scholarly journals Chronic Inflammatory Status Observed in Patients with Type 2 Diabetes Induces Modulation of Cytochrome P450 Expression and Activity

2021 ◽  
Vol 22 (9) ◽  
pp. 4967
Author(s):  
Lucy Darakjian ◽  
Malavika Deodhar ◽  
Jacques Turgeon ◽  
Veronique Michaud
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Cytochrome P450 ◽  
Competitive Inhibition ◽  
Drug Metabolizing Enzymes ◽  
Necrosis Factor Alpha ◽  
Metabolizing Enzymes ◽  
Inflammatory Status ◽  
Tnf Α

Diabetes mellitus is a metabolic disease that causes a hyperglycemic status which leads, over time, to serious damage to the heart, blood vessels, eyes, kidneys and nerves. The most frequent form of diabetes is type 2 diabetes mellitus (T2DM) which is often part of a metabolic syndrome (hyperglycaemia, hypertension, hypercholesterolemia, abdominal obesity) that usually requires the use of several medications from different drug classes to bring each of these conditions under control. T2DM is associated with an increase in inflammatory markers such as interleukin-6 (IL-6) and the tumor necrosis factor alpha (TNF-α). Higher levels of IL-6 and TNF-α are associated with a downregulation of several drug metabolizing enzymes, especially the cytochrome P450 (P450) isoforms CYP3As and CYP2C19. A decrease in these P450 isoenzymes may lead to unexpected rise in plasma levels of substrates of these enzymes. It could also give rise to a mismatch between the genotypes determined for these enzymes, the predicted phenotypes based on these genotypes and the phenotypes observed clinically. This phenomenon is described as phenoconversion. Phenoconversion typically results from either a disease (such as T2DM) or concomitant administration of medications inducing or inhibiting (including competitive or non-competitive inhibition) a P450 isoenzyme used by other substrates for their elimination. Phenoconversion could have a significant impact on drug effects and genotypic-focused clinical outcomes. As the aging population is exposed to polypharmacy along with inflammatory comorbidities, consideration of phenoconversion related to drug metabolizing enzymes is of importance when applying pharmacogenomic results and establishing personalized and more precise drug regimens.

scholarly journals Advanced glycation end product levels were correlated with inflammation and carotid atherosclerosis in type 2 diabetes patients

2020 ◽  
Vol 15 (1) ◽  
pp. 364-372 ◽  
Author(s):  
Jie Li ◽  
Haiyan Shangguan ◽  
Xiaoqian Chen ◽  
Xiao Ye ◽  
Bin Zhong ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Color Doppler ◽  
Enzyme Linked Immunosorbent Assay ◽  
Advanced Glycation ◽  
Advanced Glycation End Product ◽  
Inflammatory Status ◽  
Tnf Α ◽  
Ifn Γ

AbstractDiabetes mellitus with atherosclerosis (AS) adds to the social burden. This study aimed to investigate whether advanced glycation end product (AGE) levels were correlated with inflammation and carotid AS (CAS) in type 2 diabetes mellitus (T2DM) patients. A total of 50 elderly T2DM patients and 50 age-matched senior healthy subjects were recruited in this study. T2DM patients were classified into two groups based on the intima–media thickness (IMT) of the carotid artery from color Doppler ultrasonography. Patients with IMT > 1 mm were classified into the T2DM + CAS group (n = 28), and patients with IMT < 1 mm were assigned as the T2DM + non-atherosclerosis (NAS) group (n = 22). The plasma levels of AGEs, receptor for AGE (RAGE), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) of all subjects were measured by enzyme-linked immunosorbent assay. The T-lymphocyte subsets were analyzed by a flow detector. T2DM + CAS patients showed significantly higher concentrations of AGEs, RAGE, TNF-α, and IFN-γ in the peripheral blood. The highest levels of CD4+ T cells were observed in the T2DM + CAS group. The AGE level was positively correlated with the concentrations of RAGE, TNF-α, IFN-γ, and CD4+. In summary, the results showed that the levels of AGEs may be correlated with the inflammatory status in T2DM patients with CAS.

scholarly journals Dermal fibroblasts cultured from donors with type 2 diabetes mellitus retain an epigenetic memory associated with poor wound healing responses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aaiad H. A. Al-Rikabi ◽  
Desmond J. Tobin ◽  
Kirsten Riches-Suman ◽  
M. Julie Thornton
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Wound Healing ◽  
Type 2 Diabetes Mellitus ◽  
Chronic Wounds ◽  
Dermal Fibroblasts ◽  
Necrosis Factor Alpha ◽  
Tnf Α

AbstractThe prevalence of Type 2 diabetes mellitus (T2DM) is escalating globally. Patients suffer from multiple complications including the development of chronic wounds that can lead to amputation. These wounds are characterised by an inflammatory environment including elevated tumour necrosis factor alpha (TNF-α). Dermal fibroblasts (DF) are critical for effective wound healing, so we sought to establish whether there were any differences in DF cultured from T2DM donors or those without diabetes (ND-DF). ND- and T2DM-DF when cultured similarly in vitro secreted comparable concentrations of TNF-α. Functionally, pre-treatment with TNF-α reduced the proliferation of ND-DF and transiently altered ND-DF morphology; however, T2DM-DF were resistant to these TNF-α induced changes. In contrast, TNF-α inhibited ND- and T2DM-DF migration and matrix metalloprotease expression to the same degree, although T2DM-DF expressed significantly higher levels of tissue inhibitor of metalloproteases (TIMP)-2. Finally, TNF-α significantly increased the secretion of pro-inflammatory cytokines (including CCL2, CXCL1 and SERPINE1) in ND-DF, whilst this effect in T2DM-DF was blunted, presumably due to the tendency to higher baseline pro-inflammatory cytokine expression observed in this cell type. Collectively, these data demonstrate that T2DM-DF exhibit a selective loss of responsiveness to TNF-α, particularly regarding proliferative and secretory functions. This highlights important phenotypic changes in T2DM-DF that may explain the susceptibility to chronic wounds in these patients.

Enhanced spontaneous and induced secretion of the proinflammatory cytokine TNF-alpha by monocytes-macrophages from the blood of the patients presenting with type 2 diabetes mellitus

2014 ◽  
Vol 60 (5) ◽  
pp. 22-25
Author(s):  
L A Mirzoeva ◽  
N G Nikiforov ◽  
V A Aladinsky ◽  
I A Sobenin ◽  
L V Nedosugova ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Proinflammatory Cytokine ◽  
Blood Monocytes ◽  
Necrosis Factor Alpha ◽  
Systemic Inflammatory Reaction ◽  
Tnf Α ◽  
Α Level

Type 2 diabetes mellitus (DM2) is known to be associated with the accelerated development of atherosclerosis. The current concepts of atherosclerosis take into consideration the possible role of inflammation in its pathogenesis which theoretically implies the modification of macrophages in accordance with the proinflammatory phenotype and the production of the proinflammatory cytokine tumour necrosis factor-alpha (TNF-α) by these cells. In connection with this, we undertook a study of spontaneous and induced secretion of proinflammatory cytokine TNF-α by monocytes-macrophages from the blood of 20 patients presenting with newly diagnosed type 2 diabetes mellitus (HbA1c - 8,9%) and the healthy volunteers showing up no disturbances of carbohydrate metabolism. It was shown that blood monocytes-macrophages of the patients presenting with DM2 are characterized by the enhanced ability (compared with the cells from the healthy subjects) to synthesize TNF-α in both native and interferon-y stimulated states up to 750 versus 270 pg/ml culture medium and to 1653 pg/ml versus 378 pg/ml culture respectively. This difference was statistically significant (p <0.05). It is concluded that the results of the study help to explain the elevated blood TNF-α level in the patients with type 2 diabetes mellitus and provide an insight into the mechanism underlying the development of the systemic inflammatory reaction accelerating the progression of atherosclerosis associated with diabetes mellitus.

scholarly journals Association of polymorphism of some candidate genes of lipid and carbohydrate metabolism with anthropometric indices and inflammatory markers in patients with type 2 diabetes mellitus in the population of Azerbaijan

2012 ◽  
Vol 9 (3) ◽  
pp. 26-28
Author(s):  
Z G Akhmedova
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Necrosis Factor Alpha ◽  
Mutant Variant ◽  
Tnf Α ◽  
Heterozygous Form ◽  
High Level ◽  
Homozygous Form

The purpose of the study was to analyze the association of gene polymorphisms of leptin, adiponectin, tumor necrosis factor alpha (TNF-α), insulin-induced gene, and the parameters of carbohydrate and lipid metabolism, level of C-reactive protein (CRP) in patients with type 2 diabetes mellitus (T2DM) with anthropometric data. A total of 95 patients with T2DM of Azerbaijan population. The average age at the time of the survey was 50,4±0,51 years. Duration of the disease was 5,8±1,5 years. We found that patients with T2DM and obesity in the Azerbaijan population have most common polymorphism of insulin-induced gene in the homozygous form (GG), a mutant version of the gene in heterozygous form of leptin, adiponectin gene mutant variant in homozygous form and the normal version of the gene TNF-α in homozygous form. In 47.3% of cases there was a high level of CRP, a linear body mass index with normal homozygous GG allele of the TNF-a gene , insulin-induced gene, and a mutant version of the adiponectin and leptin genes.

Analysis of the Potential Association of Drug-Metabolizing Enzymes CYP2C9*3 and CYP2C19*3 Gene Variations With Type 2 Diabetes: A Case-Control Study

2020 ◽  
Vol 21 (14) ◽  
pp. 1152-1160
Author(s):  
Imadeldin Elfaki ◽  
Rashid Mir ◽  
Faisel Mohammed Abu-Duhier ◽  
Chandan Kumar Jha ◽  
Adel Ibrahim Ahmad Al-Alawy ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Antiplatelet Drug ◽  
Drug Metabolizing Enzymes ◽  
Genotype Distribution ◽  
Nucleotide Polymorphisms ◽  
Metabolizing Enzymes ◽  
Specific Pcr ◽  
Increased Risk ◽  
Different Populations

Background:: Cytochrome P450s (CYPs) are drug-metabolizing enzymes catalyzing the metabolism of about 75% of drug in clinical use. CYP2C9 represents 20% CYP proteins in liver cells and is a crucial member of CYPs superfamily. CYP2C19 metabolizes very important drugs such as antiulcer drug omeprazole, the antiplatelet drug clopidogrel and anticonvulsant mephenytoin. Single nucleotide polymorphisms (SNPs) of CYP genes have been associated with unexpected drug reactions and diseases in different populations. Objective:: We examined the associations of CYP2C9*3 (rs1057910) and CYP2C19*3 (rs4986893) with T2D in Saudi population. Methods:: We used the allele-specific PCR (AS-PCR) and DNA sequencing in 111 cases and 104 controls for rs1057910, and in 119 cases and 110 controls for rs4986893. Results:: It is indicated that the genotype distribution of rs1057910 in cases and controls were not significantly different (P=0.0001). The genotypes of rs1057910 were not associated with type 2 diabetes (T2D) (P>0.05). Whereas the genotype distribution of rs4986893 in cases and controls was significantly different (P=0.049). The AA genotype of rs4986893 may be associated in increased risk to T2D with OR=17.25 (2.06-143.8), RR=6.14(0.96-39.20), P=0.008. Conclusion:: The CYP2C9*3 (rs1057910) may not be associated with T2D, while CYP2C19*3 (rs4986893) is probably associated with T2D. These findings need to be validated in follow-up studies with larger sample sizes and different populations.

scholarly journals Application value of combination therapy of periodontal curettage and root planing on moderate-to-severe chronic periodontitis in patients with type 2 diabetes

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Yonghuan Bian ◽  
Changhao Liu ◽  
Zhaojiang Fu
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Blood Glucose ◽  
Chronic Periodontitis ◽  
Root Planing ◽  
Tnf Α ◽  
Significant Difference ◽  
Hs Crp

Abstract Background Our study attempted to observe the value of periodontal curettage combined with root planing on moderate-to-severe chronic periodontitis in patients with type 2 diabetes. Methods There involved 72 patients with type 2 diabetes mellitus complicated with moderate-to-severe chronic periodontitis who were diagnosed and treated in our hospital from January 2019 to December 2019. The patients enrolled were randomly divided into four groups using a computer-generated table: root planing and periodontal curettage combined group (n = 18), root planning group (n = 18), periodontal curettage group (n = 18) and cleansing group (n = 18). Blood glucose, plaque index (PI), gingival index (GI), probing depth (PD), attachment loss (AL), serum levels of inflammatory factors (Tumor Necrosis Factor Alpha [TNF- α] and hypersensitive C-reactive protein [hs-CRP]) were observed before and after treatment. The collecting dates were analyzed by the chi-square χ 2 test, repeated measurement analysis of variance, or t-test according to different data types and research objectives. Results Before treatment, there was no significant difference in PI, GI, PD and AL among the four groups (P> 0.05), while after 3-month treatment, the levels of PI, GI, PD and AL in the combined group were lower than those in the root planing group, periodontal curettage group and cleansing group, with both root planing group and periodontal curettage group significantly lower than cleansing group (P< 0.05). The fasting blood glucose, 2-h postprandial blood glucose and glycosylated hemoglobin in the combined group, root planing group, periodontal curettage group and cleansing group were significantly lower than those before treatment (P < 0.05). Before treatment, there was no significant difference in TNF- α and hs-CRP among the four groups (P> 0.05), but the levels of TNF- α and hs-CRP in the four groups decreased significantly after 3-month treatment (P< 0.05). The levels of TNF- α and hs-CRP in the combined group were lower than those in the root planing group, periodontal curettage group and cleansing group, and those in the root planing group and periodontal curettage group were significantly lower than those in the cleansing group (P< 0.05). Conclusion The combination therapy of periodontal curettage and root planing exerted beneficial effects on moderate-to-severe chronic periodontitis in patients with type 2 diabetes mellitus, which holds the potential to maintain the level of blood glucose and improve the quality of life of the patients.

Correlation between TNF-α- serum level and TNF-α -308 gene polymorphism in Iraqi patients with type 2 diabetes mellitus

Gene Reports ◽  
2021 ◽  
Vol 23 ◽  
pp. 101136
Author(s):  
Sarah Rahman Rasool ◽  
Othman Taha Qasim ◽  
Salaam Khudhur Muslem ◽  
Muataz Mohammed Al-Taee
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Serum Level ◽  
Gene Polymorphism ◽  
Tnf Α

scholarly journals A Pilot Study towards the Impact of Type 2 Diabetes on the Expression and Activities of Drug Metabolizing Enzymes and Transporters in Human Duodenum

2019 ◽  
Vol 20 (13) ◽  
pp. 3257 ◽  
Author(s):  
Sophie Gravel ◽  
Benoit Panzini ◽  
Francois Belanger ◽  
Jacques Turgeon ◽  
Veronique Michaud
Keyword(s):  
Type 2 Diabetes ◽  
Mrna Expression ◽  
Drug Metabolizing Enzymes ◽  
Mrna Levels ◽  
Metabolizing Enzymes ◽  
Expression Levels ◽  
The Impact ◽  
Duodenal Biopsies ◽  
Mrna Expression Levels

To characterize effects of type 2 diabetes (T2D) on mRNA expression levels for 10 Cytochromes P450 (CYP450s), two carboxylesterases, and three drug transporters (ABCB1, ABCG2, SLCO2B1) in human duodenal biopsies. To compare drug metabolizing enzyme activities of four CYP450 isoenzymes in duodenal biopsies from patients with or without T2D. mRNA levels were quantified (RT-qPCR) in human duodenal biopsies obtained from patients with (n = 20) or without (n = 16) T2D undergoing a scheduled gastro-intestinal endoscopy. CYP450 activities were determined following incubation of biopsy homogenates with probe substrates for CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2J2 (ebastine), and CYP3A4/5 (midazolam). Covariables related to inflammation, T2D, demographic, and genetics were investigated. T2D had no major effects on mRNA levels of all enzymes and transporters assessed. Formation rates of metabolites (pmoles mg protein−1 min−1) determined by LC-MS/MS for CYP2C9 (0.48 ± 0.26 vs. 0.41 ± 0.12), CYP2J2 (2.16 ± 1.70 vs. 1.69 ± 0.93), and CYP3A (5.25 ± 3.72 vs. 5.02 ± 4.76) were not different between biopsies obtained from individuals with or without T2D (p > 0.05). No CYP2B6 specific activity was measured. TNF-α levels were higher in T2D patients but did not correlate with any changes in mRNA expression levels for drug metabolizing enzymes or transporters in the duodenum. T2D did not modulate expression or activity of tested drug metabolizing enzymes and transporters in the human duodenum. Previously reported changes in drug oral clearances in patients with T2D could be due to a tissue-specific disease modulation occurring in the liver and/or in other parts of the intestines.

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