Gut-lung dysbiosis accompanied by diabetes mellitus leads to pulmonary fibrotic change through the NF-κB signaling pathway

In cases of patients with rapidly progressive diabetes mellitus (DM), autologous stem cell transplantation is considered as one of the regenerative treatments. However, whether the effects of autonomous stem cell transplantation on DM patients are equivalent to transplantation of stem cells derived from healthy persons is unclear. This study revealed that adipose-derived mesenchymal stem cells (ADSC) derived from type II DM patients had lower transplantation efficiency, proliferation potency, and stemness than those derived from healthy persons, leading to a tendency to induce apoptotic cell death. To address this issue, we conducted a cyclopedic mRNA analysis using a next-generation sequencer and identified G6PC3 and IGF1, genes related to the FoxO signaling pathway, as the genes responsible for lower performance. Moreover, it was demonstrated that the lower transplantation efficiency of ADSCs derived from type II DM patients might be improved by knocking down both G6PC3 and IGF1 genes. This study clarified the difference in transplantation efficiency between ADSCs derived from type II DM patients and those derived from healthy persons and the genes responsible for the lower performance of the former. These results can provide a new strategy for stabilizing the quality of stem cells and improving the therapeutic effects of regenerative treatments on autonomous stem cell transplantation in patients with DM.

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Role of TLR4/MyD88/NF-κB signaling in heart and liver-related complications in a rat model of type 2 diabetes mellitus

Journal of International Medical Research ◽

10.1177/0300060521997590 ◽

2021 ◽

Vol 49 (3) ◽

pp. 030006052199759

Author(s):

Jiajia Tian ◽

Yanyan Zhao ◽

Lingling Wang ◽

Lin Li

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Signaling Pathway ◽

Rat Model ◽

Fasting Blood Glucose ◽

Diabetic Rats ◽

Primary Response ◽

Monocyte Chemoattractant Protein 1

Aims To analyze expression of members of the Toll-like receptor (TLR)4/myeloid differentiation primary response 88 (MyD88)/nuclear factor (NF)-κB signaling pathway in the heart and liver in a rat model of type 2 diabetes mellitus (T2DM). Our overall goal was to understand the underlying pathophysiological mechanisms. Methods We measured fasting blood glucose (FBG) and insulin (FINS) in a rat model of T2DM. Expression of members of the TLR4/MyD88/NF-κB signaling pathway as well as downstream cytokines was investigated. Levels of mRNA and protein were assessed using quantitative real-time polymerase chain reaction and western blotting, respectively. Protein content of tissue homogenates was assessed using enzyme-linked immunosorbent assays. Results Diabetic rats had lower body weights, higher FBG, higher FINS, and higher intraperitoneal glucose tolerance than normal rats. In addition, biochemical indicators related to heart and liver function were elevated in diabetic rats compared with normal rats. TLR4 and MyD88 were involved in the occurrence of T2DM as well as T2DM-related heart and liver complications. TLR4 caused T2DM-related heart and liver complications through activation of NF-κB. Conclusions TLR4/MyD88/NF-κB signaling induces production of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1, leading to the heart- and liver-related complications of T2DM.

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Transcriptional Profiling and Biological Pathway(s) Analysis of Type 2 Diabetes Mellitus in a Pakistani Population

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17165866 ◽

2020 ◽

Vol 17 (16) ◽

pp. 5866

Author(s):

Zarish Noreen ◽

Christopher A. Loffredo ◽

Attya Bhatti ◽

Jyothirmai J. Simhadri ◽

Gail Nunlee-Bland ◽

...

Keyword(s):

Gene Expression ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Mitochondrial Dysfunction ◽

Signaling Pathway ◽

Health Concern ◽

Receptor Signaling ◽

Small Pilot Study

The epidemic of type 2 diabetes mellitus (T2DM) is an important global health concern. Our earlier epidemiological investigation in Pakistan prompted us to conduct a molecular investigation to decipher the differential genetic pathways of this health condition in relation to non-diabetic controls. Our microarray studies of global gene expression were conducted on the Affymetrix platform using Human Genome U133 Plus 2.0 Array along with Ingenuity Pathway Analysis (IPA) to associate the affected genes with their canonical pathways. High-throughput qRT-PCR TaqMan Low Density Array (TLDA) was performed to validate the selected differentially expressed genes of our interest, viz., ARNT, LEPR, MYC, RRAD, CYP2D6, TP53, APOC1, APOC2, CYP1B1, SLC2A13, and SLC33A1 using a small population validation sample (n = 15 cases and their corresponding matched controls). Overall, our small pilot study revealed a discrete gene expression profile in cases compared to controls. The disease pathways included: Insulin Receptor Signaling, Type II Diabetes Mellitus Signaling, Apoptosis Signaling, Aryl Hydrocarbon Receptor Signaling, p53 Signaling, Mitochondrial Dysfunction, Chronic Myeloid Leukemia Signaling, Parkinson’s Signaling, Molecular Mechanism of Cancer, and Cell Cycle G1/S Checkpoint Regulation, GABA Receptor Signaling, Neuroinflammation Signaling Pathway, Dopamine Receptor Signaling, Sirtuin Signaling Pathway, Oxidative Phosphorylation, LXR/RXR Activation, and Mitochondrial Dysfunction, strongly consistent with the evidence from epidemiological studies. These gene fingerprints could lead to the development of biomarkers for the identification of subgroups at high risk for future disease well ahead of time, before the actual disease becomes visible.

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Use of Network Pharmacology to Explore the Mechanism of Gegen (Puerariae lobatae Radix) in the Treatment of Type 2 Diabetes Mellitus Associated with Hyperlipidemia

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6633402 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Guozhen Yuan ◽

Shuai Shi ◽

Qiulei Jia ◽

Jingjing Shi ◽

Shuqing Shi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Signaling Pathway ◽

Fluid Shear Stress ◽

Chinese Herbs ◽

Network Pharmacology ◽

Biological Processes ◽

Active Ingredients

Rapid increases in metabolic disorders, such as type 2 diabetes mellitus (T2DM) and hyperlipidemia, are becoming a substantial challenge to worldwide public health. Traditional Chinese medicine has a long history and abundant experience in the treatment of diabetes and hyperlipidemia, and Puerariae lobatae Radix (known as Gegen in Chinese) is one of the most prevalent Chinese herbs applied to treat these diseases. The underlying mechanism by which Gegen simultaneously treats diabetes and hyperlipidemia, however, has not been clearly elucidated to date. Therefore, we systematically explored the potential mechanism of Gegen in the treatment of T2DM complicated with hyperlipidemia based on network pharmacology. We screened the potential targets of Gegen, T2DM, and hyperlipidemia in several online databases. Then, the hub targets were analyzed by performing protein-protein interaction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment assays, and finally, the complicated connections among compounds, targets, and pathways were visualized in Cytoscape. We found that isoflavones, including daidzein, genistein, and puerarin, as well as β-sitosterol, are the key active ingredients of Gegen responsible for its antidiabetic and antihyperlipidemia effects, which mainly target AKR1B1, EGFR, ESR, TNF, NOS3, MAPK3, PPAR, CYP19A1, INS, IL6, and SORD and multiple pathways, such as the PI3K-Akt signaling pathway; the AGE-RAGE signaling pathway in diabetic complications, fluid shear stress, and atherosclerosis; the PPAR signaling pathway; insulin resistance; the HIF-1 signaling pathway; the TNF signaling pathway; and others. These active ingredients also target multiple biological processes, including the regulation of glucose and lipid metabolism, the maintenance of metabolic homeostasis, and anti-inflammatory and antioxidant pathways. In conclusion, Gegen is a promising therapeutic phytomedicine for T2DM with hyperlipidemia that targets multiple proteins, biological processes, and pathways.

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Oleuropein alleviates gestational diabetes mellitus by activating AMPK signaling

Endocrine Connections ◽

10.1530/ec-20-0466 ◽

2020 ◽

Author(s):

Zhiwei Zhang ◽

Hui Zhao ◽

Aixia Wang

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Body Weight ◽

Blood Glucose ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Signaling Pathway ◽

Hepatic Glycogen ◽

Ampk Signaling ◽

Tnf Α

Background: Gestational diabetes mellitus (GDM) has a high incidence rate among pregnant women. The objective of the study was to assess the effect of plant-derived oleuropein in attenuating inflammatory and oxidative stress of GDM. Methods: Oleuropein was administered to GDM mice at the doses of 5 or 10 mg/kg/day. Body weight, blood glucose, insulin and hepatic glycogen levels were recorded. To evaluate the effect of oleuropein in reducing oxidative stress, enzyme-linked immunosorbent assay (ELISA) was used to measure the hepatic oxidative stress markers. The inflammation levels of GDM mice were evaluated by measuring serum levels of IL-6 and TNF-α by ELISA, and mRNA levels of IL-1β, TNF-α and IL-6 by real-time PCR (RT-PCR). The AMP-activated protein kinase (AMPK) signaling pathway was assessed by Western blot. Gestational outcome was analyzed through comparing litter size and birth weight. Results: Oleuropein attenuated the elevated body weight of GDM mice, and efficiently reduced blood glucose, insulin and hepatic glycogen levels. Oxidative stress and inflammation were alleviated by oleuropein treatment. The AMPK signaling was activated by oleuropein in GDM mice. Gestational outcome was markedly improved by oleuropein treatment. Conclusions: Our study suggests that oleuropein is effective in alleviating symptoms of GDM and improving gestational outcome in the mouse model. This effect is achieved by attenuating oxidative stress and inflammation, which is mediated by the activation of the AMPK signaling pathway.

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Glycation End-Products and their Receptors: Pathophysiology and Therapeutic Targeting in Diabetes Mellitus

Al-Rafidain Journal of Medical Sciences ( ISSN: 2789-3219 ) ◽

10.54133/ajms.v1i.23 ◽

2021 ◽

Vol 1 ◽

pp. 19-35

Author(s):

Hussein Saad Alzadi ◽

Naza Mohammed Ali Mahmood

Keyword(s):

Diabetes Mellitus ◽

Signaling Pathway ◽

Cellular Metabolism ◽

Fragility Fractures ◽

Clinical Results ◽

Diabetic Patients ◽

Advanced Glycation ◽

Soluble Rage ◽

Glycation End Products ◽

End Products

Diabetes mellitus (DM) compromises cell metabolism and function in many organs, resulting in increased risks of complications in many organs such as kidney, nervous system, eye, and fragility fractures. Advanced glycation end products (AGEs) are chemical moieties produced during long-term hyperglycemia; they interact with the specific receptors for AGEs (RAGEs) and make a meaningful contribution to cellular metabolism and/or alteration of their functions. Searches in PubMed using the keywords "advanced glycation end product "RAGE", "sRAGE", "DM", and "complications” were made to reveal some of the clinical outcomes of DM in cellular metabolism and organ function through the AGE-RAGE signaling pathway. All published experimental and clinical studies were included in tables. The AGE-RAGE signaling is involved in diabetic complications such as nephropathy, neuropathy, retinopathy, and osteopathy. Some clinical results in diabetic patients could be potentially attributed to AGE-RAGE signaling consequences. However, the AGE-RAGE signaling pathway has some helpful roles in many tissues, including an increase in osteogenic function. Soluble RAGE (sRAGE), as a ligand decoy, may increase in either condition of RAGE production or destruction, and then it cannot always reflect the AGE-RAGE signaling. Although various medicines are capable to target the AGE-RAGE axis. They can also limit the associated damaging consequences. Recombinant sRAGE can block the AGE-RAGE signaling pathway; however, it is associated with some limitations such as accessibility to AGEs, increase in other RAGE ligands, and a long half-life (24 hours). It is associated with losing the beneficial effect of AGE/RAGE. As a result, sRAGE is not a helpful marker to assess the activity of the RAGE signaling pathway. The recombinant sRAGE cannot be translated into clinical practice due to its limitations.

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Gene Expression Profiling of Type 2 Diabetes Mellitus by Bioinformatics Analysis

Computational and Mathematical Methods in Medicine ◽

10.1155/2020/9602016 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Huijing Zhu ◽

Xin Zhu ◽

Yuhong Liu ◽

Fusong Jiang ◽

Miao Chen ◽

...

Keyword(s):

Gene Expression ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Candidate Genes ◽

Signaling Pathway ◽

Bioinformatics Analysis ◽

Kegg Pathway ◽

Ppi Network ◽

Kegg Pathway Analysis

Objective. The aim of this study was to identify the candidate genes in type 2 diabetes mellitus (T2DM) and explore their potential mechanisms. Methods. The gene expression profile GSE26168 was downloaded from the Gene Expression Omnibus (GEO) database. The online tool GEO2R was used to obtain differentially expressed genes (DEGs). Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by using Metascape for annotation, visualization, and comprehensive discovery. The protein-protein interaction (PPI) network of DEGs was constructed by using Cytoscape software to find the candidate genes and key pathways. Results. A total of 981 DEGs were found in T2DM, including 301 upregulated genes and 680 downregulated genes. GO analyses from Metascape revealed that DEGs were significantly enriched in cell differentiation, cell adhesion, intracellular signal transduction, and regulation of protein kinase activity. KEGG pathway analysis revealed that DEGs were mainly enriched in the cAMP signaling pathway, Rap1 signaling pathway, regulation of lipolysis in adipocytes, PI3K-Akt signaling pathway, MAPK signaling pathway, and so on. On the basis of the PPI network of the DEGs, the following 6 candidate genes were identified: PIK3R1, RAC1, GNG3, GNAI1, CDC42, and ITGB1. Conclusion. Our data provide a comprehensive bioinformatics analysis of genes, functions, and pathways, which may be related to the pathogenesis of T2DM.

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Kalpaamruthaa modulates oxidative stress in cardiovascular complication associated with type 2 diabetes mellitus through PKC-β/Akt signaling

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2012-0443 ◽

2013 ◽

Vol 91 (11) ◽

pp. 901-912 ◽

Cited By ~ 4

Author(s):

Raja Latha ◽

Palanivelu Shanthi ◽

Panchanadham Sachdanandam

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Signaling Pathway ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Protein Carbonyl Content ◽

Pkc Β

This study aimed at investigating the efficacy of Kalpaamruthaa (KA) on cardiovascular damage (CVD) associated with type 2 diabetes mellitus in experimental rats by reducing oxidative stress and the modulation of the protein kinase C-β (PKC-β)/Akt signaling pathway. CVD-induced rats were treated with KA (200 mg·(kg body mass)–1·(day)–1) orally for 4 weeks. KA effectively reduced insulin resistance with alterations in blood glucose, hemoglobin, and glycosylated hemoglobin in CVD-induced rats. Elevated levels of lipids in CVD-induced rats were decreased upon KA administration. In CVD-induced rats the levels of lipoproteins were returned to normal by KA treatment. KA effectively reduced the lipid peroxidative product and protein carbonyl content in liver of CVD-induced rats. KA increased the activities and (or) levels of enzymatic and nonenzymatic antioxidants in liver of CVD-induced rats. KA treatment reduced the fatty inclusion and mast cell infiltration in liver of CVD-induced rats. Further, treatment with KA reduced the chromatin condensation and marginization in myocardium of CVD-induced rats. KA alters insulin signaling by decreasing PKC-β and increasing p-Akt and GLUT4 expressions in heart of CVD-induced rats. The above findings suggest that KA renders protection against CVD induced by type 2 diabetes mellitus by augmenting the cellular antioxidant defense capacity and modulating PKC-β and the p-Akt signaling pathway.

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