composition and expression revealed cell diversity in human GSVs, particularly endothelial cells (ECs). Our results unraveled that functional adaptation drove great expression differences between venous ECs and valvular ECs. For instance, cell surface receptor ACKR1 demarcated venous Ecs, whereas ACRK3/ACKR4 were exclusively expressed by valvular ECs. Differential gene expression analysis suggested that genes highly expressed in venous ECs were mainly involved in vasculature development and regulation of leukocyte adhesion, whereas valvular ECs have more pronounced expression of genes participating in extracellular matrix organization, ossification and platelet degranulation. Of note, pseudo-time trajectory analysis provided in silico evidence indicating that venous ECs, valvular ECs and lymphatic vessels were developmentally connected. Further, valvular ECs might be an importance source for lymphatic vessel differentiation in adults. Additionally, we found a venous EC subset highly expressing IL6, which might be associated with undesirable prognosis. Meanwhile, we identified a population of ANGPTL7+ fibroblasts (FBs), which may be profibrotic and involved in insulin resistance in human GSVs. Additionally, our data suggest that immune cells only accounted for a small fraction, most of which were macrophages. By assessing the intertwined remodeling in metabolic dysfunction that potentially increases the gene expression regulatory network in mural cells and leukocytes, we found that transcription factor KLF9 likely operated a proinflammatory program, inducing the transcription of metallothionein proteins in two mural cell subsets and proinflammatory immune cells. Lastly, cellular communication analysis revealed that proinflammatory signaling, including TRAIL, PVR, CSF and GDF, were uniquely activated in patients with metabolic dysfunction. Conclusions: Our results identified critical cell-specific responses and cellular interactions in GSVs. Beyond serving as a repertoire, this work illustrates multifactorial likelihood of VGF.

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Section: Resultsmentioning

confidence: 99%

A Single-Cell Survey of Cellular Heterogeneity in Human Great Saphenous Veins

Sun

Zhang

et al. 2022

Cells

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“…These anemia responsible genes might be candidate biomarkers or therapeutic targets for CD. CXCR1 [679], CXCL1 [680], C2 [681], MMP3 [682], TAP1 [683], NOS2 [684], CXCL10 [685], SLC11A1 [686], GDF15 [687], IL1RN [688], PYGL (glycogen phosphorylase L) [689], CYP27B1 [690], SOCS3 [691], CD55 [692], CXCR2 [693], CCL3 [694], CCL2 [695], SOD2 [696], CD14 [697], IGFBP2 [698], PCSK9 [699], [700], IDO1 [701], FOXP3 [702], CD163 [703], LPL (lipoprotein lipase) [704], TLR2 [705], CCR2 [706], VWF (von Willebrand factor) [707], NOD2 [708], ATF3 [709], TIMP1 [682], ICAM1 [710], FFAR2 [711], IFNG (interferon gamma) [712], APOE (apolipoprotein E) [713], IL6 [714], CCL4 [715], CA2[716], MMP12 [717], MMP2 [718], CCL1 [719], CD24 [720], PLAU (plasminogen activator, urokinase) [721], CTLA4 [722], MASP1 [723], MPO (myeloperoxidase) [724], HP (haptoglobin) [725], MMP10 [726], CD300E [727], CUBN (cubilin) [728], SLC19A3 [729], APOB (apolipoprotein B) [730], APOC3 [731], HMGCS2 [732], OTC (ornithine transcarbamylase) [733], ACE2 [734], SLC22A4 [735], SLC22A5 [735], DPP4 [736], ACE (angiotensin I converting enzyme) [737], SLC6A19 [738], BTNL2 [739], FCRL3 [451], BCHE (butyrylcholinesterase) [740] and APOM (apolipoprotein M) [741] might be involved in type 1 diabetes mellitus. These type 1 diabetes mellitus responsible genes might be important participant in CD.…”

Section: Discussionmentioning

confidence: 99%

Identification of hub genes and key pathways in pediatric Crohn’s disease using next generation sequencing and bioinformatics analysis

Vastrad¹,

Vastrad²

2022

Preprint

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Pediatric Crohn's Disease (CD) also known as inflammatory bowel diseases, affects millions of people all over the world. The aim of this investigation is to identify the key genes in CD and uncover their potential functions. We downloaded the next generation sequencing (NGS) dataset GSE73374 from the Gene Expression Omnibus (GEO) database. The NGS dataset GSE73374 was used to screen differentially expressed genes (DEGs) between samples from patients with CD and healthy controls. Gene ontology (GO) and REACTOME pathway enrichment analyses were applied for the DEGs. Subsequently, a protein - protein interaction (PPI) network, modules, miRNA- hub gene regulatory network and TF - hub gene regulatory network were constructed to identify hub genes, miRNAs and TFs. Receiver operating characteristic curve (ROC) analysis was applied to validate the hub genes. A total of 957 DEGs were identified, including 478 up regulated genes and 479 down regulated genes. GO and REACTOME results suggested that several Go terms and pathways are involved in response to stimulus, extracellular region, signaling receptor binding, small molecule metabolic process, membrane, transporter activity, immune system and biological oxidations. The top centrality hub genes MDFI, MNDA, FBXO6, TFRC, STAT1, DPP4, MME, SLC39A4, APOA1 and TMEM25 were screened out as the critical genes among the DEGs from the PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network. This investigation identified key genes and signal pathways, which might help us improve our understanding of the molecular mechanisms of CD and identify some novel therapeutic targets for CD.

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“…High blood glucose and p53 increase the expression of GDF15 in adipose tissue, thus inhibition of p53 or reduction of blood glucose by antidiabetic agents could inhibit GDF15 expression 6,19 . Highly expressed GDF15 in obesity and IR induces the release of pro‐inflammatory cytokines, and in turn, these pro‐inflammatory cytokines induce the expression of GDF15 20 . High GDF15 expression is linked to the development of endothelial dysfunction due to the exaggerated release of pro‐inflammatory cytokines 20,76 .…”

Section: Introductionmentioning

confidence: 99%

“…Overall, β‐cell protection by GDF15, if demonstrated in humans, could significantly improve T1D patient outcomes. However, there are still significant questions that need to be addressed by thorough fundamental work to understand the precision, efficacy, and long‐term effects GDF15 in humans 20 …”

Section: Introductionmentioning

confidence: 99%

“… 6 , 19 Highly expressed GDF15 in obesity and IR induces the release of pro‐inflammatory cytokines, and in turn, these pro‐inflammatory cytokines induce the expression of GDF15. 20 High GDF15 expression is linked to the development of endothelial dysfunction due to the exaggerated release of pro‐inflammatory cytokines. 20 , 76 It has been suggested that administration of GDF15 therapy at the right stage of type 1 diabetes mellitus could delay clinical onset by potentially preserving the remaining β cells.…”

Section: Introductionmentioning

confidence: 99%

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Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: A hidden treasure

Al-Kuraishy

Al-Gareeb

Αλεξίου³

et al. 2022

Journal of Diabetes

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Type 2 diabetes mellitus (T2DM) is a chronic endocrine disorder due to the reduction of insulin sensitivity and relative deficiency of insulin secretion.Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor beta (TGF-β) superfamily and was initially identified as macrophage inhibitory cytokine-1 (MIC-1). GDF15 is considered a cytokine with an anti-inflammatory effect and increases insulin sensitivity, reduces body weight, and improves clinical outcomes in diabetic patients. GDF15 acts through stimulation of glial-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), which is highly expressed in the brain stem to induce taste aversion. Metformin belongs to the group of biguanides that are derived from the plant Galega officinalis. It is interesting to note that metformin is an insulin-sensitizing agent used as a first-line therapy for T2DM that has been shown to increase the circulating level of GDF15. Thus, the present review aims to determine the critical association of the GDF15 biomarker in T2DM and how metformin agents affect it. This review illustrates that metformin activates GDF15 expression, which reduces appetite and leads to weight loss in both diabetic and nondiabetic patients. However, the present review cannot give a conclusion in this regard. Therefore, experimental,

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GDF15: a potential therapeutic target for type 1 diabetes

Cited by 15 publications

References 126 publications

A Single-Cell Survey of Cellular Heterogeneity in Human Great Saphenous Veins

A Single-Cell Survey of Cellular Heterogeneity in Human Great Saphenous Veins

Identification of hub genes and key pathways in pediatric Crohn’s disease using next generation sequencing and bioinformatics analysis

Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: A hidden treasure

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