Identification of Circular RNAs Regulating Islet β-Cell Autophagy in Type 2 Diabetes Mellitus

This study is to identify the circular RNA (circRNA) expression profile that is functionally related to pancreatic islet β-cell autophagy and their potential regulation mechanisms in type 2 diabetes mellitus (T2DM). T2DM rat model was constructed by administration of high-fat and high-sugar diet. β-cells were isolated from islets by flow cytometry. CircRNA expression profile in β-cells was detected by circRNA microarrays, and the differentially expressed circRNAs were identified and validated by qRT-PCR. MicroRNA (miRNA) target prediction software and multiple bioinformatic approaches were used to construct a map of circRNA-miRNA interactions for the differentially expressed circRNAs. A total of 825 differentially expressed circular transcripts were identified in T2DM rats compared with control rats, among which 388 were upregulated and 437 were downregulated. Ten circRNAs were identified to have significant differences by qRT-PCR. GO analysis enriched terms such as organelle membrane and protein binding and the top enriched pathways for the circRNAs included MAPK signaling pathway. The differentially expressed circRNAs might involve in MAPK signaling pathway, apoptosis, and Ras signaling pathway. We speculate that these circRNAs, especially rno_circRNA_008565, can regulate the autophagy of islet β-cells via interactions with miRNA. Dysregulation of several circRNAs may play a role in T2DM development, and rno_circRNA_008565 may be a potential regulator of β-cell autophagy.

Download Full-text

Identification of Perturbed Pathways Rendering Susceptibility to Tuberculosis in Type 2 Diabetes Mellitus Patients Using BioNSi Simulation of Integrated Network of Implicated Human Genes

10.21203/rs.3.rs-863821/v1 ◽

2021 ◽

Author(s):

Jyoti Rani ◽

Anasuya Bhargav ◽

Malabika Datta ◽

Urmi Bajpai ◽

Srinivasan Ramachandran

Keyword(s):

Gene Expression ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Mapk Signaling ◽

Differentially Expressed ◽

P Value ◽

Receptor Signaling ◽

Chronic Hyperglycemia

Abstract Adaptive immune response of the Th1 arm is the main defense against tuberculosis (TB). However, in Type 2 Diabetes Mellitus (T2DM) patients, chronic hyperglycemia and inflammation underlie susceptibility to TB and results in poor TB control. The molecular pathways causing susceptibility of diabetics to tuberculosis is not fully understood. Here, an integrative pathway-based approach is used to investigate the perturbed pathways in T2DM patients rendering susceptibility to TB. We obtained 36 genes implicated in the Type 2 diabetes associated tuberculosis (T2DMTB) from literature. Gene expression analysis on T2DM patients’ data (GSE28168) showed that DEFA1 is differentially expressed at Padj < 0.05. The genes CAMP, CD14, CORO1A, LAMP1, TLR4, IL17F and SOCS3 were differentially expressed in T2DM patients at P value < 0.05. 7 microRNAs associated with these T2DMTB genes were obtained from NetworkAnalyst and verified for their literature evidences. The hsa-miR-146a microRNA was differentially expressed at Padj < 0.05. The human host TB susceptibility genes TNFRSF10A, MSRA, GPR148, SLC37A3, PXK, PROK2, REV3L, PGM1, HIST3H2A, PLAC4, LETM2, EMP2 and were also differentially expressed at Padj < 0.05. We included all these genes and added the remaining 28 genes from the T2DMTB set and the rest of differentially expressed genes at Padj < 0.05 in STRING and obtained a well-connected network with high confidence score greater than 0.7. From this network we extracted the KEGG pathways at FDR < 0.05 and retained only Diabetes and TB pathways among the disease pathways. The network was simulated with BioNSi using gene expression data from GSE26168. The Necroptosis pathway showed the maximum perturbations in T2DM patients, followed by NOD-like receptor signaling, Toll-like receptor signaling, NF-kappa-B signaling and MAPK signaling. These pathways likely underlie susceptibility to TB in T2DM patients.

Download Full-text

Retraction: “MicroRNA‐219 decreases hippocampal long‐term potentiation inhibition and hippocampal neuronal cell apoptosis in type 2 diabetes mellitus mice by suppressing the NMDAR signaling pathway,” by Zhang, L, Chen, Z‐W, Yang, S‐F, et al. CNS Neurosci Ther. 2019; 25: 69–77

CNS Neuroscience & Therapeutics ◽

10.1111/cns.13709 ◽

2021 ◽

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Signaling Pathway ◽

Cell Apoptosis ◽

Neuronal Cell ◽

Long Term Potentiation ◽

Term Potentiation

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text