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Evaluating the impact of type 2 diabetes mellitus on CYP450 metabolic activities: protocol for a case-control pharmacokinetic study.

ABSTRACT: Diabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequences on drug response. The aim of this study is to characterise the activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in T2DM versus non-T2DM subjects following the administration of a cocktail of probe drug substrates.This single-centre clinical study proposes the first detailed characterisation of T2DM impacts on major CYP450 drug-metabolising enzyme activities. We intend to recruit 42 patients with controlled T2DM (A1C?7%), 42 patients with uncontrolled T2DM (A1C>7%) and 42 non-diabetic control subjects. The primary objective is to determine and compare major CYP450 activities in patients with T2DM versus non-diabetic subjects by dosing in plasma and urine probe drug substrates and metabolites following the oral administration of a drug cocktail: caffeine (CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4/5). Secondary objectives will evaluate the influence of variables such as glycaemia, insulinaemia, genetic polymorphisms and inflammation. The value of an endogenous biomarker of CYP3A activity is also evaluated. The first patient was recruited in May 2015 and patients will be enrolled up to completion of study groups.Approval was obtained from the ethic review board of the CHUM research centre (Montreal, Canada).NCT02291666.

SUBMITTER: Gravel S

PROVIDER: S-EPMC5829905 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Evaluating the impact of type 2 diabetes mellitus on CYP450 metabolic activities: protocol for a case-control pharmacokinetic study.

Gravel Sophie S Chiasson Jean-Louis JL Dallaire Suzanne S Turgeon Jacques J Michaud Veronique V

BMJ open 20180208 2

<h4>Introduction</h4>Diabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequence ...[more]

PMID: 29439084

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Project description:BACKGROUND:Type 1 diabetes mellitus (T1DM) is one of the most common pediatric diseases and its incidence is rising in many countries. Recently, it has been shown that metabolites other than glucose play an important role in insulin deficiency and the development of diabetes. The aim of our study was to look for discriminating variation in the concentrations of small-molecule metabolites in the plasma of T1DM children as compared to non-diabetic matched controls using proton nuclear magnetic resonance (1H-NMR)-based metabolomics. METHODS:A cross-sectional study was set-up to examine the metabolic profile in fasting plasma samples from seven children with poorly controlled T1DM and seven non-diabetic controls aged 8-18 years, and matched for gender, age and BMI-SDS. The obtained plasma 1H-NMR spectra were rationally divided into 110 integration regions, representing the metabolic phenotype. These integration regions reflect the relative metabolite concentrations and were used as statistical variables to construct (train) a classification model in discriminating between T1DM patients and controls. RESULTS:The total amount of variation explained by the model between the groups is 81.0% [R2Y(cum)] and within the groups is 75.8% [R2X(cum)]. The predictive ability of the model [Q2(cum)] obtained by cross-validation is 50.7%, indicating that the discrimination between the groups on the basis of the metabolic phenotype is valid. Besides the expected higher concentration of glucose, the relative concentrations of lipids (triglycerides, phospholipids and cholinated phospholipids) are clearly lower in the plasma of T1DM patients as compared to controls. Also the concentrations of the amino acids serine, tryptophan and cysteine are slightly decreased. CONCLUSIONS:The present study demonstrates that metabolic profiling of plasma by 1H-NMR spectroscopy allows to discriminate between T1DM patients and controls. The metabolites that significantly differ between both groups might point to disturbances in biochemical pathways including (1) choline deficiency, (2) increased gluconeogenesis, and (3) glomerular hyperfiltration. Although the sample size of this study is still somewhat limited and a validation should be performed, the proof of principle looks promising and justifies a deeper investigation of the diagnostic possibilities of 1H-NMR metabolomics in follow-up studies. Trial registration NCT03014908. Registered 06/01/2017. Retrospectively registered.

Project description:BackgroundThe increase in the prevalence of type 2 diabetes mellitus (T2DM) and its associated complications is burdensome to the South African health system. Understanding the role of comorbid diseases, such as periodontal disease (PD), and their effect on metabolic control in patients with DM in South Africa will raise awareness about the importance of periodontal interventions among patients with DM in South Africa.ObjectiveThe review will aim to determine the effect of PD on the metabolic control of T2DM in a South African population.MethodsA systematic review of the relationship between PD and metabolic control in patients with T2DM in a South African population will be conducted. Cohort, cross-sectional, and case-controlled studies will be considered in which the outcome of interest is diabetic control. A search will be done in the following sources: EBSCOhost (academic search complete; dentistry and oral sciences), PubMed, ScienceDirect, and the South African National ETD Portal for articles published in English. There will be no limit placed on the date of the publication. The reference list of articles will be reviewed for further inclusion of critical articles. Two independent reviewers (AJ and FK-D) will do study selection, data extraction, and quality analysis. All disputes will be resolved by discussion, and the entire team will verify final decisions.ResultsThe systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO). A preliminary search was conducted using the keywords ((perio*) AND (diabet*)) AND ("South Africa"). The review process should be completed by December 2021.ConclusionsThe review will determine the effect of PD on metabolic control in patients with T2DM in South Africa. The outcome would inform health policy to highlight the need to include periodontal care into treatment protocols in patients with T2DM. In this process, the feasibility for future research in this area of interest will also be defined.Trial registrationPROSPERO International Prospective Register of Systematic Reviews CRD42020221064; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=221064.International registered report identifier (irrid)PRR1-10.2196/27471.

Project description:BackgroundThe relationship between diabetes mellitus (DM) and periodontal disease is bidirectional. DM is a predisposing and modifying factor of periodontitis, which, in turn, worsens glycemic control and increases proteins found in the acute phase of inflammation, such as C-reactive protein. The gold standard for the treatment of periodontal disease is oral hygiene orientation, scaling and planing. Moreover, systemic antibiotic therapy may be employed in some cases. In an effort to minimize the prescription of antibiotics, photodynamic therapy (PDT) has been studied as an antimicrobial technique and has demonstrated promising results. The aim of the proposed study is to determine whether PDT as a complement to periodontal therapy (PT) is helpful in the metabolic control of individuals with type 2 diabetes and the reduction of acute-phase inflammatory markers.Methods/designThe patients will be randomized using a proper software program into two groups: 1) PT + placebo PDT or 2) PT + active PDT. All patients will first be examined by a specialist, followed by PT performed by two other healthcare professionals. At the end of each session, PDT (active or placebo) will be administered by a fourth healthcare professional. The following will be the PDT parameters: diode laser (660 nm); power output = 110 mW; exposure time = 90 s per point (9 J/point); and energy density = 22 J/cm(2). The photosensitizer will be methylene blue (50 μg/mL). The patients will be re-evaluated 15, 30, 90 and 180 days after treatment. Serological examinations with complete blood count, fasting glucose, glycated hemoglobin and salivary examinations to screen for tumor necrosis factor alpha, interleukin 1, interleukin 6, ostelocalcin, and osteoprotegerin/RANKL will be performed at each evaluation. The data will be statistically evaluated using the most appropriate tests.DiscussionThe results of this study will determine the efficacy of photodynamic therapy as an adjuvant to periodontal treatment in diabetic patients.Trial registrationThe protocol for this trial was registered with Clinical Trials registration number NCT01964833 on 14 October 2013.

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Evaluating the impact of type 2 diabetes mellitus on CYP450 metabolic activities: protocol for a case-control pharmacokinetic study.

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Evaluating the impact of type 2 diabetes mellitus on CYP450 metabolic activities: protocol for a case-control pharmacokinetic study.

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