scholarly journals Transcript Levels of Aldo-Keto Reductase Family 1 Subfamily C (AKR1C) Are Increased in Prostate Tissue of Patients with Type 2 Diabetes

2020 ◽  
Vol 10 (3) ◽  
pp. 124 ◽  
Author(s):  
Andras Franko ◽  
Lucia Berti ◽  
Jörg Hennenlotter ◽  
Steffen Rausch ◽  
Marcus O. Scharpf ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Cancer Progression ◽  
Transcript Level ◽  
Prostate Tissue ◽  
Transcript Levels ◽  
Pc3 Cells ◽  
The Impact

Aldo-keto reductase family 1 (AKR1) enzymes play a crucial role in diabetic complications. Since type 2 diabetes (T2D) is associated with cancer progression, we investigated the impact of diabetes on AKR1 gene expression in the context of prostate cancer (PCa) development. In this study, we analyzed benign (BEN) prostate and PCa tissue of patients with and without T2D. Furthermore, to replicate hyperglycemia in vitro, we treated the prostate adenocarcinoma cell line PC3 with increasing glucose concentrations. Gene expression was quantified using real-time qPCR. In the prostate tissue of patients with T2D, AKR1C1 and AKR1C2 transcripts were higher compared to samples of patients without diabetes. In PC3 cells, high glucose treatment induced the gene expression levels of AKR1C1, C2, and C3. Furthermore, both in human tissue and in PC3 cells, the transcript levels of AKR1C1, C2, and C3 showed positive associations with oncogenes, which are involved in proliferation processes and HIF1α and NFκB pathways. These results indicate that in the prostate glands of patients with T2D, hyperglycemia could play a pivotal role by inducing the expression of AKR1C1, C2, and C3. The higher transcript level of AKR1C was furthermore associated with upregulated HIF1α and NFκB pathways, which are major drivers of PCa carcinogenesis.

Gene Expression Analysis of Troglitazone Reveals Its Impact on Multiple Pathways in Cell Culture: A Case for In Vitro Platforms Combined with Gene Expression Analysis for Early (Idiosyncratic) Toxicity Screening

2006 ◽  
Vol 25 (2) ◽  
pp. 85-94 ◽  
Author(s):  
Gordon Vansant ◽  
Patrick Pezzoli ◽  
Robert Saiz ◽  
Aaron Birch ◽  
Chris Duffy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Peroxisome Proliferator ◽  
Toxicity Screening ◽  
The Impact

Peroxisome proliferator-activated receptor gamma (PPAR γ) agonists of the thiazolidinedione family are used for the treatment of type 2 diabetes mellitus due to their ability to reduce glucose and lipid levels in patients with this disease. Three thiazolidinediones that were approved for treatment are Rezulin (troglitazone), Avandia (rosiglitazone), and Actos (pioglitazone). Troglitazone was withdrawn from the market due to idiosyncratic drug toxicity. Rosiglitazone and pioglitazone are still on the market for the treatment of type 2 diabetes. The authors present data from a gene expression screen that compares the impact these three compounds have in rats, in rat hepatocytes, and in the clone 9 rat liver cell line. The authors monitored the changes in expression in multiple genes, including those related to xenobiotic metabolism, proliferation, DNA damage, oxidative stress, apoptosis, and inflammation. Compared to the other two compounds, troglitazone had a significant impact on many of the pathways monitored in vitro although no major perturbation was detected in vivo. The changes detected predict not only general toxicity but potential mechanisms of toxicity. Based on gene expression analysis, the authors propose there is not just one but multiple ways troglitazone could be toxic, depending on a patient’s environment and genetic makeup, including immune response-related toxicity.

scholarly journals The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis

2012 ◽  
Vol 303 (9) ◽  
pp. E1166-E1176 ◽  
Author(s):  
Wilfred Ip ◽  
Weijuan Shao ◽  
Yu-ting Alex Chiang ◽  
Tianru Jin
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Wnt Signaling ◽  
Wnt Signaling Pathway ◽  
Glucose Production ◽  
Hepatic Gluconeogenesis

Certain single nucleotide polymorphisms (SNPs) in transcription factor 7-like 2 (TCF7L2) are strongly associated with the risk of type 2 diabetes. TCF7L2 and β-catenin (β-cat) form the bipartite transcription factor cat/TCF in stimulating Wnt target gene expression. cat/TCF may also mediate the effect of other signaling cascades, including that of cAMP and insulin in cell-type specific manners. As carriers of TCF7L2 type 2 diabetes risk SNPs demonstrated increased hepatic glucose production, we aimed to determine whether TCF7L2 expression is regulated by nutrient availability and whether TCF7L2 and Wnt regulate hepatic gluconeogenesis. We examined hepatic Wnt activity in the TOPGAL transgenic mouse, assessed hepatic TCF7L2 expression in mice upon feeding, determined the effect of insulin on TCF7L2 expression and β-cat Ser675 phosphorylation, and investigated the effect of Wnt activation and TCF7L2 knockdown on gluconeogenic gene expression and glucose production in hepatocytes. Wnt activity was observed in pericentral hepatocytes in the TOPGAL mouse, whereas TCF7L2 expression was detected in human and mouse hepatocytes. Insulin and feeding stimulated hepatic TCF7L2 expression in vitro and in vivo, respectively. In addition, insulin activated β-cat Ser675 phosphorylation. Wnt activation by intraperitoneal lithium injection repressed hepatic gluconeogenic gene expression in vivo, whereas lithium or Wnt-3a reduced gluconeogenic gene expression and glucose production in hepatic cells in vitro. Small interfering RNA-mediated TCF7L2 knockdown increased glucose production and gluconeogenic gene expression in cultured hepatocytes. These observations suggest that Wnt signaling and TCF7L2 are negative regulators of hepatic gluconeogenesis, and TCF7L2 is among the downstream effectors of insulin in hepatocytes.

Abstract 458: Omega-3 Supplementation Does Not Affect Inflammatory Gene Expression in the Small Intestine of Patients with Type 2 Diabetes

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Marie-ève Labonté ◽  
Patrick Couture ◽  
André J Tremblay ◽  
Jean-Charles Hogue ◽  
Valéry Lemelin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Small Intestine ◽  
Mrna Expression ◽  
Omega 3 ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Anti Inflammatory ◽  
The Impact

Recent evidence suggests that diet-induced inflammation in the small intestine is linked to obesity and insulin resistance. Long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to have anti-inflammatory effects by down-regulating inflammatory gene expression in adipocytes and mononuclear cells. However, the extent to which EPA and DHA may exert their anti-inflammatory effects by down-regulating inflammation in the gut is unknown. The objective of the study was to investigate the impact of EPA+DHA supplementation on the expression of inflammatory genes in the small intestine of patients with type 2 diabetes. A total of 12 men with type 2 diabetes were recruited in this placebo-controlled randomized crossover study. After a 4-week run-in period, patients received in random sequence 5 g/d of fish oil providing 3 g of EPA+DHA or placebo (corn and soybean oil) for 8 weeks, each separated by a 12-week washout period. Gene expression was assessed by real-time PCR in duodenal biopsy samples obtained in the fasted state at the end of each treatment phase. Intestinal mRNA expression levels for interleukin(IL)-6 and tumor-necrosis factor(TNF)-α were hardly detectable after either treatment (< 100 copies/10^5 copies of the reference gene ATP synthase O subunit, ATP5o). Intestinal mRNA expression of IL-18 and of the transcription factor STAT3 (signal transducer and activator of transcription 3) was higher (> 5000 copies/10^5 copies ATP5o) but still relatively low and EPA+DHA supplementation had no impact on any of these levels (P ≥ 0.73 between treatments). Plasma C-reactive protein (CRP) concentrations after supplementation with EPA+DHA (5.2 ± 4.5 mg/L) were not significantly different than values measured after placebo (8.0 ± 10.8 mg/L, P = 0.2). In conclusion, these data suggest that gene expression of pro-inflammatory cytokines and STAT3 in duodenal cells is low in patients with type 2 diabetes and not affected by EPA+DHA supplementation.

scholarly journals Synaptosomal Protein of 25 kDa (Snap25) Polymorphisms Associated with Glycemic Parameters in Type 2 Diabetes Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-4 ◽  
Author(s):  
Nasser M. Al-Daghri ◽  
Andrea S. Costa ◽  
Majed S. Alokail ◽  
Milena Zanzottera ◽  
Amal M. Alenad ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Genomic Dna ◽  
Fasting Glucose ◽  
Glucose Levels ◽  
Intron 1 ◽  
Hba1c Levels

A possible role ofSnap25polymorphisms in type 2 diabetes mellitus (T2DM) was evaluated by analyzing three SNPs within intron 1 in a region known to affect the gene expression in vitro. Genomic DNA from 1019 Saudi individuals (489 confirmed T2DM and 530 controls) was genotyped for SNPs rs363039, rs363043, and rs363050 inSnap25using the TaqMan Genotyping Assay. Significantly higher levels of fasting glucose and HbA1c were detected in T2DM patients carrying the rs363050 (AG/GG) genotypes compared to the (AA) genotype (f=4.41,df=1, andp=0.03andf=5.31,df=1, andp=0.03, resp.). In these same patients, insulin levels were significantly decreased compared to the (AA) individuals (f=7.29,df=1, andp=0.009). Significant associations were detected between rs363050 (AG/GG) genotypes and increasing fasting glucose levels (p=0.01and OR: 1.05), HbA1c levels (OR: 5.06 andp=0.02), and lower insulinemia (p=0.03and OR: 0.95) in T2DM patients. The minorSnap25rs363050 (G) allele, which results in a reduced expression ofSnap25, is associated with altered glycemic parameters in T2DM possibly because of reduced functionality in the exocytotic machinery leading to suboptimal release of insulin.

scholarly journals Type 2 Diabetes Modifies Skeletal Muscle Gene Expression Response to Gastric Bypass Surgery

2021 ◽  
Author(s):  
Matthew D. Barberio ◽  
G. Lynis Dohm ◽  
Walter J. Pories ◽  
Natalie A. Gadaleta ◽  
Joseph A. Houmard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Gastric Bypass ◽  
Clinical Symptoms ◽  
Vastus Lateralis ◽  
Gene Expression Response ◽  
Muscle Health ◽  
The Impact

AbstractRoux-en-Y gastric bypass (RYGB) is an effective treatment for type 2 diabetes mellitus (T2DM) which can result in remission of clinical symptoms, yet mechanisms for improved skeletal muscle health are poorly understood. We sought to define the impact of existing T2DM on RYGB-induced muscle transcriptome changes.MethodsVastus lateralis biopsy transcriptomes were generated pre- and 1-yr post-RYGB in black adult females with (T2D; n = 5, age=51±6 yr, BMI=53.0±5.8 kg/m2) and without (CON; n = 7,43±6 yr,51.0±9.2 kg/m2) T2DM. Insulin, glucose, and HOMA-IR were measured in blood at the same time points. ANCOVA detected differentially expressed genes (p< 0.01, Fold change<|1.2|), which were used to identify enriched biological pathways.ResultsPre-RYGB, 95 probes were downregulated with T2D including subunits of mitochondrial complex I. Post-RYGB, the T2D group had normalized gene expression when compared to their non-diabetic counterparts with only 3 probes remaining significantly different. In the T2D, we identified 52 probes upregulated from pre- to post-RYGB, including NDFUB7 and NDFUA1.ConclusionBlack females with T2DM show extensive down regulation of genes across aerobic metabolism pathways prior to RYGB, which resolves 1 year post-RYGB and is related to improvements in clinical markers. These data support efficacy of RYGB for improving skeletal muscle health, especially in patients with T2DM.

scholarly journals Effect of liraglutide on expression of inflammatory genes in type 2 diabetes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emilie H. Zobel ◽  
Rasmus S. Ripa ◽  
Bernt J. von Scholten ◽  
Viktor Rotbain Curovic ◽  
Andreas Kjaer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Placebo Group ◽  
Treated Group ◽  
Inflammatory Gene Expression ◽  
Inflammatory Genes ◽  
Inflammatory Gene ◽  
Anti Inflammatory

AbstractAnti-inflammatory effects of glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment in T2D may contribute to the cardiovascular benefits observed with GLP-1 RAs in outcome studies. We investigated if the GLP-1 RA liraglutide exerts anti-inflammatory effects through modulation of inflammatory gene expression in peripheral blood mononuclear cells (PBMCs). From 54 participants of a double-blinded trial where individuals with type 2 diabetes (T2D) were randomized to liraglutide (1.8 mg/day) or placebo for 26 weeks, a sub-study was performed in which PBMCs were extracted from fresh blood at study start and at end-of-treatment. The expression of selected inflammatory genes in PBMCs were measured by quantitative real-time polymerase chain reaction (PCR). Moreover, the expression of the GLP-1 receptor (GLP1R) was examined in a subset (n = 40) of the PBMC samples. The human monocytic cell line THP-1 was used for in vitro GLP-1 exposure experiments. The expression of tumor necrosis factor-α (TNFA) (p = 0.004) and interleukin-1β (IL1B) was downregulated (p = 0.046) in the liraglutide-treated group (n = 31), and unchanged in the placebo group (n = 21, p ≥ 0.11), with no significant differences between the two groups (p ≥ 0.67). The expression of interferon-γ (IFNG) and cluster of differentiation 163 (CD163) were upregulated in both groups (p ≤ 0.006) with no differences between groups (p ≥ 0.47). C–C Motif Chemokine Ligand 5 (CCL5) was upregulated in the liraglutide-treated group (p = 0.002) and unchanged in the placebo group (p = 0.14), with no significant difference between groups (p = 0.36). Intercellular adhesion molecule 1 (ICAM1) was unchanged in both groups (p ≥ 0.43). GLP1R expression in the PBMCs was undetectable. In vitro experiments showed no effect of GLP-1 treatment on inflammatory gene expression in THP-1 cells. GLP1R expression in THP-1 cells was not detectable. In summary, we observed a discrete modulatory effect of liraglutide on the expression of inflammatory genes in PBMCs. The lack of evidence for GLP1R expression in PBMCs and THP-1 cells suggests that possible effects of liraglutide on the PBMCs’ gene expression are most likely indirect. Further investigations are needed to establish the anti-inflammatory potential of GLP-1 RAs.

scholarly journals BET protein inhibitor apabetalone (RVX-208) suppresses pro-inflammatory hyper-activation of monocytes from patients with cardiovascular disease and type 2 diabetes

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Sylwia Wasiak ◽  
Kim E. Dzobo ◽  
Brooke D. Rakai ◽  
Yannick Kaiser ◽  
Miranda Versloot ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Gene Transcription ◽  
Ex Vivo ◽  
Cytokine Gene Expression ◽  
Cytokine Gene ◽  
Bet Protein ◽  
The Impact

Abstract Background Patients with cardiovascular disease (CVD) and type 2 diabetes (DM2) have a high residual risk for experiencing a major adverse cardiac event. Dysregulation of epigenetic mechanisms of gene transcription in innate immune cells contributes to CVD development but is currently not targeted by therapies. Apabetalone (RVX-208) is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins—histone acetylation readers that drive pro-inflammatory and pro-atherosclerotic gene transcription. Here, we assess the impact of apabetalone on ex vivo inflammatory responses of monocytes from DM2 + CVD patients. Results Monocytes isolated from DM2 + CVD patients and matched controls were treated ex vivo with apabetalone, interferon γ (IFNγ), IFNγ + apabetalone or vehicle and phenotyped for gene expression and protein secretion. Unstimulated DM2 + CVD monocytes had higher baseline IL-1α, IL-1β and IL-8 cytokine gene expression and Toll-like receptor (TLR) 2 surface abundance than control monocytes, indicating pro-inflammatory activation. Further, DM2 + CVD monocytes were hyper-responsive to stimulation with IFNγ, upregulating genes within cytokine and NF-κB pathways > 30% more than control monocytes (p < 0.05). Ex vivo apabetalone treatment countered cytokine secretion by DM2 + CVD monocytes at baseline (GROα and IL-8) and during IFNγ stimulation (IL-1β and TNFα). Apabetalone abolished pro-inflammatory hyper-activation by reducing TLR and cytokine gene signatures more robustly in DM2 + CVD versus control monocytes. Conclusions Monocytes isolated from DM2 + CVD patients receiving standard of care therapies are in a hyper-inflammatory state and hyperactive upon IFNγ stimulation. Apabetalone treatment diminishes this pro-inflammatory phenotype, providing mechanistic insight into how BET protein inhibition may reduce CVD risk in DM2 patients.

scholarly journals Expression Profile of Genes Potentially Associated with Adequate Glycemic Control in Patients with Type 2 Diabetes Mellitus

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Sâmia Cruz Tfaile Corbi ◽  
Alliny Souza Bastos ◽  
Rafael Nepomuceno ◽  
Thamiris Cirelli ◽  
Raquel Alves dos Santos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glycemic Control ◽  
Candidate Genes ◽  
Affy Package ◽  
Hla Dqa1 ◽  
The Impact

Despite increasing research in type 2 diabetes mellitus (T2D), there are few studies showing the impact of the poor glycemic control on biological processes occurring in T2D. In order to identify potential genes related to poorly/well-controlled patients with T2D, our strategy of investigation included a primary screen by microarray (Human Genome U133) in a small group of individuals followed by an independent validation in a greater group using RT-qPCR. Ninety patients were divided as follows: poorly controlled T2D (G1), well-controlled T2D (G2), and normoglycemic individuals (G3). After using affy package in R, differentially expressed genes (DEGs) were prospected as candidate genes potentially relevant for the glycemic control in T2D patients. After validation by RT-qPCR, the obtained DEGs were as follows—G1 + G2 versus G3: HLA-DQA1, SOS1, and BRCA2; G2 versus G1: ENO2, VAMP2, CCND3, CEBPD, LGALS12, AGBL5, MAP2K5, and PPAP2B; G2 versus G3: HLA-DQB1, MCM4, and SEC13; and G1 versus G3: PPIC. This demonstrated a systemic exacerbation of the gene expression related to immune response in T2D patients. Moreover, genes related to lipid metabolisms and DNA replication/repair were influenced by the glycemic control. In conclusion, this study pointed out candidate genes potentially associated with adequate glycemic control in T2D patients, contributing to the knowledge of how the glycemic control could systemically influence gene expression.

scholarly journals The Impact of Altered Metabolism on the Regulation of IGF-II/H19 Imprinting Status in Prostate Cancer.

2020 ◽  
Author(s):  
Georgina Kingshott ◽  
Kalina Biernacka ◽  
Alex Sewell ◽  
Paida Gwiti ◽  
Rachel Barker ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Type 2 Diabetes ◽  
Small Subset ◽  
Cancer Type ◽  
Tissue Samples ◽  
Positive Correlation ◽  
The Impact

Abstract Background: Prostate cancer is the most frequently diagnosed cancer type and the second major cause of cancer deaths amongst men. A link exists between obesity, type 2 diabetes, and cancer risk. Insulin-like growth factor II (IGF-II) plays a role in numerous cellular events, including proliferation and survival. The IGF-II gene shares its locus with the lncRNA, H19. IGF-II/H19 was also the first gene to be identified as being ‘imprinted’ – where the paternal copy is not transcribed. This silencing phenomenon is lost in many cancer types. Methods: We disrupted imprinting behaviour in vitro through the alteration of metabolic conditions and quantified it using RFLP, qPCR and pyrosequencing; changes to peptide were measured using RIA. Prostate tissue samples were analysed using ddPCR, pyrosequencing and IHC. We then compared with in silico data, provided by TGCA on the cBIO Portal.Results: Disruption of imprinting behaviour, in vitro, occurs at the molecular level with no changes to peptide. In vivo, most specimens primarily retained imprinting status, apart from a small subset which showed reduced imprinting. A positive correlation was seen between IGF-II and H19 mRNA expression, which concurred with findings of larger Cancer Genome Atlas (TGCA) cohorts. This positive correlation did not affect IGF-II peptide. Conclusions: Type 2 diabetes and / or obesity directly affect regulation growth factors involved in carcinogenesis.Trial registration: Prostate Cancer Evidence of Exercise and Nutrition Trial: nutritional and physical activity interventions for men with localised prostate cancer – feasibility study (ISRCTN99048944). Registered on 17 November 2014

scholarly journals Pancreatic fat cells of humans with type 2 diabetes display reduced adipogenic and lipolytic activity

2021 ◽  
Author(s):  
Morgana Barroso Oquendo ◽  
Dorothea Siegel-Axel ◽  
Felicia Gerst ◽  
Estela Lorza-Gil ◽  
Anja Moller ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Lipolytic Activity ◽  
Pde5 Inhibitor ◽  
Western Blots ◽  
Akt Phosphorylation ◽  
Triglyceride Accumulation ◽  
Pancreatic Fat ◽  
The Impact

Obesity, especially visceral fat accumulation, increases the risk of type 2 diabetes (T2D). The purpose of this study was to investigate the impact of T2D on the pancreatic fat depot. Pancreatic fat pads from 17 partial pancreatectomized patients (PPP) were collected, pancreatic preadipocytes isolated and in vitro differentiated. Patients were grouped using HbA1c into normal glucose tolerant (NGT), prediabetic (PD) and T2D. Transcriptome profiles of preadipocytes and adipocytes were assessed by RNAseq. Insulin sensitivity was estimated by quantifying AKT phosphorylation on western blots. Lipogenic capacity was assessed with oil red O staining, lipolytic activity via fatty acid release. Secreted factors were measured using ELISA. Comparative transcriptome analysis of preadipocytes and adipocytes indicates defective upregulation of genes governing adipogenesis (NR1H3), lipogenesis (FASN, SCD, ELOVL6, FADS1) and lipolysis (LIPE) during differentiation of cells from T2D-PPP. In addition, the ratio of leptin/adiponectin mRNA was higher in T2D than in NGT-PPP. Preadipocytes and adipocytes of NGT-PPP were more insulin sensitive than T2D-PPP cells in regard to AKT phosphorylation. Triglyceride accumulation was similar in NGT and T2D adipocytes. Despite a high expression of the receptors NPR1 and NPR2 in NGT and T2D adipocytes, lipolysis was stimulated by ANP 1.74-fold in NGT cells only. This stimulation was further increased by the PDE5 inhibitor dipyridamole (3.09-fold). Dipyridamole and forskolin increased lipolysis receptor-independently 1.88-fold and 1.48-fold, respectively, solely in NGT cells. In conclusion, the metabolic status persistently affects differentiation and lipolysis of pancreatic adipocytes. These alterations could aggravate the development of T2D.

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