scholarly journals Secreted Wnt6 mediates diabetes-associated centrosome amplification via its receptor FZD4

2020 ◽  
Vol 318 (1) ◽  
pp. C48-C62 ◽  
Author(s):  
Qin Ju He ◽  
Pu Wang ◽  
Qin Qin Liu ◽  
Qi Gui Wu ◽  
Yuan Fei Li ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Culture ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Integration Site ◽  
Cellular Protein ◽  
Centrosome Amplification ◽  
Protein Levels

We recently published that type 2 diabetes promotes cell centrosome amplification via upregulation of Rho-associated protein kinase 1 (ROCK1) and 14-3-3 protein-σ (14-3-3σ). This study further investigates the molecular mechanisms underlying diabetes-associated centrosome amplification. We found that treatment of cells with high glucose, insulin, and palmitic acid levels increased the intracellular and extracellular protein levels of Wingless-type MMTV integration site family member 6 (Wnt6) as well as the cellular level of β-catenin. The treatment also activated β-catenin and promoted its nuclear translocation. Treatment of cells with siRNA species for Wnt6, Frizzled-4 (FZD4), or β-catenin as well as introduction of antibodies against Wnt6 or FZD4 to the cell culture medium could all attenuate the treatment-triggered centrosome amplification. Moreover, we showed that secreted Wnt6-FZD4-β-catenin was the signaling pathway that was upstream of ROCK1 and 14-3-3σ. We found that advanced glycation end products (AGEs) were also able to increase the cellular and extracellular levels of Wnt6, the cellular protein level of β-catenin, and centrosome amplification. Treatment of the cells with siRNA species for Wnt6 or FZD4 as well as introduction of antibodies against Wnt6 or FZD4 to the cell culture could all inhibit the AGEs-elicited centrosome amplification. In colon tissues from a diabetic mouse model, the protein levels of Wnt6 and 14-3-3σ were increased. In conclusion, our results showed that the pathophysiological factors in type 2 diabetes, including AGEs, were able to induce centrosome amplification. It is suggested that secreted Wnt6 binds to FZD4 to activate the canonical Wnt6 signaling pathway, which is upstream of ROCK1 and 14-3-3σ, and that this is the cell signaling pathway underlying diabetes-associated centrosome amplification.

scholarly journals Resveratrol attenuates diabetes-associated cell centrosome amplification via inhibiting the PKCα-p38 to c-myc/c-jun pathway

2019 ◽  
Vol 52 (1) ◽  
pp. 72-83 ◽  
Author(s):  
Qigui Wu ◽  
Xiaoyu Chen ◽  
Qinju He ◽  
Lang Lang ◽  
Peng Xu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Palmitic Acid ◽  
Signaling Pathway ◽  
High Glucose ◽  
Mononuclear Cells ◽  
Centrosome Amplification ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Protein Levels

Abstract Type 2 diabetes increases the risk for cancer. Centrosome amplification can initiate tumorigenesis. We have described that type 2 diabetes increases the centrosome amplification of peripheral blood mononuclear cells, with high glucose, insulin, and palmitic acid as the triggers, which suggests that centrosome amplification is a candidate biological mechanism linking diabetes to cancer. In this study, we aimed to further investigate the signaling pathways of the diabetes-associated centrosome amplification and to examine whether and how resveratrol inhibits the centrosome amplification. The results showed that treatment with high glucose, insulin, and palmitic acid, alone or in combination, could increase the protein levels of phospho-protein kinase C alpha (p-PKCα), phospho-p38 mitogen-activated protein kinases (p-p38), c-myc, and c-jun, as well as the mRNA levels of c-myc and c-jun. PKCα inhibitor could inhibit the treatment-induced increase in the protein levels of p-p38, c-myc, and c-jun. Inhibitor or siRNA of p38 was also able to inhibit the treatment-induced increase in the levels of p-p38, c-myc, and c-jun. Meanwhile, knockdown of c-myc or c-jun did not alter the treatment-induced increase in the phosphorylation of PKCα or p38. Importantly, inhibition of the phosphorylation of PKCα or p38 and knockdown of c-myc or c-jun could attenuate the centrosome amplification. In diabetic mice, the levels of p-PKCα, p-p38, c-myc, and c-jun were all increased in the colon tissues. Interestingly, resveratrol, but not metformin, was able to attenuate the treatment-induced increase in the levels of p-PKCα, p-p38, c-myc, and c-jun, as well as the centrosome amplification. In conclusion, our results suggest that PKCα-p38 to c-myc/c-jun is the signaling pathway of the diabetes-associated centrosome amplification, and resveratrol attenuates the centrosome amplification by inhibiting this signaling pathway.

scholarly journals Distinct Molecular Signatures of Clinical Clusters in People with Type 2 Diabetes: an IMI-RHAPSODY Study

2021 ◽  
Author(s):  
Roderick C Slieker ◽  
Louise A Donnelly ◽  
Hugo Fitipaldi ◽  
Gerard A Bouland ◽  
Giuseppe N. Giordano ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Molecular Signature ◽  
Akt Pathway ◽  
Molecular Profile ◽  
Molecular Signatures ◽  
Insulin Resistant ◽  
Protein Levels ◽  
Mild Diabetes

Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity a previous study clustered people with diabetes into five diabetes subtypes. The aim of the current study is to investigate the aetiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic- (N=12828), metabolomic- (N=2945), lipidomic- (N=2593) and proteomic (N=1170) data were obtained in plasma. In each datatype each cluster was compared with the other four clusters as the reference. The insulin resistant cluster showed the most distinct molecular signature, with higher BCAAs, DAG and TAG levels and aberrant protein levels in plasma enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher cytokines. A subset of the mild diabetes cluster with high HDL showed the most beneficial molecular profile with opposite effects to those seen in the insulin resistant cluster. This study showed that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease

scholarly journals Distinct Molecular Signatures of Clinical Clusters in People with Type 2 Diabetes: an IMI-RHAPSODY Study

2021 ◽  
Author(s):  
Roderick C Slieker ◽  
Louise A Donnelly ◽  
Hugo Fitipaldi ◽  
Gerard A Bouland ◽  
Giuseppe N. Giordano ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Molecular Signature ◽  
Akt Pathway ◽  
Molecular Profile ◽  
Molecular Signatures ◽  
Insulin Resistant ◽  
Protein Levels ◽  
Mild Diabetes

Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity a previous study clustered people with diabetes into five diabetes subtypes. The aim of the current study is to investigate the aetiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic- (N=12828), metabolomic- (N=2945), lipidomic- (N=2593) and proteomic (N=1170) data were obtained in plasma. In each datatype each cluster was compared with the other four clusters as the reference. The insulin resistant cluster showed the most distinct molecular signature, with higher BCAAs, DAG and TAG levels and aberrant protein levels in plasma enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher cytokines. A subset of the mild diabetes cluster with high HDL showed the most beneficial molecular profile with opposite effects to those seen in the insulin resistant cluster. This study showed that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease

scholarly journals Constitution of a comprehensive phytochemical profile and network pharmacology based investigation to decipher molecular mechanisms of Teucrium polium L. in the treatment of type 2 diabetes mellitus

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10111
Author(s):  
Vahap Murat Kutluay ◽  
Neziha Yagmur Diker
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Network Pharmacology ◽  
Teucrium Polium ◽  
Phytochemical Profile

Background Type 2 diabetes mellitus (T2DM) is a metabolic disease affecting a huge population worldwide. Teucrium polium L. has been used as a folk medicine for the treatment of T2DM in Anatolia, Turkey. The antihyperglycemic effect of the plant was reported previously. However, there was no detailed study on the underlying molecular mechanisms. In this study, we generated a research plan to clarify the active constituents of the extract and uncover the molecular mechanisms using network pharmacology analysis. Methods For this purpose, we composed a dataset of 126 compounds for the phytochemical profile of the aerial parts of T. polium. Drug-likeness of the compounds was evaluated, and 52 compounds were selected for further investigation. A total of 252 T2DM related targets hit by selected compounds were subjected to DAVID database. Results The KEGG pathway analysis showed enrichment for the TNF signaling pathway, insulin resistance, the HIF-1 signaling pathway, apoptosis, the PI3K-AKT signaling pathway, the FOXO signaling pathway, the insulin signaling pathway, and type 2 diabetes mellitus which are related to T2DM . AKT1, IL6, STAT3, TP53, INS, and VEGFA were found to be key targets in protein-protein interaction. Besides these key targets, with this study the role of GSK3β, GLUT4, and PDX1 were also discussed through literature and considered as important targets in the antidiabetic effect of T. polium. Various compounds of T. polium were shown to interact with the key targets activating PI3K-AKT and insulin signaling pathways. Conclusions According to these findings, mainly phenolic compounds were identified as the active components and IRS1/PI3K/AKT signaling and insulin resistance were identified as the main pathways regulated by T. polium. This study reveals the relationship of the compounds in T. polium with the targets of T2DM in human. Our findings suggested the use of T. polium as an effective herbal drug in the treatment of T2DM and provides new insights for further research on the antidiabetic effect of T. polium.

scholarly journals Abnormal Peripheral Neutrophil Transcriptome in Newly Diagnosed Type 2 Diabetes Patients

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Qiuqiu Lin ◽  
Wenzhi Zhou ◽  
Yanfei Wang ◽  
Juan Huang ◽  
Xiaoyan Hui ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Signaling Pathway ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Receptor Interaction ◽  
Healthy Controls ◽  
Newly Diagnosed ◽  
Diabetes Patients

Aim. There are increasing evidence demonstrating that neutrophil-mediated inflammation plays a role in the etiology of type 2 diabetes. However, the molecular mechanisms by which neutrophils contribute to type 2 diabetes remain largely unknown. The aim of the present work was to identify possible changes in circulating neutrophils to better elucidate neutrophil involvement in human type 2 diabetes. Methods. Patients newly diagnosed with type 2 diabetes (n=5) and age- and sex-matched healthy controls (n=5) were recruited. Neutrophils were purified from type 2 diabetes patients and controls, and RNA sequencing (RNA-seq) was used for comprehensive transcriptome analysis. Differentially expressed genes (DEGs) were screened, and Gene Ontology (GO) and KEGG pathway enrichment analyses were performed. Real-time polymerase chain reaction (qPCR) was used for validation in external samples of type 2 diabetes patients (n=8) and healthy controls (n=8). Results. Gene expression analysis showed that, compared with neutrophils from healthy controls, there were 1990 upregulated DEGs and 1314 downregulated DEGs in neutrophils from type 2 diabetes patients. GO analysis demonstrated that the DEGs were mainly involved in myeloid leukocyte activation, T cell activation, adaptive immunity, and cytokine production. The top 20 enriched KEGG pathways included the cytokine-cytokine receptor interaction pathway, NF-κB signaling pathway, cell adhesion molecules, and chemokine signaling pathway. Furthermore, qPCR of genes related to neutrophil activation revealed that the expression of SELL, SELP, CXCR1, and S100A8 was significantly increased in neutrophils from type 2 diabetes patients compared with that in neutrophils from controls. Conclusions. Our study reveals an abnormal activation of circulating neutrophils at the transcriptome level in type 2 diabetes patients. These findings suggest a potential involvement of neutrophil dysfunction in the pathologic process of type 2 diabetes and provide insight into potential therapeutic targets for type 2 diabetes.

scholarly journals Molecular mechanisms linking peri-implantitis and type 2 diabetes mellitus revealed by transcriptomic analysis

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7124 ◽  
Author(s):  
Tianliang Yu ◽  
Aneesha Acharya ◽  
Nikos Mattheos ◽  
Simin Li ◽  
Dirk Ziebolz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Signaling Pathway ◽  
Cross Talk ◽  
Molecular Mechanisms ◽  
Hub Genes ◽  
Ppi Networks

Aims To explore molecular mechanisms that link peri-implantitis and type 2 diabetes mellitus (T2DM) by bioinformatic analysis of publicly available experimental transcriptomic data. Materials and methods Gene expression data from peri-implantitis were downloaded from the Gene Expression Omnibus database, integrated and differentially expressed genes (DEGs) in peri-implantitis were identified. Next, experimentally validated and computationally predicted genes related to T2DM were downloaded from the DisGeNET database. Protein–protein interaction network (PPI) pairs of DEGs related to peri-implantitis and T2DM related genes were constructed, “hub” genes and overlapping DEG were determined. Functional enrichment analysis was used to identify significant shared biological processes and signaling pathways. The PPI networks were subjected to cluster and specific class analysis for identifying “leader” genes. Module network analysis of the merged PPI network identified common or cross-talk genes connecting the two networks. Results A total of 92 DEGs overlapped between peri-implantitis and T2DM datasets. Three hub genes (IL-6, NFKB1, and PIK3CG) had the highest degree in PPI networks of both peri-implantitis and T2DM. Three leader genes (PSMD10, SOS1, WASF3), eight cross-talk genes (PSMD10, PSMD6, EIF2S1, GSTP1, DNAJC3, SEC61A1, MAPT, and NME1), and one signaling pathway (IL-17 signaling) emerged as peri-implantitis and T2DM linkage mechanisms. Conclusions Exploration of available transcriptomic datasets revealed IL-6, NFKB1, and PIK3CG expression along with the IL-17 signaling pathway as top candidate molecular linkage mechanisms between peri-implantitis and T2DM.

scholarly journals Network-Based Association Study of Obesity and Type 2 Diabetes with Gene Expression Profiles

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Siyi Zhang ◽  
Bo Wang ◽  
Jingsong Shi ◽  
Jing Li
Keyword(s):  
Type 2 Diabetes ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Receptor ◽  
Mapk Signaling ◽  
Chemokine Signaling ◽  
Chemokine Signaling Pathway

The increased prevalence of obesity and type 2 diabetes (T2D) has become an important factor affecting the health of the human. Obesity is commonly considered as a major risk factor for the development of T2D. However, the molecular mechanisms of the disease relations are not well discovered yet. In this study, the combination of multiple differential expression profiles and a comprehensive biological network of obesity and T2D allowed us to identify and compare the disease-responsive active modules and subclusters. The results demonstrated that the connection between obesity and T2D mainly relied on several pathways involved in the digestive metabolism, immunization, and signal transduction, such as adipocytokine, chemokine signaling pathway, T cell receptor signaling pathway, and MAPK signaling pathways. The relationships of almost all of these pathways with obesity and T2D have been verified by the previous reports individually. We also found that the different parts in the same pathway are activated in obesity and T2D. The association of cancer, obesity, and T2D was identified too here. As a conclusion, our network-based method not only gives better support for the close connection between obesity and T2D, but also provides a systemic view in understanding the molecular functions underneath the links. It should be helpful in the development of new therapies for obesity, T2D, and the associated diseases.

scholarly journals Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3σ

2018 ◽  
Vol 47 (1) ◽  
pp. 356-367 ◽  
Author(s):  
Pu Wang ◽  
Yu Cheng Lu ◽  
Jie Wang ◽  
Lan Wang ◽  
Hanry Yu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Palmitic Acid ◽  
High Glucose ◽  
Molecular Mechanisms ◽  
Fasting Blood Glucose ◽  
Centrosome Amplification ◽  
Immunofluorescent Staining ◽  
Diabetic Patients

Background/Aims: Type 2 diabetes is associated with oxidative stress and DNA damage which can cause centrosome amplification. Thus, the study investigated centrosome amplification in type 2 diabetes and the underlying mechanisms. Methods: Centrosome numbers in human peripheral blood mononuclear blood cells (PBMC) from healthy subjects and patients with type 2 diabetes were compared to access the association between type 2 diabetes and centrosome amplification. Colon cancer cells were used to investigate the molecular mechanisms underlying the centrosome amplification triggered by high glucose, insulin and palmitic acid. Western blot analysis was used to quantify the level of protein and protein phosphorylation. Immunofluorescent staining was performed to detect centrosomes. ROS was quantified using flow cytometry technique. Transcriptpmic profiling was performed using Illumina HiSeqTM500 platform. Results: We found that centrosome amplification was increased PBMC from the type 2 diabetic patients, which correlated with the levels of fasting blood glucose and HbA1c. High glucose, insulin and palmitic acid, alone or in combinations, induced ROS production and centrosome amplification. Together, they increased AKT activation as well as the expression, binding and centrosome translation of ROCK1 and 14-3-3σ. Results from further analyses showed that AKT-ROS-dependent upregulations of expression, binding and centrosome translocation of ROCK1 and 14-3-3σ was the molecular pathway underlying the centrosome amplification in vitro triggered by high glucose, insulin and palmitic acid. Moreover, the key in vitro molecular signalling events activated by high glucose, insulin and palmitic acid were verified in PBMC from the patients with type 2 diabetes. Conclusion: Our results show that type 2 diabetes promotes cell centrosome amplification, and suggest that the diabetic pathophysiological factors-activated AKT-ROS-dependent signalling of ROCK1 and 14-3-3σ is the underlying molecular mechanism.

Epigenetic modulation of autophagy genes linked to diabetic nephropathy by administration of isorhamnetin in Type 2 diabetes mellitus rats

Epigenomics ◽  
2021 ◽  
Author(s):  
Marwa Matboli ◽  
Doaa Ibrahim ◽  
Amany H Hasanin ◽  
Mohamed Kamel Hassan ◽  
Eman K Habib ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Blood Glucose ◽  
Fasting Blood Glucose ◽  
Light And Electron Microscopy ◽  
Lipid Profiles ◽  
Mirna Regulation ◽  
Protein Levels

Aim: To assess isorhamnetin efficacy for diabetic kidney disease in a Type 2 diabetes mellitus rat model, through investigating its effect at the epigenetic, mRNA and protein levels. Materials & methods: Type 2 diabetes mellitus was induced in rats by streptozotocin and high-fat diet. Rats were treated with isorhamnetin (50 mg/kg/d) for 4 or 8 weeks. Fasting blood glucose, renal and lipid profiles were evaluated. Renal tissues were examined by light and electron microscopy. Autophagy genes ( FYCO1, ULK, TECPR1 and  WIPI2) and miR-15b, miR-34a and miR-633 were assessed by qRT-PCR, and LC3A/B by immunoblotting. Results: Isorhamnetin improved fasting blood glucose, renal and lipid profiles with increased autophagosomes in renal tissues. It suppressed miRNA regulation of autophagy genes Conclusion: We propose a molecular mechanism for the isorhamnetin renoprotective effect by modulation of autophagy epigenetic regulators.

scholarly journals Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia

2021 ◽  
Vol 22 (2) ◽  
pp. 660
Author(s):  
María Aguilar-Ballester ◽  
Gema Hurtado-Genovés ◽  
Alida Taberner-Cortés ◽  
Andrea Herrero-Cervera ◽  
Sergio Martínez-Hervás ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Leukocyte Adhesion ◽  
Experimental Studies ◽  
Lipid Lowering ◽  
Foam Cell Formation ◽  
Relevant Parameter

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.

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